A Multicenter, Open-label, Uncontrolled, Long-term Trial to Assess the Safety and Efficacy of ETC-1002 in Patients With Hyper-LDL Cholesterolemia
Phase: PHASE3
Conditions: Hyper-low-density Lipoprotein (LDL) Cholesterolemia
Sponsor: Otsuka Pharmaceutical Co., Ltd.

 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A Multicenter, Open-label, Uncontrolled, Long-term Trial to Assess the Safety and Efficacy of ETC-
1002 in Patients With Hyper-LDL Cholesterolemia 
 
A Long-term Trial of ETC-1002 in Patients With Hyper-LDL Cholesterolemia 
 
 
 
 
 
 
NCT Number: NCT05687071 
Protocol No. 346-102-00003 
Version Date: 04 Oct 2022 (Version 1.0) 

Otsuka Pharmaceutical Co., Ltd. 
 
Investigational Medicinal Product 
 
ETC-1002 (Nonproprietary name: Bempedoic acid) 
Translation of Japanese Original 
CLINICAL PROTOCOL 
 
A Multicenter, Open-label, Uncontrolled, Long-term Trial to Assess the Safety and 
Efficacy of ETC-1002 in Patients With Hyper-LDL Cholesterolemia 
 
A Long-term Trial of ETC-1002 in Patients With Hyper-LDL Cholesterolemia 
 
Protocol No. 346-102-00003 
 
CONFIDENTIAL  PROPRIETARY INFORMATION 
 
 
Clinical Development Phase: 
3 
 
Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
 
Immediately Reportable Event: 
Office of PV Operations,  
Department of Pharmacovigilance,  
Otsuka Pharmaceutical Co., Ltd. 
 
 
 
Approval: 
04 Oct 2022 
Date of Translation: 
16 Jan 2023 
 
 
 
 

Protocol 346-102-00003 
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Approval: 04 Oct 2022 
Table of Contents 
Table of Contents ........................................................................................... 2 
List of In-text Tables ..................................................................................... 7 
List of In-text Figures .................................................................................... 8 
List of Abbreviations ..................................................................................... 9 
1 
Protocol Summary ..............................................................................11 
1.1 
Synopsis............................................................................................................ 11 
1.2 
Schema ............................................................................................................. 22 
1.3 
Schedule of Assessments.................................................................................. 23 
1.3.1 
Screening Period ............................................................................................ 25 
1.3.1.1 
Informed Consent ....................................................................................... 25 
1.3.1.2 
Screening Visit ........................................................................................... 25 
1.3.2 
Treatment Period ........................................................................................... 26 
1.3.3 
Follow-up Period ........................................................................................... 27 
1.3.4 
Discontinuation Visit ..................................................................................... 27 
2 
Introduction ........................................................................................27 
2.1 
Trial Rationale .................................................................................................. 29 
2.2 
Background ...................................................................................................... 31 
2.3 
Known and Potential Risks and Benefits ......................................................... 32 
3 
Objectives and Endpoints ..................................................................33 
4 
Trial Design .........................................................................................34 
4.1 
Type/Design of Trial ........................................................................................ 34 
4.2 
Scientific Rationale for Trial Design................................................................ 35 
4.3 
Dosing Rationale .............................................................................................. 36 
4.4 
End of Trial Definition ..................................................................................... 36 
4.5 
Definition of Completed Subjects .................................................................... 37 
5 
Trial Population ..................................................................................37 
5.1 
Subject Selection and Numbering .................................................................... 37 
5.2 
Eligibility Criteria............................................................................................. 38 
5.2.1 
Inclusion Criteria ........................................................................................... 38 
5.2.2 
Exclusion Criteria .......................................................................................... 41 

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5.3 
Lifestyle Considerations ................................................................................... 46 
5.3.1 
Meals and Dietary Restrictions ...................................................................... 46 
5.3.2 
Caffeine, Alcohol, and Tobacco .................................................................... 47 
5.3.3 
Activity .......................................................................................................... 47 
5.4 
Screen Failures ................................................................................................. 47 
6 
Trial Treatments .................................................................................49 
6.1 
Trial Treatments Administered ........................................................................ 49 
6.1.1 
Medical Devices ............................................................................................ 49 
6.2 
Management of Investigational Medicinal Product ......................................... 49 
6.2.1 
Packaging and Labeling ................................................................................. 50 
6.2.2 
Storage ........................................................................................................... 50 
6.2.3 
Accountability ................................................................................................ 50 
6.2.4 
Returns and Destruction ................................................................................ 50 
6.2.5 
Reporting of Product Quality Complaints ..................................................... 50 
6.2.5.1 
Eliciting and Reporting Product Quality Complaints ................................ 51 
6.2.5.2 
Information Required for Reporting Product Quality Complaints ............ 51 
6.2.5.3 
Return Process in Case of Product Quality Complaints ............................ 51 
6.2.5.4 
Assessment/Evaluation .............................................................................. 52 
6.2.6 
Investigational Medicinal Product Reserve Sample Requirements ............... 52 
6.3 
Measures to Minimize/Avoid Bias ................................................................... 52 
6.4 
Subject Compliance .......................................................................................... 52 
6.5 
Concomitant Medications or Therapies ........................................................... 52 
6.5.1 
Prohibited Medications .................................................................................. 53 
6.5.2 
Prohibited Therapies ...................................................................................... 54 
6.5.3 
Permitted Medications or Therapies .............................................................. 54 
6.5.4 
Rescue Medications ....................................................................................... 55 
6.6 
Intervention After the End of the Trial ............................................................. 55 
7 
Discontinuation of Trial/Treatment and Subject 
Discontinuation/Withdrawal .............................................................55 
7.1 
Entire Trial or Treatment Discontinuation ....................................................... 55 
7.2 
Individual Site Discontinuation ........................................................................ 55 
7.3 
Individual Subject Discontinuation .................................................................. 56 

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7.3.1 
Treatment Interruption ................................................................................... 56 
7.3.2 
Treatment Discontinuation ............................................................................ 56 
7.3.3 
Documenting Reasons for Treatment Discontinuation .................................. 56 
7.3.4 
Withdrawal of Consent .................................................................................. 57 
7.3.5 
Procedures to Encourage Continued Trial Participation ............................... 58 
7.4 
Definition of Subjects Lost to Follow-up ......................................................... 58 
8 
Trial Procedures .................................................................................59 
8.1 
Efficacy Assessments ....................................................................................... 59 
8.2 
Pharmacokinetic Assessments .......................................................................... 60 
8.3 
Pharmacodynamic Assessments ....................................................................... 60 
8.4 
Pharmacogenomic Assessments ....................................................................... 60 
8.5 
Biomarker Assessments ................................................................................... 60 
8.6 
Future Biospecimen Research Samples ........................................................... 60 
8.6.1 
Scope of Future Biospecimen Research ........................................................ 61 
8.6.2 
Summary of Procedures for Future Biospecimen Research Samples ........... 62 
8.6.3 
Storage of Future Biospecimen Research Samples ....................................... 62 
8.6.4 
Genomic/Genetic Analysis ............................................................................ 62 
8.6.5 
Acquisition and Withdrawal of Informed Consent for Future 
Biospecimen Research ................................................................................... 63 
8.6.6 
Disclosure of the Results of Genomic/Genetic Analysis to Subjects ............ 63 
8.7 
Safety Assessments .......................................................................................... 63 
8.7.1 
Clinical Laboratory Assessments .................................................................. 64 
8.7.2 
Physical Examination .................................................................................... 65 
8.7.3 
Vital Signs ..................................................................................................... 65 
8.7.4 
Electrocardiogram .......................................................................................... 66 
8.7.5 
Suicidality Monitoring ................................................................................... 66 
8.7.6 
Other Safety Variables ................................................................................... 66 
8.7.6.1 
Body Weight .............................................................................................. 66 
8.8 
Adverse Events ................................................................................................. 66 
8.8.1 
Definitions ..................................................................................................... 66 
8.8.2 
Eliciting and Reporting Adverse Events ........................................................ 69 
8.8.3 
Immediately Reportable Events ..................................................................... 70 
8.8.4 
Medical Device Incidents (Including Malfunctions) ..................................... 70 

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8.8.5 
Adverse Events of Special Interest ................................................................ 70 
8.8.6 
Potential Serious Hepatotoxicity ................................................................... 70 
8.8.7 
Procedure for Breaking the Blind .................................................................. 70 
8.8.8 
Follow-up of Adverse Events ........................................................................ 71 
8.8.8.1 
Follow-up of Nonserious Adverse Events ................................................. 71 
8.8.8.2 
Follow-up of Immediately Reportable Events ........................................... 71 
8.8.8.3 
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact ................................................... 72 
8.9 
Treatment of Overdose ..................................................................................... 72 
8.10 
Subject Assessment Recording ........................................................................ 72 
8.10.1 
Completion of the Subject Diary ................................................................... 72 
8.11 
Other Assessments ........................................................................................... 72 
8.11.1 
Pregnancy Test ............................................................................................... 72 
8.11.2 
Endocrine Test and Virus Test ...................................................................... 73 
9 
Statistical Considerations ..................................................................74 
9.1 
Sample Size ...................................................................................................... 74 
9.2 
Datasets for Analysis ........................................................................................ 74 
9.3 
Handling of Missing Data for Primary Endpoint Analysis .............................. 74 
9.4 
Statistical Analyses........................................................................................... 74 
9.4.1 
Efficacy Analyses .......................................................................................... 74 
9.4.1.1 
Efficacy Endpoint Analysis ....................................................................... 74 
9.4.1.2 
Other Efficacy Endpoint Analysis ............................................................. 75 
9.4.2 
Safety Analysis .............................................................................................. 75 
9.4.2.1 
Adverse Events........................................................................................... 75 
9.4.2.2 
Clinical Laboratory Data ............................................................................ 75 
9.4.2.3 
Physical Examination and Vital Signs Data............................................... 76 
9.4.2.4 
Electrocardiogram Data ............................................................................. 76 
9.4.2.5 
Other Safety Data ....................................................................................... 76 
9.4.3 
Other Analyses ............................................................................................... 77 
9.4.3.1 
Analysis of Demographic and Baseline Characteristics ............................ 77 
9.4.3.2 
Pharmacokinetic Analysis .......................................................................... 77 
9.4.3.3 
Pharmacodynamic Analysis ....................................................................... 77 
9.4.3.4 
Pharmacokinetic/Pharmacodynamic Analysis ........................................... 77 

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9.4.3.5 
Pharmacogenomic Analysis ....................................................................... 77 
9.4.3.6 
Exploratory Endpoint Analysis .................................................................. 77 
9.5 
Interim Analysis and Adaptive Design ............................................................ 77 
9.5.1 
Data Monitoring Committee .......................................................................... 77 
10 
Supporting Documentation and Operational Considerations .......78 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations ............ 78 
10.1.1 
Ethics and Responsibility .............................................................................. 78 
10.1.2 
Informed Consent .......................................................................................... 78 
10.1.3 
Confidentiality ............................................................................................... 80 
10.1.4 
Quality Control and Quality Assurance ......................................................... 80 
10.1.4.1 
Monitoring ................................................................................................. 80 
10.1.4.2 
Auditing ..................................................................................................... 80 
10.1.5 
Protocol Deviations ....................................................................................... 81 
10.1.6 
Records Management .................................................................................... 81 
10.1.6.1 
Source Documents ..................................................................................... 81 
10.1.6.2 
Data Collection........................................................................................... 82 
10.1.6.3 
File Management at the Trial Site .............................................................. 82 
10.1.6.4 
Records Retention at the Trial Site ............................................................ 83 
10.1.6.5 
Publication Authorship Requirements ....................................................... 83 
10.2 
Appendix 2: Clinical Laboratory Tests ............................................................ 85 
10.3 
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information ....................................................................................................... 86 
10.4 
Appendix 4: Protocol Amendments ................................................................. 88 
10.4.1 
Protocol Amendment(s)/Administrative Change(s) ...................................... 88 
11 
References ............................................................................................89 
 
 
 

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List of In-text Tables 
Table 1.3-1 
Schedule of Assessments .............................................................. 23 
Table 3-1 
Trial Objectives and Endpoints ..................................................... 34 
Table 6.5.1-1 
List of Prohibited Medications, Food, and Preference 
Products......................................................................................... 53 
Table 6.5.3-1 
List of Medications or Therapies Permitted Before and 
During the Trial............................................................................. 54 
Table 10.2-1 
Clinical Laboratory Assessments .................................................. 85 
 
 

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List of In-text Figures 
Figure 1.2-1 
Trial Design Schematic ................................................................. 22 
 
 

List of Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
apo B 
Apolipoprotein B 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
CK 
Creatine kinase 
Cmax 
Maximum (peak) plasma concentration of the drug 
CSR 
Clinical study report 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
estimated glomerular filtration rate 
eICF 
Electronic informed consent form 
FBR 
Future Biospecimen Research 
FOCBP 
Females of childbearing potential 
GCP 
Good Clinical Practice 
HbA1c 
Glycosylated hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein-cholesterol 
HEENT 
Head, eyes, ears, nose, throat 
hsCRP 
High-sensitivity C-reactive protein  
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
IRE 
Immediately reportable event 
IWRS 
Interactive web response system 
LDL 
Low-density lipoprotein 
LDL-C 
Low-density lipoprotein cholesterol 
MACE 
Major adverse cardiac event 
non-HDL-C 
Non-high-density lipoprotein-cholesterol 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PPAR 
Peroxisome proliferator-activated receptor 
PQC 
Product quality complaint 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
Serious adverse event 
TC 
Total cholesterol 

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Abbreviation 
Definition 
TEAE 
Treatment-emergent adverse event 
TG 
Triglyceride 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
 
 

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1 
Protocol Summary 
1.1 
Synopsis 
Name of Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
Name of Investigational Medicinal Product: 
ETC-1002 (Nonproprietary name: Bempedoic acid) 
Protocol No.: 
346-102-00003 
Protocol Title: 
A multicenter, open-label, uncontrolled, long-term trial to assess the safety and efficacy 
of ETC-1002 in patients with hyper-LDL cholesterolemia 
Protocol Lay Person Short Title: 
A long-term trial of ETC-1002 in patients with hyper-LDL cholesterolemia 
Clinical Phase: 
Phase 3 trial/Long-term trial 
Treatment/Indication: 
Hyper-low-density lipoprotein (LDL) cholesterolemia 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary Objective: 
 
To assess the safety of ETC-1002 at 180 mg 
administered for 52 weeks in patients with 
hyper-LDL cholesterolemia 
Safety Assessments: 
 
Adverse events (AEs), clinical laboratory tests, 
vital signs (blood pressure, pulse rate, and body 
temperature), body weight, physical 
examination, and 12-lead electrocardiogram 
(ECG) 
Secondary Objectives: 
 
To assess the effects of ETC-1002 at 180 mg 
administered for 52 weeks on LDL-C in 
patients with hyper-LDL cholesterolemia 
 
To assess the effects of ETC-1002 on non-
high-density lipoprotein-cholesterol (non-
HDL-C), total cholesterol (TC), 
apolipoprotein B (apo B), high-sensitivity 
C-reactive protein (hsCRP), and glycosylated 
hemoglobin (HbA1c) 
Efficacy Assessments: 
 
Percent change in low-density lipoprotein 
cholesterol (LDL-C) from baseline to Week 52 
 
Percent change in non-HDL-C, TC, apo B, 
hsCRP, and HbA1c from baseline to Week 52 
 
Proportion of subjects whose LDL-C value 
achieves the lipid management goals based on 
the risk assessment (<100 mg/dL [history of 
coronary artery disease or heterozygous familial 
hypercholesterolemia], <120 mg/dL [high risk], 
or <140 mg/dL [intermediate risk]) at Week 52 

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Objectives 
Endpoints 
Other Efficacy Assessments: 
 
To assess the effects of ETC-1002 at 180 mg 
administered for 52 weeks on HDL-C and 
triglycerides (TG) in patients with hyper-
LDL cholesterolemia 
Other Efficacy Assessments: 
 
Percent change in HDL-C and TG from 
baseline to Week 52 
 
Trial Design: 
A multicenter, open-label, uncontrolled, long-term trial 
Trial Population: 
This is a multicenter, open-label, uncontrolled, long-term trial to assess the safety and 
efficacy of ETC-1002 long term administration in patients with hyper-LDL 
cholesterolemia, who are receiving treatment for hyper-LDL cholesterolemia but have 
inadequate control and cannot achieve the lipid management goals. The trial population 
will include patients with an inadequate response to statins who cannot achieve the lipid 
management goals despite statin therapy, and patients who are determined to have 
difficulty in treatment with statins due to the occurrence of or potential for safety 
problems and cannot achieve the lipid management goals. Subjects who have completed 
the treatment period in the phase 3 confirmatory trial (Protocol No. 346-102-00002) can 
also be enrolled in this trial, as they are in the same population and their enrolment allows 
assessments of the occurrence of AEs over a longer period. 
The number of subjects starting the treatment is set at 120 to ensure that at least 
100 patients complete the treatment at Week 52. The number of patients who have 
difficulty in treatment with statins is planned to be at least 20% among the entire number 
in this trial. 
Key Inclusion/Exclusion Criteria: 
Inclusion Criteria 
<Newly enrolled subjects > 
1) Patients who have the ability to provide informed consent, and who provide 
written informed consent prior to the start of the trial 
2) Patients, either male or female, between 18 and 85 years of age, inclusive, at the 
time of informed consent 
3) Patients with inadequate response to statins or who have difficulty in treatment 
with statins as defined below 
Statins refer to atorvastatin, pitavastatin, rosuvastatin, pravastatin, simvastatin, or 
fluvastatin. 

