Clinical trial NCT02460679
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: PTC Therapeutics
Start date: 2016-01-14; Completion date: 2018-02-23
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label study with 30-day run in phase to establish baseline parameters, 90-day treatment phase, and a 90-day withdrawal phase to determine long-term effects, duration of treatment response, and potential effects of EPI-589 therapy on known trajectory.

Detailed description:

Arms: arm 1: Participants will receive EPI-589 500 milligrams (mg) (2 tablets of 250 mg each) twice daily (BID) for 3 months, unless discontinued for safety or tolerability issues.
Interventions: intervention 1: EPI-589
Intervention descriptions: intervention 1: An immediate release film-coated table at a 250 mg dosage strength will be administered per dose and schedule specified in arm.

Protocol documents:
SAP_002.pdf: 
BioElectron Technology Corporation 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No.: EPI589-15-001 
 
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A Phase 2A Safety and Biomarker Study of EPI-589 in Subjects 
with Amyotrophic Lateral Sclerosis 
Protocol No.: EPI589-15-001 
STATISTICAL ANALYSIS PLAN 
Version: 1.1 
Date: 20-Mar-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. 
NCT# NCT02460679




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Statistical Analysis Plan 
Protocol No.: EPI589-15-001 
 
 
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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 .......................................................................................... 7 
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 
6. 
ANALYSIS OF STUDY POPULATIONS .................................................................... 7 
6.1 EFFICACY INTENT-TO-TREAT (EITT) POPULATION ..................................................... 7 
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 ........................................................................... 8 
10. 
EXTENT OF EXPOSURE AND DRUG COMPLIANCE ......................................... 10 
11. 
SAFETY ANALYSIS ................................................................................................... 10 
11.1 ADVERSE EVENTS ................................................................................................. 11 
11.2 SERIOUS ADVERSE EVENT .................................................................................... 12 
11.3 LABORATORY EVALUATION .................................................................................... 13 
11.4 VITAL SIGNS AND PHYSICAL EXAMINATION ............................................................ 14 
11.5 OTHER VARIABLES RELATED TO SAFETY ............................................................... 15 
12. 
COMPUTER METHODS ............................................................................................ 15 
 
 


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Statistical Analysis Plan 
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1. INTRODUCTION 
This is a phase 2a safety and biomarker study of EPI-589 in subjects with amyotrophic 
lateral sclerosis (ALS). Approximately 20 subjects with amyotrophic lateral sclerosis (ALS) 
will be enrolled.   
 
This statistical analysis plan (SAP) is based on protocol amendment 1.0, dated 
09-Sep-2015. 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 ALS. 
 
Secondary Objectives 
The secondary objectives are to evaluate the effects of EPI-589 in subjects with ALS on: 
(1) Glutathione (redox) cycle biomarkers as measured in blood, cerebral spinal fluid, and 
urine 
(2) Disease progression as assessed by ALS Functional Rating Scale-Revised 
(3) Respiratory function as assessed by pulmonary function tests and capnography 
(4) Failure to thrive as measured by body weight 
(5) Swallowing as assessed by change in water and solid swallowing tests 
(6) Speech as assessed by speech evaluation 
(7) Muscle function as assessed by handheld dynamometry 
(8) Drug plasma concentration measurements 
(9) Hematology, blood chemistry, electrocardiogram 
 
3. STUDY DESIGN 
This is an open-label, single arm study. After study enrollment, baseline assessments will be 
performed. Subjects participate in a 30-day run-in phase to establish baseline ALS 


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disease-related clinical and biomarker features. EPI-589 will then be administered for 3 
months, unless discontinued for safety or tolerability issues. All subjects will then be 
followed for an additional 90 days to determine long-term effects, duration of response to 
treatment, and potential effects of EPI-589 therapy on known disease trajectory. 
 
3.1 Schedule of Assessments and Dosing Schedule 
 
a. Height measurement need not be repeated after treatment begins. 
b. Physical examination includes breast examination in women at screening. 
c. Urine or Serum pregnancy test will be done for females of child bearing potential only. 
d. Run-in assessments must be performed 30 Days (+/- 3 days) prior to baseline after confirmation of 
eligibility and enrollment in the study. 


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e. Month 2 assessments and Withdrawal Phase Month 5 assessments can be conducted by telephone. 
f. Samples will be collected at 0-hour and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose on study visit days. 
g. AEs reported at Month 6 (and any associated concomitant medications) must be followed for 30 days; this 
follow-up may be conducted by telephone 
 
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 ALS following three months of EPI-589 therapy. 
 
3.3 Secondary Endpoints  
Secondary Endpoints (Efficacy) 
(1) Blood-based biomarkers 
(2) CNS-based biomarkers 
(3) Urine-based biomarkers 
(4) Disease progression as assessed by ALS Functional Rating Scale-Revised 
(5) Respiratory function as assessed by pulmonary function tests and capnography 
(6) Failure to thrive as measured by body weight 
(7) Swallowing as assessed by change in water and solid swallowing tests 
(8) Speech as assessed by speech evaluation 
(9) Muscle function as assessed by handheld dynamometry 
(10) Drug plasma concentration measurements 
 
Secondary Endpoints (Safety) 
(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) Physical exam and vital signs 
(6) 12-lead electrocardiogram  
(7) C-SSRS  
 
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 variance (SD) will be reported as the two 


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decimals more than the raw data. 
4.1 Continuous endpoints 
Descriptive statistics including number of observation, mean, median, standard deviation, 
minimum and maximum will be presented for the raw data as well as change from baseline.  
 
4.2 Categorical endpoints 
The count and percentages will be used to summarize the categorical data.  
 
4.3 Sample size estimation and power 
Approximately 20 subjects will be enrolled in this exploratory biomarker study. 
 
5. DATA HANDLING PROCEDURES 
5.1 Coding System 
All AEs will be coded according to the MedDRA dictionary, version 15.0 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. 
 
5.2 Missing Data Handling 
For missing data related to a safety or efficacy endpoint, no missing data method will be 
performed. 
 
6. ANALYSIS OF STUDY POPULATIONS 
In this study, there will be two populations, efficacy intent-to-treat (EITT) population and 
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 will be 
presented and summarized 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. 


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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 
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. 
Individual 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 
Demographics information will be listed in Listing 16.2.4.1. Demographics information will 
be summarized 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 
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 ALS. No 
primary efficacy variable is defined on protocol.  
 
9.2 Secondary Efficacy Variables 
Secondary efficacy endpoints included: 
(1) Blood-based biomarkers 
The blood-based glutathione (redox) cycle biomarkers will be summarized descriptively at 
Baseline, Month 1, Month 3, Month 4, Month 6 and change from baseline. The listings of 


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individual subjects blood-based glutathione (redox) cycle biomarkers will be presented as 
Listing 16.2.6.1. The summary results will be presented as Table 14.2.1. 
 
(2) CNS-based biomarkers 
The CNS-based glutathione (redox) cycle biomarkers will be summarized descriptively at 
Baseline, Month 3 and change from baseline. The listings of individual subjects CNS-based 
glutathione (redox) cycle biomarkers will be presented as Listing 16.2.6.2. The summary 
results will be presented as Table 14.2.2. 
 
(3) Urine-based biomarkers 
The Urine-based glutathione (redox) cycle biomarkers will be summarized descriptively at 
Baseline, Month 1, Month 3, Month 4, Month 6 and change from baseline. The listings of 
individual subjects urine-based glutathione (redox) cycle biomarkers will be presented as 
Listing 16.2.6.3. The summary results will be presented as Table 14.2.3. 
 
(4) Disease progression as assessed by ALS Functional Rating Scale-Revised 
The ALS Functional Rating Scale (ALSFRS-R) total score will be summarized descriptively 
at Baseline, Month 1, Month 3, Month 4, Month 6 and change from baseline. The listings of 
individual subjects ALS Functional Rating Scale (ALSFRS-R) will be presented as Listing 
16.2.6.4. The summary results will be presented as Table 14.2.4. 
 
(5) Respiratory function as assessed by pulmonary function tests and capnography 
The pulmonary function tests included vital capacity (VC), forced vital capacity (FVC), 
forced expiratory volume (FEV1) and maximum inspiratory pressure (MIP); and 
capnography included respiratory rate (RR), heart rate (HR), SpO2 and ETCO2. Based on 
the CRF design, only vital capacity (VC), maximum inspiratory pressure (MIP) and 
capnography will be analyzed. The pulmonary function is performed from a fast vital 
capacity (FVC) or slow vital capacity (SVC) maneuver. The vital capacity (VC) will be 
analyzed as the highest number in % among the SVC or FVC trials. The MIP will be derived 
as the maximum value in unit cmH2O of among trials. It will be summarized descriptively at 
Baseline, Month 1, Month 3, Month 6 and change from baseline. The listings of individual 
subjects Slow Vital Capacity (SVC) or Fast Vital Capacity (FVC) will be presented as Listing 
16.2.6.5; Maximum Inspiratory Pressure (MIP) will be presented as Listing 16.2.6.6; and 
capnography will be presented as Listing 16.2.6.7. The summary results will be presented 
as Table 14.2.5. 
 
(6) Failure to thrive as measured by body weight 
The failure to thrive as measured by body weight is defined as weight loss of more than 5% 


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from baseline, and the failure to thrive as measured by body weight will be summarized 
descriptively at Baseline, Month 1, Month 3, Month 4, Month 6. The listings of individual 
subjects weight will be presented as Listing 16.2.6.8. The summary results will be 
presented as Table 14.2.6. 
 
(7) Swallowing as assessed by change in water and solid swallowing tests 
The average solid and water swallowing time will be summarized descriptively at Baseline, 
Month 3, Month 6 and change from baseline. The listings of individual subjects solid and 
water swallowing tests will be presented as Listing 16.2.6.9 and Listing 16.2.6.10. The 
summary results of solid and water swallowing tests will be presented as Table 14.2.7. 
 
(8) Speech as assessed by speech evaluation 
The speech evaluation will be summarized descriptively at Baseline, Month 3, Month 6 and 
change from baseline. The listings of individual subjects speech assessment will be 
presented as Listing 16.2.6.11. The summary results of speech evaluation will be presented 
as Table 14.2.8. 
 
(9) Muscle function as assessed by handheld dynamometry 
The handheld dynamometry will be summarized descriptively at Baseline, Month 3, Month 
6 and change from baseline. The listings of individual subjects handheld dynamometry will 
be presented as Listing 16.2.6.12. The summary results of handheld dynamometry will be 
presented as Table 14.2.9. 
 
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 
Listing 16.2.5.2: Missed Dose 
Besides, the drug concentration data will be presented as Listing 16.2.5.4. 
 
11. SAFETY ANALYSIS 


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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 or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 
Grade 2 – Mild to moderate limitation in activity, some assistance may be needed; no or 
minimal medical intervention/therapy required.  
Grade 3 – Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required hospitalizations possible.  
Grade 4 – Extreme limitation in activity, significant assistance required; significant medical 
intervention/therapy required hospitalization, life threatening, or hospice care probable.  
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  
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  
 


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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 will be provided in Table 14.3.1.1.2 according to the 
following categories: 
 
CTCAE Grade 
 
Relationship to Study Medication 
 
Serious AE 
 
Dose Limiting Toxicity 
 
Action Taken with Study Medication 
 
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 Relationship to Study Drug and 
Severity - 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  


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5. A congenital anomaly/birth defect  
6. Important medical events (ie: bronchospasm, development to drug dependency) that 
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 patient or may require intervention to prevent one of the other outcomes 
listed in the serious definition  
 
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 Relationship to Study 
Drug and Severity - MedDRA 
  
11.3 Laboratory Evaluation  
Clinical laboratory tests, including standard hematology, chemistry, urinalysis and 
pregnancy test: 
 
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 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), INR, partial thromboplastin time (PTT).  
 
Serum Chemistry  
1. Liver: ALP, ALT (serum glutamic-pyruvic transaminase [SGPT]), AST (serum 
glutamic-oxaloacetic transaminase [SGOT]), bilirubin (total, direct, and indirect), 
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), CK fractionated (CK-MB, CK-MM and CK-BB) 
and troponin (baseline only), protein (total), albumin, calcium, magnesium, glucose, 
phosphate  
5. Lipids: cholesterol (total), high-density lipoprotein (HDL) cholesterol, low-density 


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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, Specific Gravity, pH, Leukocytes, Blood, Nitrite, 
Ketones, Bilirubin, Urobilinogen, Protein and Glucose. 
 
Pregnancy Test  
Serum or urine human chorionic gonadotropin (HCG), beta subunit, will be performed on all 
female subjects of childbearing potential at each study visit through to the end of treatment. 
 
By-subject listings of measured values for clinical laboratory test data (hematology, 
chemistry and urinalysis) will be prepared in Listing 16.2.8.3 ~ Listing 16.2.8.5. A listing of 
pregnancy test will be provided in Listing 16.2.8.6. Observations outside the normal range 
will be flagged. The abnormal values will be flagged with ‘L’ (low) for values below the lower 
limit of the laboratory’s normal range or ‘H’ (high) for values above the upper limit of the 
laboratory’s normal range. The abnormal values for clinical laboratory test data 
(hematology, chemistry and urinalysis) will be prepared 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. 
 
11.4 Vital Signs and Physical Examination 
Vital Signs 
Individual subject vital signs (height, weight, systolic body pressure, diastolic blood 
pressure, heart rate, respirations and body temperature) will be listed in Listing 16.4.1. 
The observed value of vital signs at Baseline, Month 1, Month 3, Month 4, Month 6 and 
change from baseline values will be summarized in Table 14.3.6. 
 
Physical Exam 
Physical exam data will be listed in Listing 16.4.2, and will be summarized for Baseline, 
Month 1, Month 3, Month 4, Month 6 in Table 14.3.7.  


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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 (heart 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 and change from baseline in Table 14.3.8. 
 
Columbia Suicide Severity Rating Scale (C-SSRS)  
Individual subject Columbia Suicide Severity Rating Scale (C-SSRS) data will be listed in 
Listing 16.4.4, and will be summarized as suicidal ideation and suicidal behavior in Table 
14.3.9.1. In addition, the Columbia Suicide Severity Rating Scale (C-SSRS) shift table will 
be provided as Table 14.3.9.2. 
 
Telephone Contact 
Individual subject telephone Contact data will be listed in Listing 16.4.5.  
 
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. 

Prot_000.pdf: 
NCT# NCT02460679


 
EPI-589 
Protocol EPI589-15-001                             
 
 Version: Amendment 2.0 
 
 
Confidential 
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                  TABLE OF CONTENTS 
I. PROTOCOL SYNOPSIS ................................................................................................. 6 
II. SCHEDULE OF ASSESSMENTS AND DOSING SCHEDULE ............................... 11 
III. BACKGROUND INFORMATION AND RATIONALE ............................................ 11 
A. Overview of Amyotrophic Lateral Sclerosis (ALS) ................................................ 12 
B. 
Rationale for the Study of EPI589-15-001 in Subjects with ALS .......................... 13 
C. Name and Description of Investigational Product .................................................. 13 
D. Findings from Non-Clinical and Clinical Studies.................................................... 13 
D1. 
Non-Clinical Studies .............................................................................................. 13 
D2. 
Clinical Studies ...................................................................................................... 15 
E. 
Human Pharmacokinetics ......................................................................................... 15 
F. 
Clinical Study ............................................................................................................. 16 
G. Selection of Drugs and Dosages................................................................................. 16 
H. Number of Subjects to Enroll in Study .................................................................... 16 
I. 
Compliance Statement ............................................................................................... 16 
J. 
Relevant Literature and Data ................................................................................... 16 
IV. STUDY OBJECTIVES ................................................................................................... 17 
A. Primary Objective ...................................................................................................... 17 
B. 
Secondary Objectives ................................................................................................. 17 
V. INVESTIGATIONAL PLAN ......................................................................................... 18 
A. General Schema of Study Design .............................................................................. 18 
A1. 
Screening Phase ..................................................................................................... 18 
A2. 
30-Day Run-in Phase ............................................................................................. 18 
A3. 
Baseline .................................................................................................................. 18 
A4. 
Treatment Phase .................................................................................................... 18 
A5. 
Study Withdrawal Phase ........................................................................................ 18 
B. 
Randomization and Blinding .................................................................................... 19 
C. Study Duration, Enrollment and Number of Sites .................................................. 19 
C1. 
Duration of Subject Treatment .............................................................................. 19 
C2. 
Total Number of Study Sites/Total Number of Subjects Projected ........................ 19 
D. Study Population ........................................................................................................ 19 
D1. 
Inclusion Criteria ................................................................................................... 19 