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 Inadequate response to statins: Patients with hyper-LDL cholesterolemia who are 
currently taking or have previously taken statins, and cannot achieve the lipid 
management goals of LDL-C based on the risk assessment (see inclusion criterion 
4)), meeting any of the following a), b), or c) 
a) Patients who have been taking statins (within the approved dose range) alone 
at the same dose and regimen from at least 4 weeks before informed consent 
b) Patients who have been taking statins (within the approved dose range) and 
nonstatins at the same dose and regimen from at least 4 weeks before 
informed consent (at least 6 weeks for fibrates and selective peroxisome 
proliferator-activated receptor [PPAR]α modulators, and at least 3 months for 
proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) 
c) Patients who have previously experienced failure to achieve the lipid 
management goals of LDL-C based on the risk assessment (see inclusion 
criterion 4)) even after taking statins within the approved dose range for at 
least 4 weeks and currently, based on medical judgment, who are taking only 
nonstatins at the same dose and regimen from at least 4 weeks before 
informed consent (at least 6 weeks for fibrates and selective PPARα 
modulators and at least 3 months for PCSK9 inhibitors) 
An outline is presented below. 
 

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Category 
LDL-C during the 
screening period 
Background lipid-lowering drugs at screening 
Type of 
drugs 
Timing of the start of 
treatment:  
before informed consent 
Dose and regimen 
a) 
The lipid 
management goals of 
LDL-C based on the 
risk assessment 
cannot be achieved 
(see inclusion 
criterion 4)). 
Statins alone 
From at least 4 weeks 
before 
Same dose and 
regimen within the 
approved dose range 
b) 
Statins + 
nonstatins 
 
Fibrates, selective 
PPARα modulators: 
From at least 6 weeks 
before 
 
PCSK9 inhibitors:  
From at least 3 months 
before 
 
Statins and drugs other 
than those above:  
From at least 4 weeks 
before 
 
Statins: Same 
dose and regimen 
within the 
approved dose 
range 
 
Nonstatins: Same 
dose and regimen 
c) 
Only 
nonstatins 
 
Fibrates, selective 
PPARα modulators: 
From at least 6 weeks 
before 
 
PCSK9 inhibitors:  
From at least 3 months 
before 
 
Drugs other than the 
above:  
From at least 4 weeks 
before 
Same dose and 
regimen 
 
 Difficulty in treatment with statins: 
Of those patients with hyper-LDL cholesterolemia for whom safety problems 
have occurred while taking at least one type of statin and who experienced 
resolution of the problems after discontinuation or dose reduction, or of those 
patients who have a history of statin administration and who are judged to have 
concerns of safety problems associated with the administration or dose increase of 
statins, those who fail to achieve the lipid management goals of LDL-C based on 
the risk assessment (see inclusion criterion 4)), meeting any of the following a), 
b), or c) 
a) Patients who have been taking statins (at or below the lowest approved dose) 
alone at the same dose and regimen, from at least 4 weeks before informed 
consent 
b) Patients who have been taking statins (at or below the lowest approved dose) 
and nonstatins at the same dose and regimen, from at least 4 weeks before 
informed consent (at least 6 weeks for fibrates and selective PPARα 
modulators, and at least 3 months for PCSK9 inhibitors) 

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c) Patients who have been taking only nonstatins at the same dose and regimen 
from at least 4 weeks before informed consent (at least 6 weeks for fibrates 
and selective PPARα modulators, and at least 3 months for PCSK9 inhibitors) 
An outline is presented below. 
 
Category 
LDL-C during the 
screening period 
Background lipid-lowering drugs at screening 
Type of 
drugs 
Timing of the start of 
treatment:  
before informed consent 
Dose and regimen 
a) 
The lipid 
management goals of 
LDL-C based on the 
risk assessment 
cannot be achieved 
(see inclusion 
criterion 4)). 
Statins alone 
From at least 4 weeks 
before 
Same dose and 
regimen at (or below) 
the lowest approved 
dose 
b) 
Statins + 
nonstatins 
 
Fibrates, selective 
PPARα modulators: 
From at least 6 weeks 
before 
 
PCSK9 inhibitors:  
From at least 3 months 
before 
 
Statins and drugs other 
than those above:  
From at least 4 weeks 
before 
 
Statins: Same 
dose and regimen 
at (or below) the 
lowest approved 
dose 
 
Nonstatins: Same 
dose and regimen 
c) 
Only 
nonstatins 
 
Fibrates, selective 
PPARα modulators: 
From at least 6 weeks 
before 
 
PCSK9 inhibitors:  
From at least 3 months 
before 
 
Drugs other than the 
above:  
From at least 4 weeks 
before 
Same dose and 
regimen 
 

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4) Patients with a history or current condition meeting any of the following criteria 
1) to 3) 
Category 
History or current condition 
LDL-C during  
the screening period 
1) 
History of coronary artery disease 
≥100 mg/dL 
Heterozygous familial hypercholesterolemia (HeFH) 
2) 
Peripheral arterial disease 
≥120 mg/dL 
History of non-cardiogenic cerebral infarction 
Chronic kidney disease 
(Provided that it does not fall under exclusion criterion 12)) 
Type 2 diabetes mellitus 
(Diagnosed at least 3 months before Week −2, without falling 
under exclusion criterion 7)) 
3) 
The total score in the coronary artery disease risk prediction 
model using the Suita score specified by the Japan 
Atherosclerosis Society is ≥56 points (high risk) 
≥120 mg/dL 
The total score in the coronary artery disease risk prediction 
model using the Suita score specified by the Japan 
Atherosclerosis Society is ≥41 and ≤55 points (intermediate risk) 
≥140 mg/dL 
 
5) Patients with fasting TG levels of <400 mg/dL at Week −2 
 
< Rollover subjects from the phase 3 confirmatory trial> 
1) Patients who provide written informed consent prior to start of the trial  
2) Subjects who have completed the 12-week treatment period in the phase 3 
confirmatory trial (Protocol No. 346-102-00002), and do not meet the 
discontinuation criteria for the investigational medicinal product (IMP) at 
Week 12 
 
Exclusion Criteria 
<Newly enrolled subjects> 
1) Females who are pregnant or breast-feeding or who have a positive pregnancy test 
(urine) result at screening (Week −2) or on Day 1 
2) Sexually active and reproductive males or sexually active females of childbearing 
potential who do not agree to practice 2 different approved methods of birth 
control or to maintain complete abstinence (the methods of periodic abstinence 
and withdrawal are not appropriate for contraception) during the trial and for 
30 days after final IMP administration. If employing birth control, 2 of the 
following methods must be used: vasectomy, tubal ligation, intrauterine device, 
birth control pill, or condom (all methods are approved or certified in Japan). 
3) Patients with homozygous familial hypercholesterolemia (HoFH) 
4) Patients who currently have or who have had within the past 3 months prior to 
screening (Week −2) any of the following cardiovascular diseases, or those who 
have developed any of these AEs during the screening period 

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 Myocardial infarction, severe or unstable angina pectoris, coronary angioplasty, 
coronary artery bypass graft, stroke, transient ischemic attack, symptomatic 
carotid artery stenosis, symptomatic peripheral arterial disease, or decompensated 
heart failure 
 Abdominal aortic aneurysm 
 Patients with risk factors for torsade de pointes, such as unexplained syncope or 
long-QT syndrome, or a family history of long-QT syndrome 
5) Patients with uncontrolled hypertension, defined as follows: sitting systolic blood 
pressure of ≥160 mmHg or diastolic blood pressure of ≥100 mmHg after resting 
5 minutes at screening (Week −2) 
6) Patients with uncontrolled and serious hematologic or coagulation disorders, or 
with hemoglobin of <10.0 g/dL at screening (Week −2) 
7) Patients with uncontrolled diabetes with HbA1c of ≥9% at screening (Week −2) 
8) Patients with uncontrolled hypothyroidism with thyroid-stimulating hormone 
(TSH) of >1.5 × the upper limit of normal (ULN) at screening (Week −2) 
9) Patients with liver disease or dysfunction, including: 
 Positive serology for hepatitis B surface antigen (HBsAg) or a positive hepatitis C 
virus (HCV) antibody test at screening (Week −2) 
 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) of 
≥3 × ULN or total bilirubin of ≥2 × ULN at screening (Week −2) 
10) Patients with a history or current chronic musculoskeletal symptoms that may be 
difficult to differentiate from myalgia 
(eg, fibromyalgia) 
11) Patients with CK of >3 × ULN at screening (Week −2) 
12) Patients with a history or current renal dysfunction, nephritic syndrome, or 
nephritis and with estimated glomerular filtration rate (eGFR) of 
≤30 mL/min/1.73 m2 at screening (Week −2) 
13) Patients who have had gastrointestinal surgery that may affect drug absorption 
(eg, Lap-Band® or gastric bypass) 
14) Patients who have undergone surgery, chemotherapy, or radiation for active 
malignancy (excluding properly treated nonmetastatic basal or squamous cell 
carcinoma of the skin and cervical carcinoma in situ) within the past 5 years prior 
to screening (Week −2) 
15) Patients with a history of drug, alcohol, or cocaine abuse within the past 2 years 
prior to screening (Week −2) 
16) Patients who have had blood collection (eg, blood donation) in a cumulative 
amount exceeding 200 mL within 4 weeks, 400 mL within 12 weeks, or 1200 mL 
within 1 year prior to screening (Week −2) 
17) Patients who have used any investigational drug not approved in Japan within 
either 4 weeks or 5 times the half-life of the drug, whichever is longer, prior to 
screening (Week −2) 

Protocol 346-102-00003 
18 
Confidential - Proprietary Information 
 
Approval: 04 Oct 2022 
18) Patients who took the IMP in Trial 346-102-00001 or patients who have used 
ETC-1002 in the past 
19) Patients who used or received the following drugs (including food) or therapies 
within the specified period or who are planning to use or receive them by the end 
of the tests at Week 52 
 
Drugs (including food) or 
therapies 
Prohibition period 
1. 
Systemic corticosteroids 
From 3 months prior to Week −2 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
However, if the drug has been used with the same dose and regimen 
since 3 months prior to Week −2, it may be used concomitantly with 
no change in dose until the end of the tests at Week 52 (or to the 
completion of the assessments at Discontinuation Visit, if 
applicable) 
2. 
Lomitapide 
From 3 months prior to Week −2 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
3. 
Probenecid 
From Week −2 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
4. 
Red yeast rice and food 
containing red yeast rice 
From 2 weeks prior to Week −2 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
5. 
LDL apheresis 
From 3 months prior to Week −2 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
 
20) Patients in whom the following drugs (therapies) are changed prior to Day 1, or in 
whom initiation of the following drugs (therapies) is planned by the end of the 
tests at Week 52 
 
Drugs or therapies 
Period in which the drug or therapy cannot be changed or  
newly started 
1. 
Female or male hormone 
replacement 
From 6 weeks prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
2. 
Thyroid replacement 
From 6 weeks prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
3. 
Diabetes medications 
From 4 weeks prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
4. 
Obesity medications 
From 3 months prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
 
21) Patients otherwise judged inappropriate for participating in the trial in the opinion 
of the investigator or subinvestigator 
 

Protocol 346-102-00003 
19 
Confidential - Proprietary Information 
 
Approval: 04 Oct 2022 
<Rollover subjects from the phase 3 confirmatory trial> 
1) Females who are pregnant or breast-feeding or who have a positive pregnancy test 
(urine) result on Day 1 
2) Sexually active and reproductive males or sexually active females of childbearing 
potential who do not agree to practice 2 different approved methods of birth 
control or to maintain complete abstinence (the methods of periodic abstinence 
and withdrawal are not appropriate for contraception) during the trial and for 
30 days after final IMP administration. If employing birth control, at least 2 of the 
following methods must be used: vasectomy, tubal ligation, intrauterine device, 
birth control pill, or condom (all methods are approved or certified in Japan). 
3) Patients with any of the following AEs during the phase 3 confirmatory trial 
(Protocol No. 346-102-00002) 
 Myocardial infarction, severe or unstable angina pectoris, coronary angioplasty, 
coronary artery bypass graft, stroke, transient ischemic attack, symptomatic 
carotid artery stenosis, symptomatic peripheral arterial disease, or decompensated 
heart failure 
 Abdominal aortic aneurysm 
 Unexplained syncope or torsade de pointes-type ventricular tachycardia 
4) Patients with uncontrolled hypertension, defined as follows: sitting systolic blood 
pressure of ≥160 mmHg or diastolic blood pressure of ≥100 mmHg after resting 
for 5 minutes on Day 1 
5) Patients with uncontrolled and serious hematologic or coagulation disorders, or 
with hemoglobin of <10.0 g/dL at Week 8 in the phase 3 confirmatory trial 
(Protocol No. 346-102-00002) 
6) Patients with liver disease or dysfunction, including: 
 Patients with positive serology for HBsAg or a positive HCV antibody test by 
Week 8 in the phase 3 confirmatory trial (Protocol No. 346-102-00002) 
 Patients with AST or ALT of ≥3 × ULN or total bilirubin of ≥2 × ULN by Week 8 
in the phase 3 confirmatory trial (Protocol No. 346-102-00002) 
7) Patients with a history or current renal dysfunction, nephritic syndrome, or 
nephritis and with eGFR of ≤30 mL/min/1.73 m2 at Week 8 in the phase 3 
confirmatory trial (Protocol No. 346-102-00002) 
8) Patients who used or received the following drugs (including food) or therapies 
within the specified period or who are planning to use or receive them by the end 
of the tests at Week 52 

Protocol 346-102-00003 
20 
Confidential - Proprietary Information 
 
Approval: 04 Oct 2022 
 
Drugs (including food) or 
therapies 
Prohibition period 
1. 
Systemic corticosteroids 
From Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
However, if the drug is being used with the same dose and regimen 
as before participation during the phase 3 confirmatory trial, it may 
be used concomitantly with no change in dose, until the end of the 
tests at Week 52 (or to the completion of the assessments at 
Discontinuation Visit, if applicable) 
2. 
Lomitapide 
From Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
3. 
Probenecid 
From Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
4. 
Red yeast rice and food 
containing red yeast rice 
From Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
5. 
LDL apheresis 
From Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
 