 
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D2. 
Exclusion Criteria .................................................................................................. 20 
VI. STUDY PROCEDURES ................................................................................................. 21 
A. Screening (-30 days ± 3 days) Visit ........................................................................... 21 
A1. 
Screening ............................................................................................................... 21 
A2. 
Run-in Assessments ................................................................................................ 21 
B. 
Treatment Phase ......................................................................................................... 21 
B1. 
Baseline Assessments ............................................................................................. 22 
B2. 
Study Visit Assessments ......................................................................................... 22 
B3. 
Early Termination of Study Medication................................................................. 23 
C. Withdrawal Phase and Study Completion ............................................................... 23 
D. Unscheduled Visits ..................................................................................................... 24 
E. 
Concomitant Medication ........................................................................................... 24 
F. 
Prohibited Medications .............................................................................................. 25 
G. Subject Withdrawals .................................................................................................. 25 
VII. STUDY ENDPOINTS AND EVALUATIONS......................................................... 26 
A. Primary Endpoint ...................................................................................................... 26 
B. 
Secondary Endpoints (Efficacy) ................................................................................ 26 
C. Secondary Endpoints (Safety) ................................................................................... 26 
C1. 
Safety Evaluations.................................................................................................. 26 
D. Sample Collection Procedures, Bioanalytical Methods and Sample Shipment .... 28 
E. 
Efficacy Evaluations ................................................................................................... 28 
E1. 
Glutathione ............................................................................................................ 28 
E2. 
ALS Functional Rating Scale-Revised (ALSFRS-R) .............................................. 28 
E3. 
Pulmonary Function Tests and Capnography ....................................................... 29 
E4. 
Water and Solid Swallowing Tests......................................................................... 29 
E5. 
Speech Assessment ................................................................................................. 29 
E6. 
Columbia Suicide Severity Rating Scale (C-SSRS)................................................ 29 
E7. 
Handheld Dynamometry (HHD) ............................................................................ 29 
VIII. 
STATISTICAL CONSIDERATIONS .................................................................. 30 
A. Statistical Analysis...................................................................................................... 30 
A1. 
Analysis Populations.............................................................................................. 30 
B. 
Efficacy Analysis ........................................................................................................ 30 
B1. 
Efficacy Variables .................................................................................................. 30 


 
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C. Safety Analysis ............................................................................................................ 30 
D. Sample Size ................................................................................................................. 31 
IX. STUDY MEDICATION ................................................................................................. 32 
A. Description .................................................................................................................. 32 
B. 
Packaging .................................................................................................................... 32 
B1. 
Labeling ................................................................................................................. 32 
B2. 
Dosage Form ......................................................................................................... 32 
B3. 
Dispensing ............................................................................................................. 32 
B4. 
Treatment Compliance and Adherence.................................................................. 32 
B5. 
Drug Accountability ............................................................................................... 32 
X. SAFETY MANAGEMENT ............................................................................................ 34 
A. Clinical Adverse Events ............................................................................................. 34 
B. 
Adverse Event Reporting .......................................................................................... 34 
B1. 
Safety Guidance ..................................................................................................... 34 
C. Definition of an Adverse Event ................................................................................. 34 
C1. 
Adverse Event ........................................................................................................ 34 
C2. 
Definition of a Serious Adverse Event (SAE) ......................................................... 35 
C3. 
Non-serious Adverse Event .................................................................................... 36 
C4. 
Definition of Relationship to Study Medication ..................................................... 36 
C5. 
Definition of Severity ............................................................................................. 36 
C6. 
Definition of Unexpected Adverse Event ............................................................... 37 
C7. 
Notification of SAEs ............................................................................................... 37 
C8. 
Follow-up Report ................................................................................................... 38 
C9. 
Investigator Reporting of a Serious Adverse Event to Sponsor ............................. 38 
D. Medical Emergencies ................................................................................................. 38 
D1. 
Emergency Sponsor Contact .................................................................................. 38 
D2. 
Emergency Treatment ............................................................................................ 38 
XI. STUDY ADMINISTRATION ........................................................................................ 39 
A. Treatment Assignment Methods ............................................................................... 39 
B. 
Data Collection and Management ............................................................................ 39 
C. Data Quality Assurance ............................................................................................. 39 
D. Retention of Study Records ....................................................................................... 40 
E. 
Confidentiality ............................................................................................................ 40 


 
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F. 
Documentation of Study Results ............................................................................... 41 
G. Regulatory and Ethical Considerations ................................................................... 41 
G1. 
Risk Assessment ..................................................................................................... 41 
G2. 
Potential Benefits of Trial Participation ............................................................... 41 
G3. 
Risk-Benefit Assessment ......................................................................................... 42 
H. Informed Consent ....................................................................................................... 42 
XII. PUBLICATION .......................................................................................................... 43 
A. Use of Study Results ................................................................................................... 43 
XIII. 
LIST OF ABBREVIATIONS ................................................................................ 45 
XIV. 
SIGNATURE OF SPONSOR AND INVESTIGATOR(S) .................................. 47 
A. Declaration of Sponsor............................................................................................... 47 
XV. 
REFERENCES............................................................................................................ 48 
 
 
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I. 
PROTOCOL SYNOPSIS 
 
Title of study  
A Phase 2A Safety and Biomarker Study of EPI-589 in Subjects 
with Amyotrophic Lateral Sclerosis 
 
 
Protocol number 
EPI589-15-001 
 
 
IND Number 
126,276 
 
 
Original protocol date 
24 March 2015 
 
 
Protocol Amendment 
1.0 date 
09 September 2015 
Protocol Amendment 
2.0 date 
17 February 2017 
Name of 
sponsor/company 
 
 
BioElectron Technology Corporation  
350 North Bernardo Ave 
Mountain View CA 94043 
 
Sponsor contact 
 
Office:  
  
 
 
Name and affiliation of 
Principal Investigator 
 
 
 
 
 
 
Name of active 
ingredient 
EPI-589 
 
 
Phase of development 
Phase 2a 
 
 
Study population 
Approximately 20 subjects with amyotrophic lateral sclerosis 
(ALS) 
 
 
Rationale for study 
ALS is a disorder characterized by high levels of oxidative stress. 
High levels of oxidative stress (OS) biomarkers have been 
measured in patients with ALS relative to age-matched unaffected 
controls. The high levels of OS are thought to be key pathogenic 
factors in disease progression. 
Reduced glutathione is an essential intermediary metabolite that 
serves as the primary native cellular antioxidant. Reduced 
glutathione (GSH) serves as the cell’s primary defense against 
reactive oxygen species (ROS); however, in diseases characterized 
by high levels of oxidative stress, ROS production outstrips the 


 
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available supply of GSH resulting in depletion of GSH and ROS-
mediated cell injury and death. Altered levels of GSH have been 
recorded in the central nervous system (CNS) of patients with 
ALS. 
EPI-589 targets enzymes critical to the synthesis of GSH. In adult 
healthy volunteer studies, EPI-589 increased levels of GSH and 
other GSH-related sulfur analytes. 
 
EPI-589 rescues ALS patient cells from oxidative stress-induced 
cell death. In a phenotypic assay system, EPI-589 is a redox active 
molecule that has demonstrated potency (EC50 <100nM ) and 
efficacy (>80% rescue from oxidative stress-induced cell death). 
 
 
Study objective(s) 
Primary Objective 
To evaluate the effects of EPI-589 on safety as assessed by 
occurrence of drug-related serious adverse events in subjects with 
ALS 
 
Secondary Objectives 
To evaluate the effects of EPI-589 in subjects with ALS on: 
 
1. Glutathione cycle biomarkers as measured in blood, 
cerebral spinal fluid, and urine 
2. Disease progression as assessed by ALS Functional Rating 
Scale-Revised 
3. Respiratory function as assessed by pulmonary function 
tests  and capnography 
4. Failure to thrive as measured by body weight 
5. Swallowing as assessed by change in water and solid 
swallowing tests 
6. Speech as assessed by speech evaluation 
7. Muscle function as assessed by hand-held dynamometry 
8. Drug plasma concentration measurements 
9. Hematology, blood chemistry, electrocardiogram  
 
 
Study design 
Open label with 30-day run-in phase to establish baseline 
parameters and a 90-day withdrawal phase to determine duration 
of treatment response. 
 
 
Study duration 
Run-in phase: 1 month 
Treatment phase: 3 months 
Withdrawal phase: 3 months 
 
 
Planned number of 
subjects 
 
Approximately 20 subjects 
 
 


 
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Test product, mode of 
administration, strength, 
and dose 
Test Product 
EPI-589 in a tablet formulation at a strength of 250 mg   
 
 
Mode of Administration 
Oral with food 
 
Dose 
EPI-589 500 mg BID 
 
 
Reference therapy 
(for controlled studies) 
 
 
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. Diagnosis of possible, probable, laboratory supported probable 
or definite amyotrophic lateral sclerosis (ALS) by El Escorial 
Criteria 
2. 
 or 
 between 21 and 70  years of age 
3. Forced vital capacity (FVC) ≥ 70% of predicted 
4. Onset of weakness within 3 years as documented in clinical 
records 
5. Agreement to use contraception if within reproductive years 
6. Willingness and ability to comply with study procedures 
7. Stable regimen of dietary supplements for 30 days prior to 
enrollment 
8. Abstention from use of other investigative or non-approved 
drugs 
9. Subjects on riluzole must be on a stable dose for at least 30 
days prior to study enrollment. 
10. Subject must be able to swallow 0.375 x 0.700 inch tablets. 
 
 
Exclusion Criteria 
1. Allergy to EPI-589 
2. Use of invasive or non-invasive ventilation 
3. Participation in other intervention studies 
4. Diagnosis of any other neurologic disease 
5. Malignancy within past two years 
6. Pregnant or plans to become pregnant 


 
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7. History of stroke 
8. History of brain surgery 
9. Hepatic insufficiency with liver function tests (LFTs) greater 
than three times upper limit of normal (ULN) 
10. Renal insufficiency requiring dialysis 
11. End stage cardiac failure 
12. Participation in a trial of a device, drug or other therapy for 
ALS within 3 months of screening and for the duration of the 
trial 
 
 
Treatment 
Following study enrollment, subjects will participate in a 30-day 
run-in phase to establish baseline ALS disease-related clinical and 
biomarker features. EPI-589 will then be administered for 3 
months unless discontinued for safety or tolerability issues. 
Following cessation of therapy, subjects will return to the clinic for 
assessments at two time points during the 90-day withdrawal 
period. 
 
 
Efficacy variables 
 
1. Blood glutathione cycle biomarkers 
2. CNS biomarkers 
3. Urine biomarkers 
4. ALS Functional Rating Scale-Revised 
5. Pulmonary function tests  (FVC, FEV1, VC, MIP) 
6. Capnography (CO2, respiratory rate, oxygen saturation) 
7. Solid and liquid swallowing tests 
8. Speech 
9. Muscle function 
10. Body weight 
 
 
Safety variables 
Clinical 
1. Routine assessments of AEs and SAEs 
2. Dose limiting toxicities 
3. Electrocardiogram 
4. C-SSRS 
 
Laboratory 
1. Routine serum chemistries with liver function tests 
2. Routine hematology tests with coagulation tests 
 
 
Safety monitoring  
Clinical 
Physical exam and vital signs 
Evaluation of adverse events 
 
Laboratory 
PT/PTT 
Standard blood and serum chemistries 
 


 
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12-lead Electrocardiogram 
 
 
Statistical 
Considerations 
Data Analysis 
This is a subject-controlled open-label study to determine the 
safety and tolerability of EPI-589 in subjects with ALS as well as 
to determine if EPI-589 can alter the biochemical signature of ALS 
as assessed by peripheral blood biomarkers, CNS biomarkers, and 
urine biomarkers. In addition, data will be collected on a number 
of disease-relevant clinical measures of disease progression, and 
assessments by the ALS Functional Rating Scale-Revised 
(ALSFRS-R) will be compared with historical control data. 
 
 
Space intentionally left blank 
 
 


 
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II. 
SCHEDULE OF ASSESSMENTS AND DOSING SCHEDULE 
 
-30 Days 
(± 3 days) 
-30 Days 
(± 3 days) 
Day 0  
Month 1 Month 2e Month 3 Month 4 Month 5e Month 6 
 
Screening Run-ind 
Baseline 
Treatment Phase 
Withdrawal Phase 
Informed consent  
 
 
 
 
 
 
 
 
 
Inclusion /Exclusion 
criteria  
 
 
 
 
 
 
 
 
 
Past Medical history 
 
 
 
 
 
 
 
 
 
Previous tests review 
 
 
 
 
 
 
 
 
 
12-lead ECG   
 
 
 
 
  
 
 
 
 
C-SSRS 
 
 
 
  
 
 
  
 
 
Physical exam, heighta, 
weight & vital signs 
b 
 
 
 
 
 
 
 
 
Pulmonary function 
assessment and 
Capnography 
 
 
 
 
 
 
 
 
 
Serum Chemistry 
 
 
 h 
 
  
 
 
 
 
Hematology (including 
coagulation panel) 
 
 
 h 
 
  
 
 
 
 
Urinalysis  
 
 
 
 
 
 
 
 
 
Pregnancy testc  
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
  
  
 
  
 
  
Blood-based glutathione 
cycle biomarkers 
 
 
 
 
  
 
 
 
 
Urine-based biomarkers 
 
 
 
 
  
 
 
 
 
Lumbar puncture (CNS) 
 
 
 
 
 
 
 
 
 
ALSFRS-R 
 
 
 
 
 
 
 
 
 
Water and solid 
swallowing tests 
 
 
 
  
 
 
 
 
 
Speech assessment 
 
 
 
  
 
 
 
 
 
Handheld dynamometry 
 
 
 
  
 
 
 
 
 
AE/SAE Assessment 
 
 
 
 
e 
 
 
e  
g 
Drug plasma 
concentrationf 
 
 
 
f 
 
f 
 
 
 
Concomitant 
medications 
 
 
 
 
e  
 
  
e  
g 
Dosing Schedule 
 
 
 
Month 1  Month 2 Month 3  
 
 
EPI-589 BID 
 
 
 
 
 
 
 
 
 
a. 
Height measurement need not be repeated after treatment begins. 
b. 
Physical examination includes breast examination in women at screening. 
c. 
Urine or Serum pregnancy test will be done for 
of child bearing potential only. 
d. 
Run-in assessments must be performed 30 Days (+/- 3 days) prior to baseline after confirmation of eligibility and 
enrollment in the study. 
e. 
Month 2 assessments and Withdrawal Phase Month 5 assessments can be conducted by telephone. 
f. 
Samples will be collected at 0-hour and 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose on study visit days. 12 hour PK can 
be obtained at time 0. 
g. 
AEs reported at Month 6 (and any associated concomitant medications) must be followed for 30 days; this follow-up 
may be conducted by telephone 
h. 
Screening values can be used if done within one month of baseline and if completed under fasted conditions


 
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III. BACKGROUND INFORMATION AND RATIONALE 
A. 
Overview of Amyotrophic Lateral Sclerosis (ALS) 
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease without an effective 
therapy. ALS causes progressive damage and loss of motor neurons in the central and peripheral 
nervous systems that result in a gradual decrease and loss of motor and brainstem function. ALS 
is estimated to occur in 1–2/100,000 people worldwide. The majority of ALS cases are sporadic, 
however about 10% of cases are inherited (familial ALS), with 20% of familial ALS resulting 
from mutant forms of the superoxide dismutase soluble gene (SOD1), a homodimer that converts 
superoxide radicals to molecular oxygen in mitochondrial membranes and cytoplasm. Symptoms 
of motor neuron death in sporadic and familial ALS are clinically indistinguishable. The role of 
oxidative stress (OS) and mitochondrial dysfunction as key pathophysiological features in all 
forms of ALS has been well established.1 
ALS is typically diagnosed between age 50 and 60. The earliest symptoms are muscle weakness 
and atrophy. Other presenting symptoms include muscle cramping, difficulty swallowing and 
altered or slurred speech. Average survival time following diagnosis is 3 to 4 years. Patients 
experience increasing difficulty with movement, dysphagia, dysarthria, and respiratory failure 
requiring chronic ventilatory or other respiratory assistive support. Most patients with ALS die 
from respiratory failure or pneumonia. 
The only approved treatment for ALS is riluzole (Rilutek®), which acts by inhibiting the release 
of glutamate in the central nervous system. Riluzole has been shown to extend survival by 2 to 3 
months. The mainstay of treatment for ALS is symptomatic: physical therapy in the early stages 
of the disease, and therapies that address oropharyngeal and psychological symptoms, motor and 
respiratory function, and pain. 
The importance of OS and mitochondrial pathology in ALS pathology is well substantiated.2,3 
OS occurs when the level of reactive oxygen species (ROS) formed from biological processes 
exceeds the supply of native antioxidants. Patients with SOD1 mutations have a clear genetic 
link to oxidative stress susceptibility given the role of superoxide dismutase in modulating OS.4 
However, OS is present in all forms of ALS.5 Pathological studies on postmortem ALS patient 
tissue have demonstrated increased levels of OS including elevated protein carbonyl levels in the 
spinal cord and motor cortex.5,6  In addition, elevated levels of OS biomarkers have been detected 
in the cerebrospinal fluid (CSF) of ALS patients including 8-hydroxy-2’-deoxyguanosine and 4-
hydroxynonenal.7,8,9,10 In addition, studies using magnetic resonance spectroscopy (MRS) have 
demonstrated that levels of reduced glutathione (GSH)—a critical component of the cellular 
antioxidant system—are more than 30% lower in patients with ALS compared to healthy 
volunteers,11 supporting the involvement of OS in the brain with disease pathology. 
There is evidence of mitochondrial structure, genetic and biochemical abnormalities in patients 
with ALS. A number of studies have demonstrated decreased activity in mitochondrial 