9) Patients in whom the following drugs (therapies) are changed prior to Day 1 or in 
whom initiation of the following drugs (therapies) is planned by the end of the 
tests at Week 52 
 
Drugs or therapies 
Period in which the drug or therapy cannot be changed or  
newly started 
1. 
Female or male hormone 
replacement 
From 6 weeks prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
2. 
Thyroid replacement 
From 6 weeks prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
3. 
Diabetes medications 
From 4 weeks prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
4. 
Obesity medications 
From 3 months prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
 
10) Patients otherwise judged inappropriate for participating in the trial in the opinion 
of the investigator or subinvestigator 
 
Trial Sites: 
Approximately 30 sites in Japan 

Protocol 346-102-00003 
21 
Confidential - Proprietary Information 
 
Approval: 04 Oct 2022 
Investigational Medicinal Product, Dose, Dosage Regimen, Treatment Duration, 
Formulation, and Mode of Administration: 
Subjects who proceed to the treatment period will orally receive ETC-1002 180-mg 
tablets once daily for 52 weeks. Administration of lipid-lowering drugs used before 
informed consent should be continued without changing the type or dose and regimen. 
Trial Assessments: 
Assessments for Efficacy: LDL-C, HDL-C, non-HDL-C, TC, TG, apo B, hsCRP, and 
HbA1c 
Trial Assessments for Future Biospecimen Research (FBR): DNA sample storage 
(optional) 
Assessments for Safety: Adverse events, clinical laboratory tests, physical examination, 
vital signs (blood pressure, pulse rate, and body temperature), 12-lead ECG, and body 
weight 
Screening/Other: Demographics, height, medical history, prior medications, virus test 
(HBsAg and HCV antibodies), endocrine test (TSH), and pregnancy test (urine, serum) 
Data Monitoring Committee: No 
Statistical Methods: 
Safety Analysis 
The incidence of treatment-emergent AEs will be calculated. Other safety assessments 
will be summarized using descriptive statistics, shift tables, etc. 
Sample Size 
The target number of subjects is set at 120 to ensure that 100 subjects will complete the 
1-year treatment to assess the safety of ETC-1002 in long-term administration. 
Trial Duration: 
Each subject in this trial is expected to participate in the following periods of the trial: 
 Screening period (2 weeks) 
 Treatment period (52 weeks) 
 Follow-up period (4 weeks) 
 
Overall, the trial duration from signing of the first informed consent form (ICF) to the 
end date of the follow-up period of the final subject assessment is expected to be 
approximately 20 months. 

Protocol 346-102-00003 
 
22 
Confidential - Proprietary Information 
Approval: 04 Oct 2022 
1.2 
Schema 
 
Figure 1.2-1 
Trial Design Schematic 
 
Screening Period
(2 weeks)
Visit
Week
−2
Week
0
Week
4
Week
8
Week
12
Week
16
Week
20
Week
24
Week
28
Week
32
Week
36
Week
40
Week
44
Week
48
Week
52
Week
56
 [Rollover subjects from Trial 346-102-00002 will proceed directly to the treatment period of this trial (52 weeks, open-label) after
completing the 12-week double-blind treatment period.]
(Start of trial)
Treatment Period
(52 weeks, Open-label)
Follow-up Period
(4 weeks)
ETC-1002  180 mg
Lipid-lowering drugs: Type and dose/regimen fixed
Modifiable
Start of 
IMP dosing
End of 
treatment
(End of trial: 
28 days after the final 
IMP administration)

Protocol 346-102-00003 
 
23 
Confidential - Proprietary Information 
Approval: 04 Oct 2022 
1.3 
Schedule of Assessments 
Table 1.3-1 
Schedule of Assessments 
 
Screening Period 
Treatment Period 
Follow-up Period 
(28 days after the 
final IMP 
administration) 
Rollover 
Subjects 
Newly 
Enrolled 
Subjects 
Visit (Week) 
−4a 
−2 
0b 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52/ 
Discontinuationc 
56 
Trial Day 
−28 ± 3 
−14 ±7 
1 
29 ± 7 57 ± 7 85 ± 7 113 ± 7 141 ± 7 169 ± 7 197 ± 7 225 ± 7 253 ± 7 281 ± 7 309 ± 7 337 ± 7 
365 ± 7 
393 ± 7 
Informed consentd 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility assessment 
● 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Body weight 
 
● 
● 
● 
 
● 
 
● 
● 
● 
 
● 
 
● 
 
● 
● 
Endocrine test (TSH), 
virus test (HBsAg, 
HCV antibody) 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signse 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
12-Lead ECGf 
 
● 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
 
● 
 
Clinical laboratory 
testsg 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Fasting lipidsh, i 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
HbA1ci 
 
● 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
 
● 
 
hsCRP, apo Bi 
 
 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
 
● 
 
Confirmation of use 
of concomitant 
medications/therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testj 
 
● 
● 
 
 
● 
 
 
● 
 
 
● 
 
 
 
● 
 
Blood sampling for 
DNA storage k 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensing of IMP 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
Provision of subject 
diary 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
Collection of unused 
IMP and subject diary 
 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
● Mandatory; ○ Optional 

Protocol 346-102-00003 
24 
Confidential - Proprietary Information 
 
Approval: 04 Oct 2022 
aThe results of the scheduled tests performed at Week 8 in the phase 3 confirmatory trial (Protocol No. 346-102-00002) will be used. 
bBody weight and 12-lead ECG will not be required on Day 1 if they have been performed within 7 days prior to Day 1 in the screening period. The results of 
the scheduled tests performed at Week 12 in the phase 3 confirmatory trial (Protocol No. 346-102-00002) will be used for rollover subjects. 
cIn cases of early discontinuation during the treatment period, the same assessments as in Week 52 are to be performed at Discontinuation Visit within 2 days 
after the last dose of the IMP as far as possible. 
dWritten informed consent will be obtained from the patient himself/herself prior to any trial-related assessments. Written informed consent will be obtained 
by Week −2 for newly enrolled subjects, and by Week 12, but on or after Week 8 in the phase 3 confirmatory trial (Protocol No. 346-102-00002) for 
rollover subjects (before the start of Day 1 of this trial). 
eBody temperature, blood pressure, and pulse rate measurements are to be performed after resting for at least 5 minutes. Vital signs should be measured before 
blood collection whenever possible to minimize effects on the assessment. 
f12-Lead ECG is to be performed after resting for at least 10 minutes. The 12-lead ECG should be performed before blood collection whenever possible to 
minimize effects on the assessment. 
gClinical laboratory tests include hematology, blood chemistry (except for HbA1c, fasting lipid assessments), and urinalysis. 
hFasting lipid assessments include LDL-C, HDL-C, non-HDL-C, TC, and TG. 
iOn scheduled visit days, subjects are to be instructed to come to the trial site without taking the IMP and reminded to take the IMP after tests are completed. 
jPregnancy test is to be performed only for females of childbearing potential. If urine test is positive, the serum test will be performed (except Week −2). 
k Blood sampling for DNA storage will only be performed for subjects who provide written consent for sample collection. Blood sampling for DNA storage 
will be performed before IMP administration on Day 1 in principle. If blood sampling cannot be performed or needs to be performed again, it will be 
performed at a feasible time during the trial period. 

Protocol 346-102-00003 
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Confidential - Proprietary Information 
 
Approval: 04 Oct 2022 
1.3.1 
Screening Period 
1.3.1.1 
Informed Consent 
Prior to starting any assessments at screening, written informed consent will be obtained 
from the patients themselves. After informed consent is obtained, each subject will be 
given a subject identification number and registered in the Interactive Web Response 
System (IWRS). Operation of the IWRS after the initial registration will be separately 
specified in the procedure as a system to manage the registration status of subjects and 
the investigational medicinal product (IMP). The investigator or subinvestigator will 
enter the subject identification number and the date of informed consent in the subject 
screening log. The subject identification number and the date of informed consent will 
also be recorded in the source document and the electronic case report form (eCRF). 
For DNA sample storage, written informed consent will be obtained from the subjects 
themselves using a separate informed consent form (ICF), and the date of informed 
consent will be recorded in the source document and the eCRF. DNA sample storage is 
optional and will not impact the subject’s participation in the trial if the subject does not 
consent. 
For rollover subjects, written informed consent will be obtained from the patients 
themselves by Week 12, but on or after Week 8 of the phase 3 confirmatory trial 
(Protocol No. 346-102-00002). The rollover subjects participating in DNA sample 
storage in the confirmatory trial will not be able to provide informed consent for DNA 
sample storage in this trial. 
 
1.3.1.2 
Screening Visit 
After obtaining informed consent, the investigator or subinvestigator will perform the 
observation and assessments at Week −4 (rollover subjects) or Week −2 (newly enrolled 
subjects) specified in Table 1.3-1, record the results in the source document and the eCRF 
with the visit date, and enter the required information in the IWRS. After judging the 
eligibility for participation in the trial, the investigator or subinvestigator will record the 
eligibility for enrollment, date of enrollment, and reasons in the case of non-enrollment in 
the subject screening log. Re-testing during the screening period will be permitted in 
terms of eligibility assessment. 
The investigator or subinvestigator will investigate the following information and record 
it in the source document and the eCRF. 

Protocol 346-102-00003 
26 
Confidential - Proprietary Information 
 
Approval: 04 Oct 2022 
 Demographics (collection date, birth date, sex, possibility of pregnancy, race, 
ethnicity, and country) 
 Height (in units of 0.1 cm) 
 Past medical history (within 1 year before informed consent, but this limitation is not 
applicable to those related to the inclusion and exclusion criteria) 
 Current condition (at the time of informed consent) 
 History of hypercholesterolemia 
History of Hypercholesterolemia: Investigation Item 
 
Name of diagnosis 
 
Date of diagnosis 
 
Presence or absence of familial hypercholesterolemia 
 
Classification and details of classification (according to the flowchart using the Suita score in the 
Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 
2017,1 and according to the flowchart using the score of the Hisayama Study in the Guidelines 
20222) 
 
Statin response (inadequate response to statins/difficulties in treatment with statins) 
 
For patients with difficulties in treatment with statins: Reasons for judging that treatment with 
statins is difficult and the name/daily dose of the statin 
 
<Information obtained during the screening period> 
 Prior lipid-lowering drugs received within 6 weeks prior to informed consent 
 Therapeutic drugs for diabetes mellitus used within 10 weeks prior to informed 
consent 
 All prior medications and prior therapies received within 4 weeks prior to informed 
consent 
 Result of eligibility assessment 
 
1.3.2 
Treatment Period 
The investigator or subinvestigator will determine whether or not a subject can proceed to 
the treatment period based on the results of the observation and assessments on Day 1 
specified in Table 1.3-1, record the result in the source document and the eCRF, and enter 
the determination result in the IWRS. If a subject who is determined to be eligible for 
proceeding to the treatment period has been receiving a lipid-lowering drug since before 
informed consent, the subject should continue the drug at the same dose and regimen in 
addition to taking ETC-1002 at 180 mg/day for 52 weeks. 
The observation and assessments specified in Table 1.3-1 will be performed during the 
treatment period, and the results will be recorded in the source document and the eCRF 

Protocol 346-102-00003 
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Approval: 04 Oct 2022 
with the visit date. The investigator or subinvestigator will enter the required information 
in the IWRS at each visit for each subject. 
For subjects who are concomitantly using proprotein convertase subtilisin/kexin type 9 
(PCSK9) inhibitors, all scheduled visits during the treatment period will be set within 
48 hours before the scheduled date and time for subsequent doses of PCSK9 inhibitor. 
 
1.3.3 
Follow-up Period 
The investigator or subinvestigator will perform the observation and assessments 
specified in Table 1.3-1 at the visit 28 days (±7 days) after the last IMP administration to 
all the subjects who proceed to the treatment period and record the results in the source 
document and the eCRF with the visit date. The investigator or subinvestigator will enter 
the required information in the IWRS at the end of the follow-up period for each subject. 
 
1.3.4 
Discontinuation Visit 
When the subject discontinues during the treatment period, the investigator or 
subinvestigator will perform the same assessments as performed at Week 52 (see 
Table 1.3-1) at Discontinuation Visit within 2 days after the last dose of the IMP as much 
as possible and record the results in the source document and the eCRF with the visit 
date. The investigator or subinvestigator will enter the required information in the IWRS 
at the time of discontinuation for each subject. 
 
2 
Introduction 
Dyslipidemia is defined as a condition in which low-density lipoprotein cholesterol 
(LDL-C), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) in the 
blood are outside the reference values. Since these abnormalities are primarily associated 
with the incidence of coronary artery disease, prophylaxis and subsequent treatment are 
considered critical. In addition, with the recent westernization of food, the number of 
patients with dyslipidemia is increasing each year in Japan, and currently stands at 
approximately 2.2 million.3 Hyper-LDL cholesterolemia, which is one of the forms of 
dyslipidemia, refers to the state of having high LDL-C levels in the blood. If left 
untreated, this condition is considered as one of the most significant risk factors 
associated with the development and progression of arteriosclerosis. Drugs currently 
launched in Japan for the treatment of hyper-LDL cholesterolemia include 3-hydroxy-3-

Protocol 346-102-00003 
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Approval: 04 Oct 2022 
methylglutaryl-coenzyme A reductase inhibitors (various statins), small intestine 
cholesterol transporter inhibitors (ezetimibe), and human anti-proprotein convertase 
subtilisin/kexin type 9 (PCSK9) monoclonal antibody formulations (evolocumab). 
Several large-scale clinical trials have demonstrated the usefulness of these drugs for the 
primary and secondary prevention of coronary artery disease.4,5,6,7,8 Japanese and non-
Japanese guidelines1,9,10 place statins as the first-line drug, and statins have been used for 
the treatment of hyper-LDL cholesterolemia. LDL-C can be controlled with statins in 
many patients. However, in some patients with a history of coronary artery disease or 
patients with familial hypercholesterolemia who require strict control of LDL-C, 
treatment with statins alone is often not able to achieve the lipid management goals of 
LDL-C based on the risk assessment for the primary and secondary prevention of 
coronary artery disease specified in Japan Atherosclerosis Society Guidelines for 
Prevention of Atherosclerotic Cardiovascular Diseases 2017.1 In such cases, combination 
therapy using drugs with mechanisms of action different from statins is performed. 
However, the fact that there are a certain number of patients with poorly controlled 
LDL-C who cannot achieve the lipid management goals remains an issue for current drug 
therapy. Statin intolerance, which requires a dose reduction or interruption of statins due 
to myopathy or hepatic impairment caused by statin therapy, is observed in some 
patients. According to the Statin Intolerance Clinical Guide 2018,11 statin intolerance is 
defined as “in the individual case treated with statins for the first time, in whom statin 
continuation becomes difficult due to an adverse event upon initial statin administration, 
and those adverse events were again observed by at least one another statin.” The 
guideline recommends dose reduction or discontinuation of statins, switching to other 
statins, or administration of nonstatins, depending on the severity of adverse events 
(AEs), if myopathy (subjective symptoms such as myalgia, twitching, stiffness, 
discomfort, or muscle weakness, laboratory abnormalities such as creatine kinase [CK] 
elevation, or rarely rhabdomyolysis), or hepatic impairment such as transaminase 
elevations occurs during statin therapy. Thus, there is a need for a therapeutic drug with a 
new mechanism of action for patients whose LDL-C cannot be adequately controlled by 
drug therapy mainly with statin alone or in combination with other drugs or patients 
whose LDL-C cannot be adequately controlled due to statin intolerance. 
ETC-1002 (nonproprietary name: bempedoic acid) is a drug with a new mechanism of 
action that inhibits cholesterol and fatty acid synthetic pathways by acting on adenosine 
triphosphate citrate lyase, an enzyme degrading citric acid in the cholesterol biosynthetic 
pathway in the liver. Esperion Therapeutics, Inc. has been developing the drug in 
countries other than Japan. In clinical trials conducted outside Japan in patients with 

Protocol 346-102-00003 
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Confidential - Proprietary Information 
 
Approval: 04 Oct 2022 
hyper-LDL cholesterolemia, administration of add-on ETC-1002 to patients who are not 
adequately controlled with their maximally tolerated statins resulted in a significant 
decrease in LDL-C levels compared with the placebo group. Treatment with ETC-1002 
also significantly reduced LDL-C levels in patients with statin-intolerant hyper-LDL 
cholesterolemia compared with placebo. No particular safety concern has been identified 
in the clinical trials that have been conducted to date. Based on the results of clinical 
trials conducted outside Japan, ETC-1002 has already been approved and marketed for 
the treatment of hyper-LDL cholesterolemia in the US in February 2020 and in Europe in 
April 2020. In addition, a large-scale cardiovascular outcome trial is currently ongoing to 
assess whether long-term treatment with ETC-1002 at 180 mg reduces the risk of major 
adverse cardiovascular events (MACE) in statin-intolerant patients with or at a high risk 
of atherosclerotic cardiovascular disease. 
Otsuka Pharmaceutical Co., Ltd. (hereinafter referred to as “Otsuka”) has obtained the 
development and marketing rights in Japan from Esperion Therapeutics, Inc. and started 
development in Japan, in the expectation that ETC-1002 can be a new treatment option 
for Japanese patients with hyper-LDL cholesterolemia in whom LDL-C values cannot be 
adequately controlled with existing statin-based therapy. A phase 2 dose-finding trial 
(Protocol No. 346-102-00001) conducted to assess the efficacy, dose-response, and safety 
in Japanese patients and determine the dose used in the phase 3 trial has already been 
concluded. 
For further information, please refer to the ETC-1002 Investigator’s Brochure (IB). 
 