 
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complexes that form the electron transport chain and muscle biopsies from patients with ALS 
demonstrate abnormal morphology: abnormal size, paracrystalline inclusions and abnormal 
cristae.12,13 The motor cortex and spinal cords of patients with ALS have also been found to have 
a higher frequency of mitochondrial DNA(mtDNA)  mutations compared to controls.14,15 
B. 
Rationale for the Study of EPI589-15-001 in Subjects with ALS 
Reduced glutathione (GSH) is an essential intermediary metabolite that serves as the primary 
native cellular antioxidant, and the cell’s primary defense against ROS. In diseases characterized 
by high levels of OS, ROS production outstrips the available supply of GSH resulting in 
depletion of GSH and ROS-mediated cell injury and cell death. 
EPI-589 is a novel redox active therapeutic being developed by BioElectron Technology 
Corporation for the treatment of diseases in which OS plays a critical role. EPI-589 acts to 
catalytically increase levels of GSH by targeting key enzymes in the glutathione synthesis 
pathway. In in vitro studies, EPI-589 has been shown to replenish levels of GSH and protect 
against OS-induced cell death. In addition, in adult healthy volunteers, EPI-589 has been found 
to augment levels of GSH and related sulfur analytes. 
Given the strong evidence of GSH depletion and OS in the pathogenesis of ALS,16,17 EPI-589 
may hold promise as a therapeutic for patients with ALS. The purpose of this study is to confirm 
target engagement of EPI-589 in adult patients with ALS by studying peripheral and central 
nervous system (CNS) glutathione cycle biomarkers. 
C. 
Name and Description of Investigational Product  
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 
manufactured from the (R)-Trolox® enantiomer, and is a pale yellow to yellow solid. The EPI-
589 drug product is an immediate release film-coated tablet at a 250-mg dosage strength. The 
tablet is oval shaped and yellow.  
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. 28-day and 3-month repeat-dose toxicity studies in rat and monkey 
showed a No Observed Adverse Effect Level (NOAEL) of 300 mg/kg/day, corresponding to 


 
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combined mean Cmax values of 37,717 – 56,500 ng/mL (rat) and 14,300 – 16,417 ng/mL 
(monkey), and combined mean AUClast values of 149,495 – 297,000 ng.h/mL (rat) and 47,300 – 
67,656 ng.h/mL (monkey). 
Exposure to 1,000 mg/kg/day EPI-589 oral dosing (PO) induced hematology changes in the rat 
and induced toxicity resulting in death or euthanasia in the monkey. Rats exposed to 1,000 
mg/kg/day PO EPI-589 for 28 days showed 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 possessing corresponding microscopic pathology. 
The majority of these findings were resolved following the 28-day recovery period. Rats exposed 
to ≥ 100 mg/kg/day PO EPI-589 exhibited mild effects on hematology parameters consistent 
with hemolysis and bone marrow regeneration. These findings were not considered adverse. 
Monkeys exposed to 1,000 mg/kg/day PO EPI-589 for 28 days showed significant test-article 
related morbidity including elevations in aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) and microscopic findings in the kidney, liver, skeletal muscle, heart, and 
lymphoid tissue. In several of the animals the primary cause of morbidity was determined to be 
test-article related renal tubular degeneration/necrosis. 
A fertility study in rat demonstrated that EPI-589 did not produce reproductive toxicity at doses 
up to 1,000 mg/kg/day. Embryo fetal development studies in rat and rabbit demonstrated the 
NOAEL for EPI-589 for developmental toxicity to be 300 mg/kg/day. EPI-589 induced toxicity 
at 1,000 mg/kg/day in rat and rabbit. Findings in the rat included 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. Findings in rabbit included 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 and rabbits is approximately 179- to 
236-fold at 1,000 mg/kg/day and 47- to 50-fold at 300 mg/kg/day. 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; 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; and negative in the in vivo micronucleus assay in rat. These data indicate a low 
clinical mutagenicity risk. 
Primary pharmacodynamics studies have demonstrated that EPI-589 is a potent rescue agent in 
in vitro cellular models of mitochondrial disorders and diseases characterized by mitochondrial 
pathology and high levels of oxidative stress. The cellular activity of EPI-589 involves a redox-
dependent mechanism of action. Secondary pharmacodynamics in vitro studies have shown that 
EPI-589 does not significantly affect off-target molecular targets. Safety pharmacology metrics 


 
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evaluated during the 28-day and 3-month repeat-dose toxicology studies in monkey 
demonstrated that EPI-589 does not affect cardiovascular in vitro hERG K+ channel current or 
electrocardiogram (ECG) parameters. EPI-589 does not change respiratory function or adversely 
impact neurobehavioral function in rat. 
Single dose exposure pharmacokinetics studies have demonstrated that EPI-589 is absorbed 
rapidly in all species with mean Tmax values ranging from .08 to 1 hour and mean T1/2 values 
ranging from 3.7 to 5.0 hours. In vitro studies suggest that EPI-589 does not significantly inhibit 
or induce CYP450 enzymes. 
D2. Clinical Studies 
Safety 
Phase I Study EPI589-13-022 evaluated the pharmacokinetics (PK), safety and tolerability of 
single ascending oral doses (SAD) of EPI-589 in healthy subjects and a preliminary evaluation of 
safety and tolerability data was performed. No severe or serious adverse events were observed. 
In total, 15 out of 32 subjects experienced 23 adverse events (AEs). Fourteen of 15 AEs were 
considered to be related to the study medication by the Investigator. All AEs were of mild 
intensity and of limited duration. 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. In total, 34 
out of 50 subjects experienced 44 AEs. Twenty-four of 34 AEs were considered by the 
Investigator to be related to the study medication. All but one AE was of mild intensity and of 
limited duration. A single event of moderate intensity and limited duration was reported: brain 
contusion (not related) in the 250 mg twice-daily (BID) cohort. None of the vital signs, ECG 
parameters or clinical laboratory test results showed a clinically relevant change compared to 
baseline. 
E. 
Human Pharmacokinetics 
In MAD study EPI589-14-001, 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. 