2.1 
Trial Rationale 
Thus far, the efficacy of ETC-1002 has been demonstrated in several phase 3 placebo-
controlled, double-blind trials and long-term trials conducted outside Japan in patients 
with hyper-LDL cholesterolemia (Trials 1002-040, 1002-046, 1002-047, and 1002-048), 
and it has been confirmed that there are no particular safety concerns. In addition, the 
results of the phase 1 trial in healthy Japanese and non-Japanese adults living outside 
Japan showed that Cmax and AUC in Japanese subjects were approximately 1.2 fold and 
1.4 fold those in white subjects, respectively. Although the Cmax and AUC in Japanese 
subjects were slightly higher than those in white subjects, it has been demonstrated that 
there was no safety problem and that ETC-1002 was well-tolerated when administered at 
up to 180 mg/day to healthy Japanese adults. 
In Japan, a phase 2 dose-finding trial (Protocol No. 346-102-00001) was conducted in 
188 patients with hyper-LDL cholesterolemia to investigate the efficacy, dose-response, 

Protocol 346-102-00003 
30 
Confidential - Proprietary Information 
 
Approval: 04 Oct 2022 
and safety of ETC-1002 at 60 mg/day, 120 mg/day, 180 mg/day, and placebo. The 
percent change (least squares mean) in LDL-C from baseline to Week 12, which was the 
primary endpoint, was −10.59% in the ETC-1002 60-mg group, −21.85% in the 120-mg 
group, and −21.26% in the 180-mg group versus −1.92% in the placebo group. The 
percent changes were significantly high in all of the ETC-1002 groups (p < 0.001 in the 
120-mg and 180-mg groups, and p = 0.002 in the 60-mg group). The incidence of AEs 
was 56.7% (80/141 subjects) in the ETC-1002 group versus 38.3% (18/47 subjects) in the 
placebo group. Adverse events that occurred in 5% or more of subjects in the ETC-1002 
group were pyrexia (7.1% [10/141 subjects]), malaise (5.0% [7/141 subjects]), hepatic 
function abnormal (5.0% [7/141 subjects]), arthralgia (5.0% [7/141 subjects]), and 
headache (5.0% [7/141 subjects]). All of these events had already been observed in the 
phase 3 trials conducted outside Japan. All AEs were mild or moderate in severity with 
no severe events. Serious adverse events (SAEs) were reported in 2 subjects (in the 
180-mg group [calculus urinary] and the placebo group [dental cyst]). However, both 
events were considered to be unrelated to the IMPs. The incidence of AEs in the 
ETC-1002 group was 58.3% (28/48 subjects) in the 180-mg group, 54.3% 
(25/46 subjects) in the 120-mg group, and 57.4% (27/47 subjects) in the 60-mg group, 
showing comparable incidences in all groups. There were no events whose incidence 
increased markedly in a dose-dependent manner. There were no clinically significant 
changes in clinical laboratory test values, vital signs, or 12-lead electrocardiogram (ECG) 
parameters in any of the treatment groups. 
The subgroup analysis by statin response (inadequate response to statins, statin 
intolerance) demonstrated that the percent change (least squares mean) in LDL-C from 
baseline to Week 12 was −5.48%, −18.13%, and −16.31% in the ETC-1002 60, 120, and 
180-mg groups, respectively, versus −0.29% in the placebo group among subjects with 
inadequate response to statins; and −20.43%, −27.44%, and −31.25% in the ETC-1002 
60, 120, and 180-mg groups, respectively, versus +1.00% in the placebo group among 
subjects with statin intolerance. These results showed higher efficacy in the ETC-1002 
120 and 180-mg groups than in the 60-mg group in both subject populations. The 
incidence of AEs was 54.5% (61/112 subjects) in the ETC-1002 group versus 35.1% 
(13/37 subjects) in the placebo group among subjects with inadequate response to statins, 
and 65.5% (19/29 subjects) in the ETC-1002 group versus 50.0% (5/10 subjects) in the 
placebo group among subjects with statin intolerance. There was no considerable 
difference in the tendency of the incidence of AEs between subjects with inadequate 
response to statins and those with statin intolerance. 

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Meanwhile, a large-scale cardiovascular outcomes trial is currently 
ongoing to evaluate the effect of ETC-1002 at 180 mg on lowering the risk of MACE in 
patients with hyper-LDL cholesterolemia, and the results will be available in the future. 
 
Based on the above results, ETC-1002 was considered to be a treatment option with a 
new mechanism of action for patients with hyper-LDL cholesterolemia who are receiving 
treatment for hyper-LDL cholesterolemia but cannot achieve the lipid management goals 
due to inadequate control. Therefore, this clinical protocol has been planned as a phase 3 
long-term trial to evaluate the safety and efficacy of ETC-1002 at 180 mg/day 
administered for 52 weeks in Japanese patients with hyper-LDL cholesterolemia. 
 
2.2 
Background 
Efficacy data supporting the indication of LDL-C reduction have been obtained from 4 
phase 3 and 10 phase 2 trials of ETC-1002 in trials conducted outside Japan. In these 
trials, the once-daily administration of ETC-1002, added to a maximum tolerated dose of 
statins (including no statin) and/or other therapeutics for hyper-LDL cholesterolemia 
(ezetimibe or PCSK9 inhibitors) resulted in a significant reduction of LDL-C from 
baseline in patients with hyper-LDL cholesterolemia (including those at high 
cardiovascular risk). 
Overall, ETC-1002 has an acceptable safety profile in 
combination with other LDL-C lowering therapies (including statins, ezetimibe, or 

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PCSK9 inhibitors) in a variety of patient populations. Available data thus far also show 
that ETC-1002 can be safely administered over a prolonged period in patients on statin 
treatment of the maximum tolerated dose. 
Single-dose and multiple-dose trials were conducted in Japanese and non-Japanese (white 
and Chinese) healthy adult subjects living outside Japan to assess the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of ETC-1002, and to determine whether there 
were differences in pharmacokinetics and pharmacodynamics between Japanese, white, 
and Chinese races. The results showed no significant differences in the mean plasma 
concentration over time between Japanese and white subjects following repeated 
administration of 180 mg of ETC-1002. The geometric mean Cmax and AUC in Japanese 
subjects were approximately 1.2 fold and 1.4 fold those in white subjects, respectively. 
Although the geometric mean Cmax and AUC in Japanese subjects were slightly higher 
than those in white subjects, no significant difference was observed. There were no SAEs 
or AEs leading to discontinuation and all AEs were mild in severity. It was demonstrated 
that there was no significant safety problem and that ETC-1002 at 180 mg/day was well-
tolerated when administered to healthy Japanese adults. 
In Japan, a dose-finding trial (Protocol No. 346-102-00001) of ETC-1002 as a phase 2 
trial was conducted in patients with hyper-LDL cholesterolemia to investigate the 
efficacy and safety of ETC-1002 at 60 mg/day, 120 mg/day, 180 mg/day, and placebo. 
The results verified the efficacy and safety of ETC-1002 at up to 180 mg/day in Japanese 
patients with hyper-LDL cholesterolemia. 
While a phase 3 confirmatory trial (Protocol No. 346-102-00002) has been designed 
based on the results of the phase 2 dose-finding trial, the present clinical trial has been 
planned to assess the safety and efficacy of ETC-1002 at 180 mg/day administered for 
52 weeks in Japanese patients. 
 
2.3 
Known and Potential Risks and Benefits 
In a drug-interaction trial conducted outside Japan, administration of ETC-1002 at 
180 mg/day increased the exposure to simvastatin lactone approximately 1.2 to 1.3 fold 
and the exposure to simvastatin hydroxy acid approximately 2 fold. 
 

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Serum uric acid increased was observed in the clinical trials conducted outside Japan. In 
pooled data from the phase 3 placebo-controlled trials, mean uric acid levels increased 
within the first 1 month, and then remained stable and returned to baseline in subjects 
who discontinued ETC-1002 for any reason. Serum uric acid increased may have been 
caused by inhibition of renal tubular organic anion transporter 2 by ETC-1002. Gout was 
reported in 1.4% of subjects receiving ETC-1002 and 0.4% of subjects receiving placebo. 
The slightly higher incidence of gout in the ETC-1002 group may be due to increased 
uric acid caused by ETC-1002. 
Although gout did not occur in the Japanese phase 2 trial, blood uric acid increased was 
observed in 6 subjects (4.3%) and hyperuricaemia was observed in 5 subjects (3.5%) in 
the ETC-1002 groups. However, uric acid levels decreased rapidly after discontinuation 
in all subjects. Increased uric acid levels as an AE may cause gout, and is considered to 
be a significant potential risk. 
The results of the clinical trials conducted outside Japan and the Japanese phase 2 trial 
have demonstrated that ETC-1002 at 180 mg/day was effective in patients with 
inadequate response to statins or statin intolerance. For safety, ETC-1002 was tolerated at 
up to 180 mg/day with no tendency for an increased incidence of AEs in a dose-
dependent manner. In addition, the incidence of muscle-related AEs or AEs associated 
with hepatic impairment, which are considered to be risk factors affecting drug 
adherence, was not significantly different from those in the placebo group. In the long-
term trials conducted outside Japan, no new safety signals were identified for the long-
term administration of ETC-1002 with the efficacy continuing to the end of the trial. 
ETC-1002 can be a useful treatment for patients with hyper-LDL cholesterolemia who 
need to continue long-term therapy for hyper-LDL cholesterolemia. 
Once the IB is revised, the revised version will be provided to the trial sites. The trial 
sites should refer to the most current version provided as needed. 
 
3 
Objectives and Endpoints 
The objectives and endpoints of this trial are shown in Table 3-1. 
 

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Table 3-1 
Trial Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objective: 
 
To assess the safety of ETC-1002 at 180 mg 
administered for 52 weeks in patients with 
hyper-LDL cholesterolemia 
Safety Assessments: 
 
Adverse events, clinical laboratory tests, vital 
signs (blood pressure, pulse rate, and body 
temperature), body weight, physical 
examination, and 12-lead ECG 
Secondary Objectives: 
 
To assess the effects of ETC-1002 at 180 mg 
administered for 52 weeks on LDL-C in 
patients with hyper-LDL cholesterolemia 
 
To assess the effects of ETC-1002 on non-
high-density lipoprotein-cholesterol (non-
HDL-C), total cholesterol (TC), 
apolipoprotein B (apo B), high-sensitivity 
C-reactive protein (hsCRP), and glycosylated 
hemoglobin (HbA1c) 
Efficacy Assessments: 
 
Percent change in low-density lipoprotein 
cholesterol (LDL-C) from baseline to 
Week 52 
 
Percent change in non-HDL-C, TC, apo B, 
hsCRP, and HbA1c from baseline to Week 52 
 
Proportion of subjects whose LDL-C value 
achieves the lipid management goals based on 
the risk assessment (<100 mg/dL [history of 
coronary artery disease or heterozygous 
familial hypercholesterolemia], <120 mg/dL 
[high risk], or <140 mg/dL [intermediate risk]) 
at Week 52 
Other Efficacy Assessments: 
 
To assess the effects of ETC-1002 at 180 mg 
administered for 52 weeks on HDL-C and 
triglycerides (TG) in patients with hyper-LDL 
cholesterolemia 
Other Efficacy Assessments: 
 
Percent change in HDL-C and TG from 
baseline to Week 52 
 
Section 9.4 describes the statistical analysis of the endpoints. 
 
4 
Trial Design 
4.1 
Type/Design of Trial 
This is a Japanese, multicenter, open-label, uncontrolled, phase 3 long-term trial to assess 
the safety and efficacy of ETC-1002 long-term administration in patients with hyper-
LDL cholesterolemia who are being treated for hyper-LDL cholesterolemia but have 
inadequate control and cannot achieve the lipid management goals. The trial population 
will include patients with an inadequate response to statins who cannot achieve the lipid 
management goals despite statin therapy, and patients who are determined to have 
difficulty in treatment with statins and cannot achieve the lipid management goals. 
Patients with difficulty in treatment with statins are defined as those who cannot achieve 
the lipid management goals for the following reasons: patients who have experienced 
safety problems caused by statin administration which resolved after discontinuation or 
dose reduction, or patients who have a history of statin administration and are judged to 
have concerns of safety problems associated with the administration or dose increase of 

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Approval: 04 Oct 2022 
statins. In addition, subjects who have completed the treatment period in the phase 3 
confirmatory trial (Protocol No. 346-102-00002) can also be enrolled in this trial, as they 
are in the same population and their enrollment allows assessments of the occurrence of 
AEs over a longer period. 
A schematic of the trial design is presented in Figure 1.2-1. 
This trial consists of the screening period, the treatment period, and the follow-up period. 
Subjects who are judged to be eligible at screening will proceed to the treatment period. 
Subjects proceeding to the treatment period who have been receiving treatment using 
lipid-lowering drugs since before informed consent should continue the treatment without 
changing the type or dose and regimen in addition to being orally administered 
ETC-1002 at 180 mg once daily for 52 weeks. 
 