 
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It appears that no significant effects of age and 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 
EPI589-15-001: A Phase 2A Safety and Biomarker Study of EPI-589 in Subjects with 
Amyotrophic Lateral Sclerosis. 
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 food. 
H. 
Number of Subjects to Enroll in Study 
Approximately 20 subjects with ALS. 
I. 
Compliance Statement 
This study will be conducted in full accordance with all applicable research policies and 
procedures, all applicable 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, obtain consent and 
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. 
J. 
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 is to evaluate the effects of EPI-589 on safety as assessed by occurrence 
of drug-related serious adverse events in subjects with ALS. 
B. 
Secondary Objectives 
The secondary objectives are to evaluate the effects of EPI-589 in subjects with ALS on: 
1. Glutathione cycle biomarkers as measured in blood, cerebral spinal fluid, and urine 
2. Disease progression as assessed by ALS Functional Rating Scale-Revised 
3. Respiratory function as assessed by pulmonary function tests and capnography 
4. Failure to thrive as measured by body weight 
5. Swallowing as assessed by change in water and solid swallowing tests  
6. Speech as assessed by speech evaluation  
7. Muscle function as assessed by handheld dynamometry 
8. Drug plasma concentration measurements 
9. Hematology, blood chemistry, electrocardiogram 
 
 
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V. 
INVESTIGATIONAL PLAN 
A. 
General Schema of Study Design 
After study enrollment, baseline assessments will be performed. Subjects participate in a 30-day 
run-in phase to establish baseline ALS disease-related clinical and biomarker features. EPI-589 
will then be administered for 3 months, unless discontinued for safety or tolerability issues. All 
subjects will then be followed for an additional 90 days to determine long-term effects, duration 
of response to treatment, and potential effects of EPI-589 therapy on known disease trajectory. 
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 ALS Functional 
Rating Scale-Revised (ALSFRS-R) measurements and CNS, urine-based and blood-based 
glutathione cycle biomarkers, will be collected.  
A3. Baseline 
ALSFRS-R, lumbar puncture, swallowing, speech, handheld dynamometry, blood-based 
biomarkers, urine biomarkers, 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 biomarker, urine biomarker, clinical measurements, and pharmacokinetic plasma 
concentrations will be collected at Day 29 (+/-3 days) and Day 85 (+/- 3 days). Lumbar puncture 
will be collected at Day 85 (+/- 3 days). 
A5. Study Withdrawal Phase 
Closeout data will be collected over a 90-day period, during the Withdrawal Phase.  
ALSFRS-R, blood-based biomarkers, urine-based biomarkers, and physical exam including 
weight and vital signs will be collected at Month 4. 


 
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ALSFRS-R, swallowing, speech, handheld dynamometry, blood-based biomarkers, urine-based 
biomarkers, and physical exam including weight and vital signs will be collected at Month 6. 
Adverse events reported as ongoing during the Withdrawal Phase, and any concomitant 
medications associated with such events will be followed for 30 days. Month 5 AE and 
concomitant medication assessments can be conducted by telephone. 
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 baseline ALS disease-related 
clinical and biomarker features. EPI-589 will then be administered for 3 months unless 
discontinued for safety or tolerability issues. Subjects will return to the clinic for assessments at 
two time points during a 90-day withdrawal period. 
C2. Total Number of Study Sites/Total Number of Subjects Projected  
This study will be conducted at the California Pacific Medical Center, San Francisco, CA. 
Additional sites may be added in order to decrease enrollment timelines. 
Projected enrollment is approximately 20 subjects with ALS. 
D. 
Study Population  
D1. Inclusion Criteria 
1. Diagnosis of possible, probable, laboratory supported probable or definite amyotrophic 
lateral sclerosis (ALS) by El Escorial Criteria. 
2. Male or female between 21 and 70 years of age 
3. Forced vital capacity (FVC) ≥ 70% of predicted 
4. Onset of weakness within 3 years as documented in clinical records 
5. Agreement to use contraception if within reproductive years 
6. Willingness and ability to comply with study procedures 
7. Stable regimen of dietary supplements for 30 days prior to enrollment 
8. Abstention from use of other investigative or non-approved drugs 
9. Subjects on riluzole must be on a stable dose for at least 30 days prior to study 
enrollment. 
10. Subject must be able to swallow 0.375 x 0.700 inch tablets. 


 
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D2. Exclusion Criteria  
1. Allergy to EPI-589 
2. Use of invasive or non-invasive ventilation 
3. Participation in other intervention studies 
4. Diagnosis of any other neurologic disease 
5. Malignancy within past two years 
6. Pregnant or plans to become pregnant 
7. History of stroke 
8. History of brain surgery 
9. Hepatic insufficiency with liver function tests (LFTs) greater than three times upper limit 
of normal (ULN) 
10. Renal insufficiency requiring dialysis 
11. End stage cardiac failure 
12. Participation in a trial of a device, drug or other therapy for ALS within 3 months of 
screening and for the duration of the trial. 
 
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VI. STUDY PROCEDURES 
A. 
Screening (-30 days ± 3 days) Visit  
A1. Screening  
The Investigator will inform each prospective subject of the nature of the study, explain the 
potential risks, and 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. Physical examination (including breast examination for women) 
4. Height, weight and vital signs 
5. Receipt and review of all previous testing 
6. 12-lead ECG   
7. Pulmonary function assessment 
8. Hematology including coagulation, serum chemistry, urine analysis 
9. Pregnancy test (women of childbearing potential must have a negative serum or urine 
pregnancy test)  
10. Concomitant medication assessment (last 60 days prior to enrollment)  
A2. Run-in Assessments 
Run-in assessments must 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. ALS Functional Rating Scale-Revised  
2. Blood-based glutathione cycle biomarkers 
3.  Urine-based glutathione cycle biomarkers 
B. 
Treatment Phase 
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 30 days (+/- 3 days) for baseline 
assessments. In-clinic study visits are scheduled at Month 1 and Month 3. Month 2 assessments 
can be conducted via telephone. End of treatment will be 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  
2. 12-Lead ECG 
3. Pulmonary function assessment and capnography 
4. Hematology including coagulation and serum chemistry*  
5. Weight and vital signs 
6. Pregnancy test (women of childbearing potential) 
7. Glutathione cycle blood, urine and CNS  biomarkers 
8. C-SSRS 
9. ALS Functional Rating Scale-Revised  
10. Water and solid swallowing tests 
11. Speech assessment 
12. Handheld dynamometry 
EPI-589 will be dispensed to the subjects along with the dosing diary. Subjects will self-
administer EPI-589 at a dose of 500 mg BID starting from Day 1.                                                   
* Screening values can be used if done within one month of baseline and if completed under 
fasted conditions                                                  
B2. Study Visit Assessments 
Adverse events and concomitant medication information will be reviewed and assessed at each 
visit.  
Clinic Visits: Month 1 and Month 3  
The following will be assessed or performed at the Month 1 (Day 29 +/-3 days) clinic visit: 
1. Physical examination  
2. 12-lead ECG   
3. Pulmonary function assessment and capnography 
4. Hematology including coagulation and serum chemistry  
5. Weight and vital signs 
6. Pregnancy test (women of childbearing potential) 
7. Glutathione cycle blood, urine, and CNS biomarkers  
8. ALS Functional Rating Scale-Revised  
9. Drug plasma concentration measurements* 
The following will be performed at the Month 3 (Day 85 +/- 3 days) clinic visit: 


 
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1. Physical examination  
2. 12-lead ECG   
3. Pulmonary function assessment and capnography 
4. Hematology including coagulation and serum chemistry  
5. Weight and vital signs 
6. Pregnancy test (women of childbearing potential) 
7. Glutathione cycle blood, urine, and CNS biomarkers  
8. Drug plasma concentration measurements* 
9. ALS Functional Rating Scale-Revised  
10. Water and solid swallowing tests 
11. Speech assessment 
12. Handheld dynamometry 
*Pharmacokinetics: Plasma concentration samples will be collected at 0-hour and 0.5, 1, 2, 4, 6, 
8, and 12 hours post-dose at the Month 1 and Month 3 clinic visits. 
Drug accountability and compliance: Subjects should bring the study medication and the dosing 
diary at the Month 1 and Month 3 visits. All the used and unused study medication should be 
returned and reconciled at the Month 3 visit. 
Month 2 Assessments  
Month 2 assessments can be conducted by telephone and will include review of concomitant 
medications and AEs. 
B3. Early Termination of Study Medication 
Subjects who terminate from the study after receiving first dose and prior to the completion of 
the treatment phase should have an end of study visit as soon as possible. All the Month 3 visit 
assessments should be completed at this visit.  
C. 
Withdrawal Phase and Study Completion 
Month 4 Clinic Visit (Day 113 +/- 1 Week) 
1. Physical examination  
2. Weight and vital signs 
3. Blood-based biomarkers  
4. Urine-based biomarkers 
5. C-SSRS 
6. ALS Functional Rating Scale-Revised  
7. AEs and SAEs  
8. Concomitant medications 


 
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Month 5 Assessments  
Month 5 assessments may be conducted by telephone. 
1. AEs and SAEs  
2. Concomitant medications 
Month 6 Clinic Visit (Day 169 +/- 1 Week) 
1. Physical examination  
2. Weight and vital signs 
3. Glutathione cycle blood-based biomarkers  
4. Glutathione cycle urine-based biomarkers 
5. ALS Functional Rating Scale-Revised  
6. Water and solid swallowing tests 
7. Speech assessment 
8. Handheld dynamometry 
9. Pulmonary function tests and capnography 
10. AEs and SAEs  
11. Concomitant medications 
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 treatment visit windows, assessments will 
be made at the Investigator’s discretion. All relevant unscheduled visit data will be recorded in 
the 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 case report form (CRF). 
During screening, each subject will be instructed to report the use of any medication to the 
Investigator. Subjects will also be instructed about the importance of not taking any medication 
throughout the study (including over-the-counter [OTC] medications) without first consulting the 
Investigator.  