4.2 
Scientific Rationale for Trial Design 
This trial has been planned as an open-label trial with the primary objective of assessing 
the safety of ETC-1002 for 52 weeks in patients with hyper-LDL cholesterolemia based 
on “The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for 
Long-term Treatment of Non-Life-Threatening Conditions (PAB/ELD Notification No. 
592 dated 24 May 1995).” The trial population will include patients with hyper-LDL 
cholesterolemia with inadequate response to statins or difficulty in treatment with statins 
who cannot achieve the lipid management goals specified in the Japan Atherosclerosis 
Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017,1 and 
who are expected to similarly respond to ETC-1002 based on the results observed in the 
previous trials conducted outside Japan and the Japanese phase 2 trial. 
Warnings for hyperuricaemia and tendon rupture are provided in the non-Japanese 
package insert for ETC-1002. In the Japanese phase 2 trial, AEs related to 
hyperuricaemia (all events were moderate or lower in severity) also occurred in 7.8% 
(11/141 subjects) of the Japanese subjects treated with ETC-1002. Furthermore, the 
results of clinical trials conducted outside Japan have shown that the concomitant use of 
ETC-1002 with statins increases exposure to the statins. Based on the above, laboratory 
values such as uric acid and CK levels will be monitored regularly to minimize safety 
risks in the subjects during the trial. In addition, although tendon rupture did not occur in 
the Japanese phase 2 trial, it is considered necessary to continue to evaluate this AE in 
long-term administration as an AE of special interest in this trial. 

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Taken together, the trial design has been determined to be scientifically and ethically 
rational as the design can be feasibly implemented, while also ensuring the safety of the 
subjects. 
 
4.3 
Dosing Rationale 
 
 
 
 
 
4.4 
End of Trial Definition 
The “end of trial date” is defined as the “last date of visit/contact” or the “date of final 
contact attempt” recorded on the page of the post-treatment follow-up in the eCRF for the 
last subject completing or withdrawing from the trial. 
 

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4.5 
Definition of Completed Subjects 
The treatment period is defined as the time period during which subjects are evaluated for 
the primary and/or secondary objectives of the trial irrespective of whether or not the 
subject was administered all doses of the IMP. For purposes of this trial, subjects who 
complete the 52 weeks of treatment with ETC-1002 and the Week 52 assessment will be 
defined as trial completers. 
 
5 
Trial Population 
This trial will include Japanese patients with hyper-LDL cholesterolemia aged 18 years 
or older at the time of informed consent and with an inadequate response to statins or 
difficulty in treatment with statins, who cannot achieve the lipid management goals 
specified in the Japan Atherosclerosis Society Guidelines for Prevention of 
Atherosclerotic Cardiovascular Diseases 2017.1 Subjects who are determined to be 
eligible by the investigator or subinvestigator in the screening period will proceed to the 
treatment period. The subjects who have completed the treatment period in the phase 3 
confirmatory trial (Protocol No. 346-102-00002) can also be enrolled in this trial, as they 
are in the same population. Such subjects who are determined to be eligible based on the 
results of the scheduled tests at Week 8, after obtaining written informed consent for 
participation in this trial following Week 8, will proceed to the treatment period of this 
trial and start receiving the IMP, ETC-1002 at 180 mg for this trial, after completion of 
the Week 12 assessments. The number of subjects starting the treatment is set at 120 to 
ensure that at least 100 patients will complete the treatment at Week 52. The number of 
patients who have difficulty in treatment with statins is planned to be at least 20% among 
the entire number in this trial. 
 
5.1 
Subject Selection and Numbering 
 
 
 

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5.2 
Eligibility Criteria 
Exceptions for eligibility criteria will not be permitted during the trial, neither by the 
investigator nor by the subinvestigator. 
 
5.2.1 
Inclusion Criteria 
Subjects are required to meet the following inclusion criteria when assessed: 
 Newly Enrolled Subjects 
1) Patients who have the ability to provide informed consent and who provide 
written informed consent prior to the start of the trial 
2) Patients, either male or female, between 18 and 85 years of age, inclusive, at the 
time of informed consent 
3) Patients with inadequate response to statins or who have difficulty in treatment 
with statins as defined below 
Statins refer to atorvastatin, pitavastatin, rosuvastatin, pravastatin, simvastatin, or 
fluvastatin. 
 Inadequate response to statins: Patients with hyper-LDL cholesterolemia who are 
currently taking or have previously taken statins, and cannot achieve the lipid 
management goals of LDL-C based on the risk assessment (see inclusion criterion 
4)), meeting any of the following a), b), or c) 
a) Patients who have been taking statins (within the approved dose range) alone 
at the same dose and regimen from at least 4 weeks before informed consent 
b) Patients who have been taking statins (within the approved dose range) and 
nonstatins at the same dose and regimen from at least 4 weeks before 
informed consent (at least 6 weeks for fibrates and selective peroxisome 
proliferator-activated receptor [PPAR]α modulators, and at least 3 months for 
proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) 
c) Patients who have previously experienced failure to achieve the lipid 
management goals of LDL-C based on the risk assessment (see inclusion 
criterion 4)) even after taking statins within the approved dose range for at 
least 4 weeks and currently, based on medical judgment, who are taking only 
nonstatins at the same dose and regimen from at least 4 weeks before 
informed consent (at least 6 weeks for selective PPARα modulators, and at 
least 3 months for PCSK9 inhibitors) 
An outline is shown below. 

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Category 
LDL-C during the 
screening period 
Background lipid-lowering drugs at screening 
Type of 
drugs 
Timing of the start of 
treatment:  
before informed consent 
Dose and regimen 
a) 
The lipid 
management goals of 
LDL-C based on the 
risk assessment 
cannot be achieved 
(see inclusion 
criterion 4)). 
Statins alone 
From at least 4 weeks 
before 
Same dose and 
regimen within the 
approved dose range 
b) 
Statins + 
nonstatins 
 
Fibrates, selective 
PPARα modulators: 
From at least 6 weeks 
before 
 
PCSK9 inhibitors:  
From at least 3 months 
before 
 
Statins and drugs other 
than those above:  
From at least 4 weeks 
before 
 
Statins: Same 
dose and regimen 
within the 
approved dose 
range 
 
Nonstatins: Same 
dose and regimen 
c) 
Only 
nonstatins 
 
Fibrates, selective 
PPARα modulators: 
From at least 6 weeks 
before 
 
PCSK9 inhibitors:  
From at least 3 months 
before 
 
Drugs other than the 
above:  
From at least 4 weeks 
before 
Same dose and 
regimen 
 
 Difficulty in treatment with statins: 
Of patients with hyper-LDL cholesterolemia for whom safety problems occurred 
while taking at least one type of statin and who experienced resolution of 
problems after discontinuation or dose reduction, or of those patients who have a 
history of statin administration and who are judged to have concerns of safety 
problems associated with the administration or dose increase of statins, those who 
cannot achieve the lipid management goals of LDL-C based on the risk 
assessment (see inclusion criterion 4)), meeting any of the following a), b), or c) 
a) Patients who have been taking statins (at or below the lowest approved dose) 
alone at the same dose and regimen from at least 4 weeks before informed 
consent 
b) Patients who have been taking statins (at or below the lowest approved dose) 
and nonstatins at the same dose and regimen from at least 4 weeks before 
informed consent (at least 6 weeks for fibrates and selective PPARα 
modulators, and at least 3 months for PCSK9 inhibitors) 
c) Patients who have been taking only nonstatins at the same dose and regimen 
from at least 4 weeks before informed consent (at least 6 weeks for fibrates 
and selective PPARα modulators, and at least 3 months for PCSK9 inhibitors) 

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Category 
LDL-C during the 
screening period 
Background lipid-lowering drugs at screening 
Type of 
drugs 
Timing of the start of 
treatment:  
before informed consent 
Dose and regimen 
a) 
The lipid 
management goals of 
LDL-C based on the 
risk assessment 
cannot be achieved 
(see inclusion 
criterion 4)). 
Statins alone 
From at least 4 weeks 
before 
Same dose and 
regimen at (or below) 
the lowest approved 
dose 
b) 
Statins + 
nonstatins 
 
Fibrates, selective 
PPARα modulators: 
From at least 6 weeks 
before 
 
PCSK9 inhibitors:  
From at least 3 months 
before 
 
Statins and drugs other 
than those above:  
From at least 4 weeks 
before 
 
Statins: Same 
dose and regimen 
at (or below) the 
lowest approved 
dose 
 
Nonstatins: Same 
dose and regimen 
c) 
Only 
nonstatins 
 
Fibrates, selective 
PPARα modulators: 
From at least 6 weeks 
before 
 
PCSK9 inhibitors:  
From at least 3 months 
before 
 
Drugs other than the 
above:  
From at least 4 weeks 
before 
Same dose and 
regimen 
 
4) Patients with a history or current condition meeting any of the following criteria 
1) to 3) 
Category 
History or current condition 
LDL-C during  
the screening period 
1) 
History of coronary artery disease 
≥100 mg/dL 
Heterozygous familial hypercholesterolemia (HeFH) 
2) 
Peripheral arterial disease 
≥120 mg/dL 
History of non-cardiogenic cerebral infarction 
Chronic kidney disease 
(Provided that it does not fall under exclusion criterion 12)) 
Type 2 diabetes mellitus 
(Diagnosed at least 3 months before Week −2, without falling 
under exclusion criterion 7)) 
3) 
The total score in the coronary artery disease risk prediction 
model using the Suita score specified by the Japan 
Atherosclerosis Society is ≥56 points (high risk) 
≥120 mg/dL 
The total score in the coronary artery disease risk prediction 
model using the Suita score specified by the Japan 
Atherosclerosis Society is ≥41 and ≤55 points (intermediate risk) 
≥140 mg/dL 
 

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5) Patients with fasting TG levels of <400 mg/dL at Week −2 
 
 Rollover subjects from the phase 3 confirmatory trial 
1) Patients who provide written informed consent prior to the start of the trial 
2) Subjects who have completed the 12-week treatment period in the phase 3 
confirmatory trial (Protocol No. 346-102-00002) and do not meet the 
discontinuation criteria for the IMP at Week 12 
 
[Rationale for the inclusion criteria] 
 Newly Enrolled Subjects 
1) This criterion is set based on ethical considerations. 
2) The lower limit of age is set as adults with sufficient ability to provide informed 
consent. The upper limit of age is set at 85 years in consideration of safety. 
3) to 4) These criteria are set to appropriately evaluate the safety and efficacy of 
ETC-1002. 
5) This criterion is set in consideration of the safety of the subjects. It is also 
considered that it will be difficult to appropriately evaluate LDL-C values using 
the Friedewald formula. 
 
 Rollover subjects from the phase 3 confirmatory trial 
1) This criterion is set based on ethical considerations. 
2) These criteria are set to appropriately evaluate the safety and efficacy of 
ETC-1002. 
 
5.2.2 
Exclusion Criteria 
Subjects will be excluded if they meet any of the following exclusion criteria when 
assessed: 
 Newly Enrolled Subjects 
1) Females who are pregnant or breast-feeding, or who have a positive pregnancy 
test (urine) result at screening (Week −2) or on Day 1 
2) Sexually active and reproductive males or sexually active females of childbearing 
potential, who do not agree to practice 2 different approved methods of birth 
control or to maintain complete abstinence (the methods of periodic abstinence 
and withdrawal are not appropriate for contraception) during the trial and for 
30 days after final IMP administration. If employing birth control, 2 of the 
following methods must be used: vasectomy, tubal ligation, intrauterine device, 
birth control pill, or condom (all methods are approved or certified in Japan). 
3) Patients with homozygous familial hypercholesterolemia (HoFH) 

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4) Patients who currently have or who have had within the past 3 months prior to 
screening any of the following cardiovascular diseases, or those who had 
developed any of the following AEs during the screening period 
 Myocardial infarction, severe or unstable angina pectoris, coronary angioplasty, 
coronary artery bypass graft, stroke, transient ischemic attack, symptomatic 
carotid artery stenosis, symptomatic peripheral arterial disease, or decompensated 
heart failure 
 Abdominal aortic aneurysm 
 Patients with risk factors for torsade de pointes, such as unexplained syncope or 
long-QT syndrome, or a family history of long-QT syndrome 
5) Patients with uncontrolled hypertension, defined as follows: sitting systolic blood 
pressure of ≥160 mmHg or diastolic blood pressure of ≥100 mmHg after resting 
5 minutes at screening (Week −2) 
6) Patients with uncontrolled and serious hematologic or coagulation disorders or 
with hemoglobin of <10.0 g/dL at screening (Week −2) 
7) Patients with uncontrolled diabetes with HbA1c of ≥9% at screening (Week −2) 
8) Patients with uncontrolled hypothyroidism with thyroid-stimulating hormone 
(TSH) of >1.5 × the upper limit of normal (ULN) at screening (Week −2) 
9) Patients with a liver disease or dysfunction, including: 
 Positive serology for hepatitis B surface antigen (HBsAg) or a positive hepatitis C 
virus (HCV) antibody test at screening (Week −2) 
 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) of 
≥3 × ULN or total bilirubin of ≥2 × ULN at screening (Week −2) 
10) Patients with a history or current chronic musculoskeletal symptoms that may be 
difficult to differentiate from myalgia 
(eg, fibromyalgia) 
11) Patients with CK of >3 × ULN at screening (Week −2) 
12) Patients with a history or current renal dysfunction, nephritic syndrome, or 
nephritis and with estimated glomerular filtration rate (eGFR) of 
≤30 mL/min/1.73 m2 at screening (Week −2) 
13) Patients who have had gastrointestinal surgery that may affect drug absorption 
(eg, Lap-Band® or gastric bypass) 
14) Patients who have undergone surgery, chemotherapy, or radiation therapy for 
active malignancy (excluding properly treated nonmetastatic basal or squamous 
cell carcinoma of the skin and cervical carcinoma in situ) within the past 5 years 
prior to screening (Week −2) 
15) Patients with a history of drug, alcohol, or cocaine abuse within the past 2 years 
prior to screening (Week −2) 
16) Patients who have had blood collection (eg, blood donation) in a cumulative 
amount exceeding 200 mL within 4 weeks, 400 mL within 12 weeks, or 1200 mL 
within 1 year prior to screening (Week −2) 

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17) Patients who have used any investigational drug not approved in Japan within 
either 4 weeks or 5 times the half-life of the drug, whichever is longer, prior to 
screening (Week −2) 
18) Patients who took the IMP in Trial 346-102-00001 or patients who have used 
ETC-1002 in the past 
19) Patients who used or received the following drugs (including food) or therapies 
within the specified period, or who are planning to use or receive them by the end 
of the tests at Week 52 
 
Drugs (including food) or 
therapies 
Prohibited period 
1. 
Systemic corticosteroids 
From 3 months prior to Week −2 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
However, if the drug has been used with the same dose and regimen 
since 3 months prior to Week −2, it may be used concomitantly with 
no change in dose until the end of the tests at Week 52 (or to the 
completion of the assessments at Discontinuation Visit, if 
applicable) 
2. 
Lomitapide 
From 3 months prior to Week −2 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
3. 
Probenecid 
From Week −2 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
4. 
Red yeast rice and food 
containing red yeast rice 
From 2 weeks prior to Week −2 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
5. 
LDL apheresis 
From 3 months prior to Week −2 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
 
20) Patients in whom the following drugs (therapies) are changed prior to Day 1 or in 
whom initiation of the following drugs (therapies) is planned by the end of the 
tests at Week 52 
 
Drugs or therapies 
Period in which the drug or therapy cannot be changed or  
newly started 
1. 
Female or male hormone 
replacement 
From 6 weeks prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
2. 
Thyroid replacement 
From 6 weeks prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
3. 
Diabetes medications 
From 4 weeks prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
4. 
Obesity medications 
From 3 months prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
 

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21) Patients otherwise judged inappropriate for participating in the trial in the opinion 
of the investigator or subinvestigator 
 
 Rollover subjects from the phase 3 confirmatory trial 
1) Females who are pregnant or breast-feeding, or who have a positive pregnancy 
test (urine) result on Day 1 
2) Sexually active and reproductive males or sexually active females of childbearing 
potential, who do not agree to practice 2 different approved methods of birth 
control or to maintain complete abstinence (the methods of periodic abstinence 
and withdrawal are not appropriate for contraception) during the trial and for 
30 days after final IMP administration. If employing birth control, 2 of the 
following methods must be used: vasectomy, tubal ligation, intrauterine device, 
birth control pill, or condom (all methods are approved or certified in Japan). 
3) Patients with any of the following AEs during the phase 3 confirmatory trial 
(Protocol No. 346-102-00002) 
 Myocardial infarction, severe or unstable angina pectoris, coronary angioplasty, 
coronary artery bypass graft, stroke, transient ischemic attack, symptomatic 
carotid artery stenosis, symptomatic peripheral arterial disease, or decompensated 
heart failure 
 Abdominal aortic aneurysm 
 Unexplained syncope or torsade de pointes-type ventricular tachycardia 
4) Patients with uncontrolled hypertension, defined as follows: sitting systolic blood 
pressure of ≥160 mmHg or diastolic blood pressure of ≥100 mmHg after resting 
5 minutes on Day 1 
5) Patients with uncontrolled and serious hematologic or coagulation disorders, or 
with hemoglobin of <10.0 g/dL at Week 8 in the phase 3 confirmatory trial 
(Protocol No. 346-102-00002) 
6) Patients with a liver disease or dysfunction, including: 
 Patients with positive serology for HBsAg or a positive HCV antibody test by 
Week 8 in the phase 3 confirmatory trial (Protocol No. 346-102-00002) 
 Patients with AST or ALT of ≥3 × ULN or total bilirubin of ≥2 × ULN by Week 8 
in the phase 3 confirmatory trial (Protocol No. 346-102-00002) 
7) Patients with a history or current renal dysfunction, nephritic syndrome, or 
nephritis, and with eGFR of ≤30 mL/min/1.73 m2 at Week 8 in the phase 3 
confirmatory trial (Protocol No. 346-102-00002) 
8) Patients who used or received the following drugs (including food) or therapies 
within the specified period, or who are planning to use or receive them by the end 
of the tests at Week 52 

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Drugs (including food) or 
therapies 
Prohibited period 
1. 
Systemic corticosteroids 
From Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
However, if the drug is being used with the same dose and regimen 
as before participation during the phase 3 confirmatory trial, it may 
be used concomitantly with no change in dose until the end of the 
tests at Week 52 (or to the completion of the assessments at 
Discontinuation Visit, if applicable) 
2. 
Lomitapide 
From Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
3. 
Probenecid 
From Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
4. 
Red yeast rice and food 
containing red yeast rice 
From Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
5. 
LDL apheresis 
From Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
 
9) Patients in whom the following drugs (therapies) are changed prior to Day 1 or in 
whom initiation of the following drugs (therapies) is planned by the end of the 
tests at Week 52 
 
Drugs or therapies 
Period in which the drug or therapy cannot be changed or  
newly started 
1. 
Female or male hormone 
replacement 
From 6 weeks prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
2. 
Thyroid replacement 
From 6 weeks prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
3. 
Diabetes medications 
From 4 weeks prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
4. 
Obesity medications 
From 3 months prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
 
10) Patients otherwise judged inappropriate for participating in the trial in the opinion 
of the investigator or subinvestigator 
 
A definition of childbearing potential can be found in Section 10.3. 
Subjects must agree to the restrictions on medications and lifestyle described in 
Section 6.5.1 and Section 5.3, respectively. 
 

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[Rationale for the exclusion criteria] 
 Newly Enrolled Subjects 
1) to 2) These criteria are set in consideration of safety, because the safety of 
administration of ETC-1002 during pregnancy and breast-feeding has not been 
established. 
3) to 9), 12), 15), 21) These criteria are set in consideration of the safety of the 
subjects. 
10) to 11), 14), 18) These criteria are set to appropriately evaluate the safety of 
ETC-1002. 
13) This criterion is set to avoid the influence of such a surgery on ETC-1002 
absorption, etc. 
16) This criterion is set according to the Blood Sampling Criteria of the New Blood 
Program Advisory Committee to ensure the safety of the subjects. 
17), 19) to 20) These criteria are set to appropriately evaluate the efficacy and safety 
of ETC-1002. 
 
 Rollover subjects from the phase 3 confirmatory trial 
1) to 2) These criteria are set in consideration of safety, because the safety of 
administration of ETC-1002 during pregnancy and breast-feeding has not been 
established. 
3) to 7), 10) These criteria are set in consideration of the safety of the subjects. 
8) to 9) These criteria are set to appropriately evaluate the efficacy and safety of 
ETC-1002. 
 
5.3 
Lifestyle Considerations 
5.3.1 
Meals and Dietary Restrictions 
To properly evaluate the efficacy and safety of ETC-1002, diet therapy receiving since 
before informed consent should not be changed from Week −2 to the end of tests at 
Week 52 (or to the completion of the assessments at Discontinuation Visit, if applicable) 
in principle. For dietary supplements that may affect cholesterol levels including LDL-C, 
the investigator or subinvestigator will explain to the subjects at each visit so that the 
intake status will not change from Week −2 to the end of the tests at Week 52 (or to the 
completion of the assessments at Discontinuation Visit, if applicable), and record the 
intake status in the source document. 
 

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5.3.2 
Caffeine, Alcohol, and Tobacco 
For alcohol and tobacco, the usual amount of alcohol consumed and the number of 
cigarettes smoked prior to participation in the trial will be checked with the subject and 
documented in the source document. The investigator or subinvestigator will instruct 
subjects not to significantly increase the amount of alcohol consumption or the number of 
cigarettes smoked during the trial period. Subjects will be monitored at each visit for any 
significant changes from Week −2 to the end of the tests at Week 52 (or to the 
completion of the assessments at Discontinuation Visit, if applicable), and the results will 
be recorded in the source document. No caffeine restrictions will be applied. 
 
5.3.3 
Activity 
To properly evaluate the efficacy and safety of ETC-1002, exercise therapy that has been 
received since before informed consent should not be changed during the trial period to 
the extent possible. In addition, the investigator or subinvestigator will instruct subjects at 
each visit to refrain from strenuous exercise from approximately 1 week before the 
scheduled visits during the trial period to avoid influence on laboratory values such as 
CK. 
 
5.4 
Screen Failures 
A screen failure is a subject from whom informed consent is obtained and is documented 
in writing (ie, subject signs an ICF), but who does not receive the IMP in the treatment 
period regardless of a newly enrolled subject or a rollover subject from the phase 3 
confirmatory trial (Protocol No. 346-102-00002). All AEs must be reported after subject 
informed consent has been obtained, including screening failures due to AEs, irrespective 
of IMP administration. If the subject meets the definition of a screen failure in this trial, 
the following information will be recorded in the eCRF: 
 Date of informed consent 
 Visit date (screening visit) 
 Demographics (collection date, birth date, sex, race, ethnicity, country) 
 History of hypercholesterolemia 

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History of Hypercholesterolemia: Investigation Item 
 
Name of diagnosis 
 
Date of diagnosis 
 
Presence or absence of familial hypercholesterolemia 
 
Classification and details of classification (according to the flowchart using the Suita score in the 
Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 
2017,1 and according to the flowchart using the score of the Hisayama Study in the Guidelines 
20222) 
 
Statin response (inadequate response to statins/difficulties in treatment with statins) 
 
For patients with difficulties in treatment with statins: Reasons for judging that treatment with 
statins is difficult and the name/daily dose of the statin 
 
 Result of eligibility assessment 
 Screen failure date 
 Reason for screen failure 
 Adverse events* 
*If a rollover subject from Trial 346-102-00002 is a screen failure, no AE collection will be necessary 
on the eCRF in this trial. 
 
Screen failures will be allowed to re-screen. In the event that the subject is re-screened 
for trial participation, a new ICF must be signed. 
 

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6 
Trial Treatments 
Trial intervention used in this trial is a test product. No trial interventions are used in this 
trial other than the IMP. 
 
6.1 
Trial Treatments Administered 
Subjects who are judged to be eligible at screening will proceed to the treatment period. 
Subjects proceeding to the treatment period who have been receiving treatment using 
lipid-lowering drugs since before informed consent should continue the treatment without 
changing the type or dose and regimen, in addition to orally receiving ETC-1002 at 
180 mg once daily. The time of IMP administration should be same to the extent 
possible. The following information will be recorded in the eCRF: for the IMP, the 
number of tablets taken per day, start and end dates of administration; for lipid-lowering 
drugs, the name of the drug, route of administration, dose and frequency, daily dose, start 
and end dates of administration. 
No change in the dose of lipid-lowering drugs is allowed in principle during the trial. 
However, if the lipid management target in the Japan Atherosclerosis Society Guidelines 
for Prevention of Atherosclerotic Cardiovascular Diseases (2017) are not achieved on and 
after Week 12, and if the investigator or subinvestigator considers that further treatment 
is necessary and there are no safety problems, starting a dose increase or concomitant 
treatment with other lipid-lowering drugs will be permitted. 
For information regarding the dose regimen and treatment period (including the post-
treatment follow-up period), see Section 4.1. 
 
6.1.1 
Medical Devices 
Not applicable. 
 
6.2 
Management of Investigational Medicinal Product 
For full details on IMP management, please refer to the IB and the separate procedures. 
 

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6.2.1 
Packaging and Labeling 
The IMP will be provided by the sponsor or designated agent to the IMP storage 
manager. The IMP will be supplied as blister cards. Each blister card used in the dosing 
period will be labeled to clearly disclose the compound ID, trial number, sponsor’s name 
and address, storage temperature, route of administration, appropriate precautionary 
statements, etc. 
 
6.2.2 
Storage 
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited 
to the IMP storage manager. 
The IMP will be stored according to the conditions indicated on the IMP label. 
The trial site staff will maintain a temperature log in the IMP storage area to record the 
temperature. 
 
6.2.3 
Accountability 
The IMP storage manager must maintain an inventory record of IMP (test product) 
received, dispensed, administered, and returned. The IMP storage manager must not 
provide IMP to any subject not participating in this protocol. 
 
6.2.4 
Returns and Destruction 
Upon completion or termination of the trial, all unused IMP and partially used IMP must 
be returned to the sponsor or a designated agent. All IMP returned to the sponsor must be 
accompanied by inventory record, etc. and be clearly identified by protocol number and 
trial site number on the outermost shipping container. Returned supplies should be in the 
original containers. The assigned trial monitor will facilitate the return of used IMP 
containers, unused IMP, and partially-used IMP. 
 
6.2.5 
Reporting of Product Quality Complaints 
A Product Quality Complaint (PQC) is any written, electronic, or oral communication 
provided by a healthcare professional, consumer, subject, medical representative, 
regulatory agency, Partner, or other third party that alleges deficiencies related to the 

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identity, quality, durability, reliability, safety, effectiveness, or performance of a Medical 
Device or Medicinal Product or a falsified, tampered, or diverted product after it is 
released for distribution to a clinical trial. Examples include, but are not limited to: 
 Failure/malfunction of IMPs to meet any of its specifications 
 Incorrect or missing labeling 
 Packaging issues (eg, damaged, dirty, crushed, missing product) 
 Blister defects (eg, missing, empty blisters) 
 Product defects (eg, odor, chipped, broken, embossing illegible) 
 Loss or theft of the product 
 
6.2.5.1 
Eliciting and Reporting Product Quality Complaints 
The investigator, subinvestigator, or designee must record each PQC identified through 
any means from the receipt of the IMP from the sponsor or sponsor’s designee, through 
and including reconciliation and up to destruction, including subject dosing. The 
investigator, subinvestigator, or designee must notify the sponsor (or sponsor’s designee) 
by e-mail 
of the 
information specified in Section 6.2.5.2 immediately after becoming aware of the PQC. 
Identification of a PQC by the subject should be reported to the site investigator or 
subinvestigator, who should then follow the reporting procedure above. 
 
6.2.5.2 
Information Required for Reporting Product Quality Complaints 
 Description of the complaint 
 Reporter identification (eg, subject, investigator, subinvestigator, trial site, etc.) 
 Reporter contact information (eg, address, phone number, e-mail address) 
 ID of the material (product/compound name, kit number) 
 Clinical protocol reference (protocol number and/or trial name) 
 Dosage form/strength (if known) 
 Pictures of complaint sample (if available) 
 Availability of the complaint sample for return 
 
6.2.5.3 
Return Process in Case of Product Quality Complaints 
Indicate during the report of the PQC if the complaint sample is available for return. If 
the complaint sample is available for return, the sponsor will provide return instructions, 
when applicable. 

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It must be documented in the site accountability record that the complaint sample has 
been forwarded to the sponsor for complaint investigation. 
 
6.2.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor. 
 
6.2.6 
Investigational Medicinal Product Reserve Sample Requirements 
Not applicable. 
 
6.3 
Measures to Minimize/Avoid Bias 
This is an open-label trial. 
 
6.4 
Subject Compliance 
To ensure compliance with the protocol, the investigator or subinvestigator will instruct 
subjects to: 
 Visit the trial site in a fasting state (fasting for at least 10 hours) without taking the 
IMP on the days specified in the protocol. 
 Not take any prohibited concomitant medications or therapies during the period from 
informed consent to the completion of the tests at Week 52 or to the completion of the 
assessments at Discontinuation Visit. 
 Comply with the dosage regimen, duration, and frequency of administration of the 
IMP and, if any, concomitant lipid-lowering drugs taken since before informed 
consent. 
 Use appropriate contraceptive methods. 
 Note the lifestyle considerations (see Section 5.3). 
 Fill in the subject diary (see Section 8.10.1) every day while taking the IMP, and 
bring it to the visit. 
 
6.5 
Concomitant Medications or Therapies 
The investigator or subinvestigator will record all of the following concomitant 
medications (including prescription medications, over the-counter medications, herbal 
remedies) and therapies in the eCRF. 

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For concomitant medications, the following will be recorded in the eCRF: medication, 
indication, dose, frequency, route, start date and end date. For concomitant therapy, the 
following will be recorded in the eCRF: therapy, indication, start date and end date. 
 
Concomitant medications or therapies 
Collection period 
Lipid-lowering drugs 
From 6 weeks prior to the date of informed consent 
to Week 52 or discontinuation 
However, for PCSK9 inhibitors, the information 
should be collected from 3 months before informed 
consent. 
Diabetes medications 
From 10 weeks prior to the date of informed 
consent to Week 52 or discontinuation 
All concomitant medications other than lipid-
lowering drugs and diabetes medications or 
concomitant therapies 
From 4 weeks prior to the date of informed consent 
to Week 52 or discontinuation 
Concomitant medications or therapies that have 
caused AEs or been used for the treatment of AEs 
From the first day of use to the final observation 
day of the subject 
 
6.5.1 
Prohibited Medications 
The use or intake of medications, food, and preference products listed in Table 6.5.1-1 is 
prohibited during the applicable period. 
 
Table 6.5.1-1 
List of Prohibited Medications, Food, and Preference 
Products 
 
Drugs (including food) 
Prohibited period 
1. 
Systemic corticosteroids 
From 3 months prior to Week −2 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
However, if the drug has been used with the same dose and regimen 
since 3 months prior to Week −2, it may be used concomitantly 
with no change in dose until the end of the tests at Week 52 (or to 
the completion of the assessments at Discontinuation Visit, if 
applicable). 
2. 
Lomitapide 
From 3 months prior to Week −2 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
3. 
Probenecid 
From Week −2 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
4. 
Red yeast rice and food 
containing red yeast rice 
From 2 weeks prior to Week −2 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
 

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6.5.2 
Prohibited Therapies 
LDL apheresis is prohibited from 3 months prior to Week −2 to the end of the tests at 
Week 52 (or to the completion of the assessments at Discontinuation Visit, if applicable). 
If performed, the subject will discontinue the trial. 
 
6.5.3 
Permitted Medications or Therapies 
Treatment with lipid-lowering drugs from before informed consent should continue 
without changing the type or dose and regimen until the end of the tests at Week 52 of the 
treatment period (or to the completion of the assessments at Discontinuation Visit, if 
applicable). If any medication or therapy shown in Table 6.5.3-1 has been taken or used 
from before informed consent, the type or dose and regimen of the concomitant 
medications or the details of the concomitant therapy should not be changed during the 
applicable period in principle. 
 