 
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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 the Screening Visit and for the duration of study in a trial 
of a device, drug or other therapy for ALS 
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. For failure to comply with the Protocol (i.e., dosing compliance, failure to complete 
diaries as instructed, failure to keep scheduled appointments) 
4. At the specific request of the Sponsor (or designee).  
5. 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 
X.B. 
Evaluations must 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 ALS following three months of EPI-589 therapy. 
B. 
Secondary Endpoints (Efficacy) 
1. Blood-based biomarkers 
2. CNS-based biomarkers 
3. Urine-based biomarkers 
4. Disease progression as assessed by ALS Functional Rating Scale-Revised 
5. Respiratory function as assessed by pulmonary function tests and capnography 
6. Failure to thrive as measured by body weight 
7. Swallowing as assessed by change in water and solid swallowing tests 
8. Speech as assessed by speech evaluation 
9. Muscle function as assessed by handheld dynamometry 
10. Drug plasma concentration measurements 
C. 
Secondary Endpoints (Safety) 
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 
C1. Safety Evaluations  
a. Physical Examination  
Complete physical exams will be conducted (excluding genital/rectal exam) at screening and 
baseline. 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 
(including breast examination in women at Screening), heart, abdomen, and extremities. 
Medical history and demographics including age, gender, race, height and weight will be 
collected at Screening.  
b. Vital Signs  
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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Weight (kg) will be assessed in ordinary indoor clothing (i.e., street clothes, scrubs, etc.). Weight 
and height (cm) will be recorded at Baseline. 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.  
c. Laboratory Evaluations and Sample Shipment  
Each subject 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 II) to assess 
safety.  
d. 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 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), INR, partial thromboplastin time (PTT). 
e. Serum Chemistry 
1. Liver: ALP, ALT (serum glutamic-pyruvic transaminase [SGPT]), AST (serum glutamic-
oxaloacetic transaminase [SGOT]), bilirubin (total, direct, and indirect), 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), CK fractionated (CK-MB, CK-MM and CK-
BB) and troponin (baseline only), protein (total), 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  
f. Pregnancy Test 
Serum or urine human chorionic gonadotropin (HCG), beta subunit, will be performed on all 
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Diagnoses associated with any NIH Common Toxicity Criteria (CTC) v4.03 Grade 3 or 4 
laboratory abnormalities will be recorded as AEs on the CRF. Repeated and verified laboratory 
tests that meet at least Grade 3 AE requirements will be reported to the institutional review board 
(IRB) per institutional requirements. The recorded AEs 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.  
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.  
D. 
Sample Collection Procedures, Bioanalytical Methods and Sample Shipment 
Urine, cerebral spinal fluid, and fasting blood samples will be collected for determination of 
levels of glutathione cycle markers. Additional information about the collection, handling, 
storage, and shipment of the glutathione cycle marker samples will be provided separately prior 
to start of the study. 
E. 
Efficacy Evaluations  
E1. Glutathione  
Blood, urine, and cerebral spinal fluid levels of oxidized glutathione (GSSH) and reduced 
glutathione (GSH) as well as glutathione metabolites will be used to evaluate EPI-589 target 
engagement and ability to correct key biochemical aspects of disease pathology. 
E2. ALS Functional Rating Scale-Revised (ALSFRS-R) 
The ALS Functional Rating Scale–Revised (ALSFRS-R) is a quickly administered (five 
minutes) ordinal rating scale that assesses patients’ capability and independence in 12 functional 
activities. All 12 activities, six bulbar-respiratory functions, three upper extremity functions 
(writing, cutting food, and dressing), two lower-extremity functions (walking and climbing), and 
one other function (turning in bed), are relevant in ALS. Each activity is recorded to the closest 
approximation from a list of 5 choices, scored 0-4, with the total score ranging from 48 (normal 
function) to 0 (unable to attempt the task). The ALSFRS has been used extensively in previous 
clinical trials and validity has been established by correlating ALSFRS scores with quantitative 
strength testing and changes in strength over time. The ALSFRS-R, which incorporates separate 
assessment of respiratory function, is validated. 


 
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E3. Pulmonary Function Tests and Capnography 
Pulmonary function tests will assess vital capacity (VC), forced vital capacity (FVC), forced 
expiratory volume (FEV1) and maximum inspiratory pressure (MIP). Capnography will assess 
end tidal CO2, oxygen saturation, respiratory rate and heart rate and will be performed in both the 
upright and supine positions. 
E4. Water and Solid Swallowing Tests  
Subjects will be observed and timed swallowing water as well as solid foods in accordance with 
a standardized protocol. 
E5. Speech Assessment 
Speech will be assessed through a perceptual assessment of overall intelligibility, vocal quality, 
and other factors by a speech language pathologist. 
E6. 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. 
E7. Handheld Dynamometry (HHD) 
The strength of designated muscle groups will be measured using handheld dynamometry 
(HHD). Upper extremity and lower extremity values will be calculated to create overall scores 
for upper and lower extremity muscles. 


 
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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. In addition, changes in the ALSFRS-R will 
be measured three months following withdrawal of therapy and compared with disease natural 
history data to determine effects of EPI-589 on disease trajectory. 
A1. Analysis Populations 
Demographic characteristics and baseline efficacy data will be presented and summarized for all 
subjects in the efficacy intent-to-treat (EITT) population. Demographic information will also be 
summarized 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. Urine-based glutathione cycle biomarkers 
3. Disease progression as assessed by ALS Functional Rating Scale-Revised 
4. Respiratory function as assessed by pulmonary function tests and capnography 
5. Failure to thrive as measured by body weight 
6. Swallowing as assessed by change in water and solid swallowing tests 
7. Speech as assessed by speech evaluation 
8. Muscle function as assessed by handheld dynamometry 
9. Drug plasma concentration measurements 
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 ALS. 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 20 subjects will be enrolled in this exploratory biomarker study. 
 
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IX. STUDY MEDICATION 
A. 
Description 
EPI-589 is presented as an instant release solid oral tablet. Each tablet contains 250 mg of 
EPI-589 and the following compendial excipients: lactose monohydrate, 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 that comply 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 HDPE 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].) 
B4. 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 reconciliation with subject-completed dosing diaries and 
returned used drug supply. 
B5. Drug Accountability 
Dosing information will be captured on a subject Dosing Diary Form. This form is part of the 
study source documentation and will be utilized as a source for the completion of CRFs 


 
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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 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 the Investigator study file to assure the study medication is 
appropriately prescribed by the Investigator or designee for the purpose of this study. At study 
completion, all drug supplies including partially used and empty containers must be either 
returned to the Sponsor or designee or destroyed per 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 the IRB/IEC policies and as 
detailed below. AEs that are not serious will be summarized in narrative or other format and 
submitted to the IRB/IEC at the time of continuing review. 
B1. Safety Guidance 
Based on the known clinical manifestations of ALS we expect that many AEs could occur during 
the course of the trial that are well documented to occur during progression of the disease. These 
include, but are not limited to worsening neuromuscular function, depression, slurred speech, 
breathing difficulty, pneumonia, and death. 
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 adverse event (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”. 
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) 
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 
6. Important medical events (ie: bronchospasm, development to drug dependency) that 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 patient or may require intervention to prevent one of the other outcomes listed in the 
serious definition 
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 patient 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 a SAE which 
hypothetically might have caused death if it were more severe. 
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. 


 
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 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, any pregnancy complications or an outcome other than a healthy, normal outcome 
will be recorded as an AE or SAE. 
C3. Non-serious Adverse Event 
A non-serious adverse event 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 
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 required. 


 
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Grade 2 – Mild to moderate limitation in activity, some assistance may be needed; no or 
minimal medical intervention/therapy required. 
Grade 3 – Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required hospitalizations possible. 
Grade 4 – Extreme limitation in activity, significant assistance required; significant medical 
intervention/therapy required hospitalization, life threatening, or hospice care 
probable. 
Grade 5 – Death 
C6. Definition of Unexpected Adverse Event 
Any AE, the specificity or severity of which is not consistent with the current investigator 
brochure or elsewhere in the current application, as amended, rather than from the perspective of 
such experience not being anticipated from the pharmacological properties of the drug. 
C7. Notification of SAEs 
The Investigator is responsible for promptly notifying the IRB/IEC of all study on-site SAEs, 
using the internal SAE reporting form, 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 External SAE form (if applicable). 
SAEs (whether unexpected or expected AEs) must be reported to the Sponsor (by telephone or 
facsimile communication)  within 24 hours, followed by a completed SAE form within 2 
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 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 follow-up SAE forms. 
The instructions for the completion of AE reports give more detailed guidance on the reporting 
of SAEs and AEs initially reported as non-serious that become serious. In the latter situation, 
when a non-serious event becomes serious, details must be forwarded immediately to the 


 
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Medical expert and BioElectron or BioElectron-assigned safety or 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 will be reported as soon as possible to the 
ethics committee and BioElectron Technology Corporation will notify the FDA of fatal or life 
threatening SUSARs within 7 calendar days after first knowledge by BioElectron Technology 
Corporation that a case qualifies as an unexpected fatal or life-threatening experience, followed 
by a written report to the FDA within 15 days after first knowledge of the qualifying event. 
Serious and unexpected AEs that are not fatal or life-threatening, but have a possible or probable 
relationship to the study drug must be filed with the ethics committee, and will be reported to the 
FDA by BioElectron Technology Corporation no later than 15 calendar days after being 
informed of the event. 
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. Investigator Reporting of a Serious Adverse Event to Sponsor 
Reporting must be consistent with regulatory, Sponsor or general clinical research center 
(GCRC) requirements (if applicable). 
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 of this study drug 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 (0.1%), a 100% database audit will be 


 
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performed. Systematic review of the database will be undertaken and corrections will be made to 
achieve an error rate of less than 0.1%. 
Adverse events will be coded using MedDRA, v15.0. Prior and concomitant medications will be 
coded according to the World Health Organization (WHO) Drug Dictionary. 
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 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. 


 
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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. 
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 EPI589-14-01 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 ALS. Therefore, we cannot assure that subjects will benefit from 
treatment with EPI-589. Potential treatment benefits may manifest. 


 
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G3. Risk-Benefit Assessment 
The treatment options for ALS are limited, 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 affect subjects with ALS. 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. 
If this Study is part of a multicenter clinical research study, 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 should this Study be conducted at other centers. Only after 
the completion of this Study at all centers, provision of the data to the FDA (or other agency if 
applicable) for review and comment, and publishing the combined data from any or all of the 
centers where the study is conducted, Principal Investigator may 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 
λz 
apparent terminal constant 
AE 
adverse event 
AI 
accumulation index 
ALS 
amyotrophic lateral sclerosis 
ALSFRS-R 
ALS Functional Rating Scale-Revised 
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase  
AR 
accumulation ratio 
AUC 
area under the curve 
BID 
twice daily 
CFR  
Code of Federal Regulations  
CHO 
Chinese hamster ovary 
Cmax 
maximum concentration 
CNS 
central nervous system 
CO2 
Carbon dioxide 
CoQ10 
Coenzyme Q 10 
CRF  
Case Report Form  
CRO  
Contract Research Organization  
CSF 
cerebrospinal fluid  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CYP450 
Cytochrome P450 
DSMB 
data safety monitoring board 
ECG  
electrocardiogram  
EITT 
efficacy intent-to-treat 
FDA  
Food and Drug Administration  
FEV1 
forced expiratory volume 
FVC 
forced vital capacity 
GCP  
Good Clinical Practices  
GCRC 
general clinical research center 
GSH 
glutathione 
HCG 
Human chorionic gonadotropin 
HDPE 
high density polyethylene  
hERG  
human  ether-a-go-go related gene 
HHD 
handheld dynamometry  
ICH  
International Committee on Harmonization  
IEC  
Independent Ethics Committee  
INR  
International Normalized Ratio  
IRB  
Institutional Review Board  
kg  
kilogram  
LFT  
liver function test  
MAD 
multiple ascending (oral) dose 
MCH 
mean corpuscular hemoglobin 


 
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MCHC 
mean corpuscular hemoglobin concentration  
MCV 
mean corpuscular volume 
mg  
milligram  
MIP 
Maximum inspiratory pressure 
mL  
milliliter  
MPV 
mean platelet volume 
MRS 
magnetic resonance spectroscopy 
mtDNA  
mitochondrial DNA  
nM  
nanomolar  
NOAEL 
no observed adverse effect level 
OTC 
over-the-counter 
OS 
oxidative stress 
PK  
pharmacokinetics 
PO 
by mouth 
PT 
Prothrombin Time  
PTT 
Partial Prothromboplastin 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 
ROS 
reactive oxygen species 
SAD 
single ascending (oral )dose 
SAE 
serious adverse event 
SOD1 
superoxide dismutase soluble gene  
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
half-life 
 
Tmax 
time to peak concentration 
ULN  
upper limit of normal  
USP  
United States Pharmacopeia  
VC 
Vital capacity 
 
 
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XV. REFERENCES 
1 Barber SC and Shaw PJ. Oxidative stress in ALS: key role in motor neuron injury and 
therapeutic target. Free radical biology & medicine. 2010;48:629-41. 
2 Luft, R. The development of mitochondrial medicine. Proc Natl Acad Sci.1994; 91, 8731-38. 
3 Cozzolino M and Carri MT. Mitochondrial dysfunction in ALS. Prog Neurobiol. 2012 
97(2):54-66. 
4 Rosen DR. Mutations in Cu/Zn superoxide dismutase gene are associated with familial 
amyotrophic lateral sclerosis. Nature. 1993; 22;364 (6435):362. 
5 Ferrante RJ, Browne SE, Shinobu LA, et al. Evidence of increased oxidative damage in both 
sporadic and familial amyotrophic lateral sclerosis. Journal of neurochemistry. 1997;69:2064-74. 
6 Shaw PJ, Ince PG, Falkous G, Mantle D. Oxidative damage to protein in sporadic motor neuron 
disease spinal cord. Annals of neurology. 1995;38:691-5 
7 Bogdanov M, Brown RH, Matson W, et al. Increased oxidative damage to DNA in ALS 
patients. Free radical biology & medicine. 2000;29:652-8. 
8 Ihara Y, Nobukuni K, Takata H, Hayabara T. Oxidative stress and metal content in blood and 
cerebrospinal fluid of amyotrophic lateral sclerosis patients with and without a Cu, Zn-
superoxide dismutase mutation. Neurological research. 2005;27:105-8 
9 Smith RG, Henry YK, Mattson MP, Appel SH. Presence of 4-hydroxynonenal in cerebrospinal 
fluid of patients with sporadic amyotrophic lateral sclerosis. Annals of neurology.1998;44:696-9. 
10 Simpson EP, Henry YK, Henkel JS, Smith RG, Appel SH. Increased lipid peroxidation in sera 
of ALS patients: a potential biomarker of disease burden. Neurology. 2004;62:1758-65. 
11 Weiduschat N, Mao X, Hupf J, et al. Motor cortex glutathione deficit in ALS measured in vivo 
with the J-editing technique. Neuroscience letters. 2014;570:102-7 
12 Bacman SR, Bradley WG, Moraes CT. Mitochondrial involvement in amyotrophic lateral 
sclerosis: trigger or target? Molecular neurobiology. 2006;33:113-31. 
13 Chung MJ and Suh YL. Ultrastructural changes of mitochondria in the skeletal muscle of 
patients with amyotrophic lateral sclerosis. Ultrastructural pathology. 2002;26:3-7. 
14 Dhaliwal GK and Grewal RP. Mitochondrial DNA deletion mutation levels are elevated in 
ALS brains. Neuroreport. 2000;3;11(11):2507-9. 
15 Wiedemann FR, Manfredi G, Mawrin C, et al. Mitochondrial DNA and respiratory chain 
function in spinal cords of ALS patients. J Neurochem. 2002;80(4):616-25. 
16 Chi L, Ke Y, Luo C, Gozal D, Liu R. Depletion of reduced glutathione enhances motor neuron 
degeneration in vitro and in vivo. Neuroscience. 2007; 9;144(3):991-1003 
                                                     


 
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17 D’Alessandro G, Calcagno E, Tartari S, Rizzardini M. Glutamate and glutathione interplay in 
a motor neuronal model of amyotrophic lateral sclerosis reveals altered energy metabolism. 
Neurobiol Dis. 2011; 43: 346-55. 
 
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