Table 6.5.3-1 
List of Medications or Therapies Permitted Before and 
During the Trial 
 
Drugs or therapies 
Period in which the drug or therapy cannot be changed or 
newly started 
1. 
Female or male hormone 
replacement 
From 6 weeks prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
2. 
Thyroid replacement 
From 6 weeks prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
3. 
Diabetes medications 
From 4 weeks prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
4. 
Obesity medications 
From 3 months prior to Day 1 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
5. 
Diet therapy 
From Week −2 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
6. 
Exercise therapy 
From Week −2 to the end of the tests at Week 52 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
 
No change in the dose of lipid-lowering drugs is allowed in principle during the trial. 
However, if the lipid management goals in the Japan Atherosclerosis Society Guidelines 
for Prevention of Atherosclerotic Cardiovascular Diseases (2017) are not achieved on and 
after Week 12, and if the investigator or subinvestigator considers that further treatment 

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is necessary and there are no safety problems, starting a dose increase or concomitant 
treatment with other lipid-lowering drugs will be permitted. 
For any of the medications or therapies shown in Table 6.5.3-1, no change in the dose 
and regimen or the details of the concomitant therapy is allowed in principle during the 
trial. However, only in cases where the investigator or subinvestigator considers the 
change to be necessary due to safety reasons on and after Week 12, changing the dose 
and regimen or frequency will be permitted. However, only a dose reduction will be 
permitted for obesity medications. 
 
6.5.4 
Rescue Medications 
Not applicable. 
 
6.6 
Intervention After the End of the Trial 
Not applicable. 
 
7 
Discontinuation of Trial/Treatment and Subject 
Discontinuation/Withdrawal 
7.1 
Entire Trial or Treatment Discontinuation 
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to the head of the trial site and regulatory authorities in accordance with regulatory 
requirements. 
 
7.2 
Individual Site Discontinuation 
Individual trial site participation may be discontinued by the sponsor, investigator, or 
Institutional Review Board (IRB) if judged necessary for medical, safety, regulatory, 
ethical, or other reasons consistent with applicable laws, regulations, and the Good 
Clinical Practice (GCP). The head of the trial site will notify the sponsor promptly if the 
trial is terminated by the investigator or IRB at the site. 
 

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7.3 
Individual Subject Discontinuation 
7.3.1 
Treatment Interruption 
Not applicable. 
 
7.3.2 
Treatment Discontinuation 
After proceeding to the treatment period, a subject may stop treatment permanently for a 
variety of reasons. Treatment discontinuations may be initiated by a subject who is not 
satisfied with treatment or may become medically necessary due to AEs, required 
treatment with a disallowed medication or therapy, or other issues, as determined by the 
investigator or subinvestigator. However, each investigator or subinvestigator must 
comprehensively review the circumstances and offer the subject options for continued 
treatment to the degree possible as described in Section 7.3.5. 
When the investigator or subinvestigator considers trial discontinuation to be necessary 
during the treatment period, the assessments at Discontinuation Visit (Week 52) specified 
in Table 1.3-1 will be performed to the extent possible, and the subject will proceed to the 
follow-up period. 
 
7.3.3 
Documenting Reasons for Treatment Discontinuation 
A subject may discontinue IMP for the reasons listed below: Only one reason for 
treatment discontinuation (primary reason) will be recorded in the source document and 
eCRF with the date of discontinuation and entered in the IWRS. 
 Adverse event 
 Death 
 Worsening of underlying disease 
 Subject decides to discontinue because of annoyance or discomfort due to a 
nonserious AE which is not otherwise determined to be an undue hazard 
 Continuing IMP places the subject at undue risk as determined by the investigator 
or subinvestigator (eg, a safety concern that is related to IMP) 
 Serious adverse event 
 Other potentially IMP-related safety concerns or AEs 
 In the event of a significant deviation from the protocol 
 Revealed to have not met the inclusion criteria or fall under the exclusion criteria 
 Use of prohibited therapies 

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 Lost to follow-up 
 Pregnancy (see Section 10.3) 
 Site terminated by the sponsor 
 Trial terminated by the sponsor 
 Withdrawal of IMP administration at the subject’s request 
 Judgment by the investigator 
 Other 
 
If the subject discontinues IMP due to an AE, the investigator/subinvestigator or other 
trial personnel will make every effort to follow the event until it has resolved or 
stabilized. Follow-up procedures in Section 7.3.2 must be followed. 
 
7.3.4 
Withdrawal of Consent 
Each subject has the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects can withdraw consent for use of data which has 
not previously been transferred into trial data sets collected as part of the trial and can 
only withdraw consent for future participation. The investigator or subinvestigator can 
also discontinue a subject’s participation in the trial at any time if medically necessary. 
Unless the subject provides their written withdrawal of consent or there is other written 
documentation by the investigator or subinvestigator confirming the subject’s verbal 
intent to completely withdraw from the trial, subjects should be followed for all protocol-
specified evaluations and assessments, if possible. 
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow-up: 
 Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by a home visit). 
 Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and trial site staff in some follow-up 
procedures refused by the subject). 
 Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives. 
 Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician). 

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 Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources). 
 
Withdrawal of consent is a critical trial event and, therefore, should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express their desire to discontinue IMP administration, though 
this is not equivalent to a complete withdrawal of consent for further participation (see 
Section 7.3.2). A subject may, however, indicate that further trial participation is creating 
a burden on their work, school, or social schedule. Therefore, the investigator or 
subinvestigator should follow the procedures outlined in Section 7.3.3 to determine if the 
subject can continue participation in the trial if modifications to his/her treatment and/or 
schedule of assessments can be accommodated. Only subjects who withdraw their 
permission for all of the above methods of follow-up are considered to have completely 
withdrawn their consent to participate in the trial. 
Details on the withdrawal of consent for the optional Future Biospecimen Research 
(FBR) substudy associated with this trial are provided in the ICF for the FBR. 
 
7.3.5 
Procedures to Encourage Continued Trial Participation 
In all cases of impending IMP discontinuation or consent withdrawal, investigators or 
subinvestigators will be instructed to meet and discuss (without undue coercion) with the 
subject their options of continuing in the trial, preferably on therapy. The investigator or 
subinvestigator should ensure understanding and documentation of the reasons for the 
subject’s desire to withdraw consent. 
 
7.4 
Definition of Subjects Lost to Follow-up 
Subjects who cannot be contacted on or before Week 52 in the treatment period, who do 
not have a known reason for discontinuation (eg, withdrew consent or AE), and for whom 
a survival status at the end of the trial cannot be determined will be classified as “lost to 
follow-up”. Survival status can be determined from a variety of sources, either by 
obtaining acceptable documentation for death (ie, death certificate, medical records, 
public records, statement by a family member or primary care physician) or acceptable 
documentation for life (ie, direct contact with the subject, medical records, successful 

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telephone contact with the subject, statement by a family member or primary care 
physician, or public records). 
The site will make 3 documented attempts to contact the subject by telephone and in the 
event the site is unable to reach the subject by telephone, the site will attempt to contact 
the subject via certified mail or an alternative similar method, where appropriate, before 
assigning a “lost to follow-up” status. 
If the subject was classified as “lost to follow-up”, “Were you able to contact the 
subject?”, “Date of contact/Date of final contact attempt” and “Contact method” will be 
recorded in the eCRF. 
 
8 
Trial Procedures 
The assessments to be conducted during the trial are summarized in Table 1.3-1. 
Investigations and assessments will be performed according to Table 1.3-1, and the 
results will be recorded in the source document and eCRF. 
 
8.1 
Efficacy Assessments 
To evaluate the efficacy of ETC-1002, blood samples for LDL-C, non-HDL-C, TC, 
HDL-C, TG, apo B, hsCRP, and HbA1c will be collected. 
The investigator or subinvestigator will instruct subjects to visit the trial site according to 
the schedule specified in Table 1.3-1 under fasting conditions and collect blood samples. 
The investigator or subinvestigator will record the date and time of blood sampling and 
the fasting state at the time of blood sampling in the source document and the eCRF. The 
test results will be directly reported to the sponsor by the central laboratory selected by 
the sponsor in electronic files. Therefore, it is not necessary to record the results in the 
source document and eCRF. The fasting state is defined as a state in which a subject has 
fasted (including abstaining from sugar-containing beverages such as juice) for 10 hours 
or more. If a subject cannot visit the trial site in a fasting state, the subject should visit the 
trial site again in a fasting state for blood sampling within the visit window for the same 
evaluation time point. If the subject cannot visit in the fasting state again within the visit 
window for the same evaluation time point, this case will be recorded as a protocol 
deviation and the blood sample will be submitted as a sample in a fed state to the central 
laboratory. Each subject will visit the trial site without taking the IMP on the visit day. 

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Samples will be sent to the central laboratory, the results of which will be used for 
analysis. LDL-C values will be measured using the direct method and calculated using 
the Friedewald formula (TC−HDL-C−TG/5). Proper sample collection, handling, and 
shipping procedures will be provided to the trial sites in a separate manual prior to the 
start of the trial. 
To maintain the blind of the trial, the test results will not be reported to the trial sites and 
the sponsor for the blind items at Week −4 and Day 1 in the rollover subjects from the 
phase 3 confirmatory trial (Protocol No. 346-102-00002). The test results will be stored 
strictly by the central laboratory, disclosed to the trial site after unblinding in the phase 3 
confirmatory trial (Protocol No. 346-102-00002), and provided to the sponsor in 
electronic files. 
 
8.2 
Pharmacokinetic Assessments 
Not applicable. 
 
8.3 
Pharmacodynamic Assessments 
Not applicable. 
 
8.4 
Pharmacogenomic Assessments 
Not applicable. 
 
8.5 
Biomarker Assessments 
Not applicable. 
 
8.6 
Future Biospecimen Research Samples 
 

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8.7 
Safety Assessments 
Details pertaining to the definitions, collection, reporting, and follow-up of AEs are 
described in Section 8.8. 

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8.7.1 
Clinical Laboratory Assessments 
Clinical laboratory samples will be collected at the time points described in the Schedule 
of Assessments (Table 1.3-1) to perform the clinical laboratory assessments described in 
Section 10.2. The total volume of blood to be collected during the trial will be 
documented in the electronic informed consent form (eICF)/ICF. 
On the day of the tests shown in the Schedule of Assessments (Table 1.3-1), subjects will 
be asked to visit the trial site in a fasting state (at least 10 hours of fasting [including 
abstaining from sugar-containing beverages such as juice]) without taking the IMP, and 
blood and urine samples will be collected from each subject. The date and time of blood 
sampling, date of urine sampling, and the fasting state at the time of blood sampling will 
be recorded in the source document and the eCRF. The sponsor will select a central 
laboratory for this trial. The test results measured by the central laboratory will be used to 
confirm the eligibility. Proper sample collection, handling, and shipping procedures will 
be provided to the trial sites in a separate manual prior to the start of the trial. The central 
laboratory will report the test results to the investigator or subinvestigator who confirms 
the results. The laboratory report will be officially documented by entering the date of 
confirmation and signing the report by the investigator or subinvestigator. The test results 
will be directly reported to the sponsor by the central laboratory in electronic files. 
Therefore, it is not necessary to record the results in the source document and the eCRF. 
Since serum uric acid increased was observed with administration of ETC-1002 in the 
clinical trials conducted outside Japan, the US package insert includes a cautionary 
statement that the presence or absence of signs and symptoms of hyperuricemia at 
administration of ETC-1002 should be monitored and treatment with antihyperuricemics 
should be initiated as necessary. The investigator or subinvestigator will check the results 
of uric acid measurements in subjects on and after Day 1 and take appropriate measures 
as necessary. Since ETC-1002 exposure in blood was increased by administration of 
probenecid in the clinical trials conducted outside Japan, antihyperuricemics other than 
probenecid should be administered if drug therapy for uric acid increased is required for 
the subject. 
In addition, since statin exposure was increased by co-administration of ETC-1002, the 
time course of laboratory values such as CK, AST, ALT, or total bilirubin should be 
carefully monitored to confirm the presence or absence of muscle-related AE or AEs 
associated with hepatic impairment due to administration of statins, and if any abnormal 

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value is observed, appropriate measures including discontinuation of administration 
should be taken. 
In the clinical trials conducted outside Japan, ETC-1002 was associated with AST and 
ALT increased, hemoglobin decreased, as well as creatinine and urea nitrogen increased, 
although these were not clinically significant. Therefore, changes in these laboratory test 
values should be carefully monitored, and appropriate measures should be taken if any 
abnormal value is observed. 
 
8.7.2 
Physical Examination 
Physical examinations will be performed at the time points described in the Schedule of 
Assessments (Table 1.3-1). The investigator or subinvestigator will perform physical 
examinations for the following assessments by methods such as interview and record the 
date and results of the assessment in the source document. For consistency of 
assessments, it is recommended that all physical examinations for individual subjects be 
performed by the same physician throughout the trial. At screening and Day 1, the dates 
and results of the examinations will be recorded in the source document and the eCRF. At 
the other time points, only the date of the examination will be recorded. If clinically 
significant physical findings are observed compared with Day 1 in the treatment and 
follow-up periods, the findings will be recorded as AEs. 
Assessments: HEENT (head, eyes, ears, nose, throat), chest, abdomen, genitourinary, 
extremities, nerves, skin/mucosae 
 
8.7.3 
Vital Signs 
Body temperature, systolic and diastolic blood pressure, and pulse rate will be measured 
in a sitting position after resting for at least 5 minutes. Vital signs will be collected at the 
time points described in the Schedule of Assessments (Table 1.3-1) and before blood 
sampling to the extent possible. Subjects should be monitored for potentially clinically 
significant vital signs values. The date and results of body temperature, systolic and 
diastolic blood pressure, and pulse rate measurements will be recorded in the source 
document and the eCRF. 
 

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8.7.4 
Electrocardiogram 
Electrocardiograms will be performed at the time points described in the Schedule of 
Assessments (Table 1.3-1) after resting for at least 10 minutes. The 12-lead ECG should 
be performed before blood collection whenever possible to minimize the effects on the 
assessment. 
The investigator or subinvestigator will perform the ECG according to the procedures 
specified at each trial site and record the date of measurement, heart rate, PR interval, RR 
interval, QRS width, QT interval, and QTcF in the source document and the eCRF. The 
investigator or subinvestigator will determine normality/abnormality by the assessment of 
the measurements, and record the determinations in the source document and the eCRF. 
Any abnormal findings will be recorded in the source document and the eCRF. The 
subjects should be monitored for potentially clinically significant ECG findings. The 
sponsor may request to provide a copy of the ECG chart for any reason, including 
additional safety analysis. 
 
8.7.5 
Suicidality Monitoring 
Not applicable. 
 
8.7.6 
Other Safety Variables 
8.7.6.1 
Body Weight 
Body weight will be measured according to the procedures specified at each trial site at 
the time points described in the Schedule of Assessments (Table 1.3-1), and the dates and 
results of the measurements will be recorded in the source document and the eCRF (in 
units of 0.1 kg). The same scale should be used for the same subject as much as possible. 
 
8.8 
Adverse Events 
8.8.1 
Definitions 
An AE is defined as any untoward medical occurrence in a clinical trial subject 
administered a trial intervention*, and does not necessarily have a causal relationship with 
 
*  Refer to the guidance in Article 2 of the revised GCP. No trial interventions other than the IMP 
will be used in this clinical trial. 

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this treatment. In this trial, any untoward medical occurrence in a subject not receiving 
the trial intervention will be included. Adverse events would not include information 
recorded as medical history at screening for pre-planned procedures for which the 
underlying condition was known and no worsening occurred. In addition, if an AE that 
developed in a rollover subject during the phase 3 confirmatory trial (Protocol No. 
346-102-00002) continues without recovery/resolution but does not worsen, the event 
will not be included as an AE in this trial. An adverse reaction is any untoward and 
unintended response to a trial intervention related to any dose administered. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
trial intervention caused the AE. 
Treatment-emergent AEs (TEAEs) are defined as AEs with an onset date on or after the 
start of IMP treatment. In more detail, TEAEs are all AEs which started after the start of 
IMP treatment; or if the event was continuous from baseline and worsened after the start 
of IMP treatment. 
An SAE includes any event that results in any of the following outcomes: 
 Death 
 Life-threatening; ie, the subject was, in the opinion of the investigator or 
subinvestigator, at immediate risk of death from the event as it occurred. It does not 
include an event that, had it occurred in a more severe form, might have caused death. 
 Persistent or significant incapacity/disability or substantial disruption of the ability to 
conduct normal life functions. 
 Requires inpatient hospitalization or prolongs hospitalization. 
 Hospitalization itself should not be reported as an SAE; whenever possible, the 
reason for hospitalization should be reported. 
 Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other nonmedical need) are not considered 
SAEs. 
 Prescheduled hospitalization to address a condition that has existed prior to the 
signing of the ICF should not be considered an SAE. 
 Congenital anomaly/birth defect. 
 Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above; eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse. 
 
Nonserious AEs are all AEs that do not meet the criteria for a “serious” AE. 

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Adverse Events of Special Interest (AESIs): A noteworthy event for the particular 
product/IMP or class of products that a sponsor may wish to monitor carefully. All AESIs 
are to be reported as immediately reportable events (IREs). No AESIs have been 
identified for the IMP to be administered during this trial. 
Immediately Reportable Event: 
 Any SAE. 
 Any AE related to occupational exposure. 
 Potential serious hepatotoxicity (see Section 8.8.6). 
 Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on an IRE form and the 
Pregnancy Surveillance Form(s) to the sponsor. This includes pregnancy of the 
subject or the partner of the subject. Pregnancy will only be documented on the AE 
eCRF if the pregnancy occurs in a female and there is an abnormality or medical 
problem. 
 
Occupational exposure refers to the exposure of a medical personnel member to a 
medicinal product during the preparation and/or administration of the product. Any AE 
related to occupational exposure should be reported to the sponsor using forms including 
an IRE form, as soon as possible. 
Clinical Laboratory Test Value Changes: It is the investigator/subinvestigator’s 
responsibility to review the results of laboratory tests for each individual subject as they 
become available. This review will be documented by the investigator/subinvestigator’s 
dated signature on the laboratory report. The investigator or subinvestigator may repeat 
the laboratory test or request additional tests to confirm the results of the original 
laboratory tests. If this laboratory test value is considered medically relevant (ie, 
clinically significant) by the investigator or subinvestigator (subject is symptomatic, 
requiring corrective treatment or further evaluation), or if the laboratory test value leads 
to discontinuation, and/or fulfills a seriousness criterion, this is considered an AE. 
However, if an abnormal result is found in a test performed at the central laboratory and 
is considered an AE, the course should be confirmed with the test results of the central 
laboratory in principle. 
 
Severity: Adverse events will be graded on a 3-point scale below: 
1 = Mild:  
Discomfort noticed, but no disruption to daily activity. 
2 = Moderate: 
Discomfort sufficient to reduce or affect normal daily activity. 
3 = Severe:  
Inability to work or perform normal daily activity. 

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IMP Causality: Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows: 
Related:  
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE. 
Not Related:  
There is no temporal or causal relationship between the IMP and 
the AE. 
 
8.8.2 
Eliciting and Reporting Adverse Events 
The investigator or subinvestigator will regularly assess the subjects for the occurrence of 
AEs. To avoid bias in eliciting AEs, subjects should be asked the nonleading question: 
“How have you felt since your last visit?” All AEs (serious and nonserious) reported by 
the subject must be recorded on the source documents and eCRF provided by the 
sponsor. Adverse event collection will begin after a subject signs the ICF and will 
continue until the end of the follow-up period. All AEs must be recorded in the eCRF 
after subject informed consent has been obtained, including screening failures due to 
AEs, irrespective of trial intervention. In this trial, AEs during the treatment and follow-
up periods will be assessed compared to Day 1. 
Medical terminology should be used for AE reporting. Adverse events should be reported 
as a single unifying diagnosis whenever possible or, in the absence of a unifying 
diagnosis, as individual signs or symptoms. 
Exacerbation or disease progression should be reported as an AE only if there are unusual 
or severe clinical features that were not present, or experienced earlier, or not expected 
based on the course of the condition. A reported AE that undergoes worsening in severity 
or seriousness should be reported as a new AE in the eCRF. However, if worsening of the 
condition is observed on Day 1 or later, the AE should be reported as a new AE in the 
eCRF without limiting to worsening in severity or seriousness. If a subject is suspected to 
have COVID-19 during the trial, the investigator or subinvestigator will confirm the 
results of an antigen test, etc., and take necessary measures such as a determination on the 
necessity for discontinuation of the IMP in consideration of the safety of the subjects. A 
positive result will be reported as an AE in the eCRF. 
In addition, the sponsor must be notified immediately by e-mail in principle of any IREs 
according to the procedure outlined below, in Section 8.8.3. Special attention should be 
paid to recording hospitalization and concomitant medications. 

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The AE, start date, end date, seriousness, severity, relationship to trial treatment (IMP 
causality), action taken with trial treatment, and outcome will be recorded on the source 
documents and in the eCRF. 
 
8.8.3 
Immediately Reportable Events 
The investigator/subinvestigator or designee must immediately report (within 24 hours), 
using forms including an IRE form, after he/she or site personnel become aware of any 
IRE (SAE, AE related to occupational exposure, potential serious hepatotoxicity, or 
confirmed pregnancy), by e-mail in principle to the sponsor or designee using the contact 
information on the cover page of this protocol (please note that the IRE form is NOT the 
entry column for AEs in the eCRF). Patient confidentiality must be protected and contact 
information such as name, address, phone number or any other protected health 
information as determined by applicable local regulation must be redacted when 
forwarding Safety Information and supporting documentation. Details regarding the 
follow-up of IREs are included in Section 8.8.8.2. 
 
8.8.4 
Medical Device Incidents (Including Malfunctions) 
Not applicable. 
 
8.8.5 
Adverse Events of Special Interest 
Not applicable. 
 
8.8.6 
Potential Serious Hepatotoxicity 
For a subject who experiences an elevation in AST or ALT that is ≥3 times the ULN, a 
total bilirubin level should also be evaluated. If the total bilirubin is ≥2 times the ULN, 
complete an IRE form or other documentation with all values listed and also report as an 
AE in the eCRF. 
 
8.8.7 
Procedure for Breaking the Blind 
This trial does not use blinding procedures. 
 

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8.8.8 
Follow-up of Adverse Events 
8.8.8.1 
Follow-up of Nonserious Adverse Events 
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eCRF with the current status (ongoing or resolved/recovered) noted. All nonserious 
events (that are not IREs) that are ongoing at the last scheduled contact will be recorded 
as ongoing in the eCRF. For any AE having been identified throughout the trial, during 
analysis, additional relevant medical history information may be requested by the sponsor 
to further ascertain causality (including, but not limited to, information such as risk-
related behavior, family history, and occupation). 
 
8.8.8.2 
Follow-up of Immediately Reportable Events 
This trial requires that subjects be actively monitored for IREs up to the last scheduled 
contact (Week 56, 28 days after the last dose of IMP is administered). 
Immediately reportable events that are identified or ongoing at the last scheduled contact 
must be recorded as such on the AE eCRF page and the IRE form or other 
documentation. If updated information (eg, resolved status) on IRE status becomes 
available after a subject’s last scheduled contact (up to last in-clinic visit for the entire 
trial), this must be reported to the sponsor and recorded on the AE eCRF page and the 
IRE form or other documentation, according to the appropriate reporting procedures 
described in Section 8.8.3. 
It is expected that the investigator or subinvestigator will provide or arrange appropriate 
supportive care for the subject and will provide prompt updates on the subject’s status to 
the sponsor. The investigator or subinvestigator will follow IREs until: 
 The events have resolved, 
 The events have stabilized, 
 The subject is lost to follow-up, or 
 The subject has died. 
 
Resolution means that the subject has returned to the baseline state of health and 
stabilized means that the investigator or subinvestigator does not expect any further 
improvement or worsening of the subject’s condition. The investigator or subinvestigator 
will continue to report any significant follow-up information to the sponsor up to the 
point the event has resolved or stabilized, or the subject is lost to follow-up, or has died. 

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Refer to Section 10.3 for additional information regarding the duration of follow-up for 
subjects that become pregnant or for pregnant partners of male subjects. 
 
8.8.8.3 
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact 
Any new IREs reported to the investigator or subinvestigator which occur after the last 
scheduled contact and are determined by the investigator or subinvestigator to be 
reasonably associated with the use of the trial intervention, should be reported to the 
sponsor according to the procedures outlined in Section 8.8.3. This may include IREs that 
are captured on follow-up telephone contact or at any other time point after the defined 
trial period and continue to report any significant follow-up information to the sponsor 
until the events are resolved or stabilized, or the subject is lost to follow-up or has died. 
 
8.9 
Treatment of Overdose 
For treatment of overdose, refer to the overdose section of the IB. There is no specific 
treatment for overdose with ETC-1002. In the event of overdose, symptomatic and 
supportive therapies should be provided as appropriate. 
 
8.10 
Subject Assessment Recording 
8.10.1 
Completion of the Subject Diary 
The investigator or subinvestigator will instruct the subjects who are judged able to 
receive the IMP to enter the status of compliance with the IMP and lipid-lowering drugs 
in the subject diary, and bring it to the visit. The investigator or subinvestigator will 
record the status of compliance with the IMP and lipid-lowering drugs in the eCRF based 
on the contents entered in the subject diary. 
 
8.11 
Other Assessments 
8.11.1 
Pregnancy Test 
A urine test will be performed for females of childbearing potential according to the 
schedule specified in Table 1.3-1, and the date and result of the test will be recorded in 
the source document and the eCRF. A definition of childbearing potential can be found in 
Section 10.3. Subjects with a positive urine test will be withdrawn from the trial. 

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However, any positive urine test on or after Day 1 will lead to a re-test using serum to 
confirm the diagnosis, and the date of blood sampling will be recorded in the source 
document and the eCRF. If the serum test is positive, the investigator or subinvestigator 
will report it to the sponsor as an IRE. 
The serum test will be performed by the central laboratory selected by the sponsor. 
Proper sample collection, handling, and shipping procedures will be provided to the trial 
sites in a separate manual prior to the start of the trial. The central laboratory will report 
the test results to the investigator or subinvestigator who confirms the test results. The 
laboratory report will be officially documented by entering the date of confirmation and 
signing the report by the investigator or subinvestigator. The results of the serum test will 
be directly reported to the sponsor by the central laboratory in electronic files. Therefore, 
it is not necessary to record the results in the source document and the eCRF. 
 
8.11.2 
Endocrine Test and Virus Test 
Samples for the endocrine test (of TSH) and the virus test (of HBsAg and HCV 
antibodies) will be collected at Week −2 in newly enrolled subjects to confirm eligibility 
of subjects regarding thyroid and liver function. The date of blood sampling will be 
recorded in the source document and the eCRF. Samples will be shipped to the central 
laboratory selected by the sponsor, and eligibility will be confirmed based on the test 
results measured by the central laboratory. Proper sample collection, handling, and 
shipping procedures will be provided to the trial sites in a separate manual prior to the 
start of the trial. The central laboratory will report the test results to the investigator or 
subinvestigator who confirms the results. The laboratory report will be officially 
documented by entering the date of confirmation and signing the report by the 
investigator or subinvestigator. The test results will be directly reported to the sponsor by 
the central laboratory in electronic files. Therefore, it is not necessary to record the results 
in the source document and the eCRF. Since the eligibility of the rollover subjects has 
been confirmed in the phase 3 confirmatory trial (Protocol No. 346-102-00002), it is not 
necessary to conduct the test in this trial. 
 

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9 
Statistical Considerations 
9.1 
Sample Size 
Assuming a withdrawal of approximately 20 subjects during the treatment period, the 
target number of subjects is set at 120 to ensure that 100 subjects will complete the 1-year 
treatment to assess the safety of ETC-1002 at 180 mg in long-term administration. 
 
9.2 
Datasets for Analysis 
The safety analysis set will include subjects who receive at least one dose of the IMP 
during the treatment period. 
The efficacy analysis set will include subjects who receive at least one dose of the IMP 
during the treatment period, and who have LDL-C measurements at baseline and at one 
or more time points after administration of the IMP during the treatment period. 
 
9.3 
Handling of Missing Data for Primary Endpoint Analysis 
Missing data will not be imputed. 
 
9.4 
Statistical Analyses 
9.4.1 
Efficacy Analyses 
Efficacy analyses will be performed using the efficacy analysis set by rollover subjects, 
newly enrolled subjects, and overall (rollover and newly enrolled) subjects. Baseline is 
defined as the last data before the start of IMP administration in the treatment period. 
 
9.4.1.1 
Efficacy Endpoint Analysis 
Descriptive statistics of the actual value and the percent change from baseline will be 
calculated at each time point for LDL-C. 
Descriptive statistics of the actual value and the percent change from baseline will be 
calculated at each time point for non-HDL-C, TC, apo B, hsCRP, and HbA1c. 
The number and percentage of subjects whose LDL-C value achieves the lipid 
management goals based on the risk assessment (<100 mg/dL [history of coronary artery 

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disease or heterozygous familial hypercholesterolemia], <120 mg/dL [high risk], or 
<140 mg/dL [intermediate risk]) will be calculated at each time point. 
 
9.4.1.2 
Other Efficacy Endpoint Analysis 
Descriptive statistics of the actual value and the percent change from baseline will be 
calculated at each time point for HDL-C and TG. 
 
9.4.2 
Safety Analysis 
Safety analyses will be performed using the safety analysis set by rollover subjects, 
newly enrolled subjects, and overall (rollover and newly enrolled) subjects. Baseline is 
defined as the last data before the start of IMP administration in the treatment period. 
 
9.4.2.1 
Adverse Events 
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities preferred term. The incidence of the following events will be summarized: 
 Treatment-emergent AEs 
 TEAEs by severity 
 TEAEs causally related to the IMP 
 TEAEs with an outcome of death 
 Serious TEAEs 
 TEAEs leading to discontinuation of the IMP 
 TEAEs of special interest (including muscle-related TEAE and TEAE associated with 
hepatic impairment) 
 
9.4.2.2 
Clinical Laboratory Data 
For parameters other than qualitative urinalysis, descriptive statistics of the actual value 
and change from baseline will be calculated at each time point. For qualitative urinalysis 
parameters, shift tables at each time point from baseline will be prepared. For parameters 
other than qualitative urinalysis, measured values will be categorized using the reference 
range to “below the lower limit of reference range,” “within the reference range,” and 
“above the upper limit of reference range,” and shift tables at each time point from 
baseline will be prepared. 

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The number and percentage of subjects meeting Criteria for Identifying Laboratory 
Values of Potential Clinical Relevance will be calculated. 
 
9.4.2.3 
Physical Examination and Vital Signs Data 
Physical examination results will be tabulated. 
For vital signs (blood pressure, pulse rate, and body temperature), descriptive statistics of 
the actual value and change from baseline will be calculated at each time point. 
The number and percentage of subjects meeting Criteria for Identifying Vital Signs of 
Potential Clinical Relevance will be calculated. 
 
9.4.2.4 
Electrocardiogram Data 
For ECG parameters (heart rate, PR interval, RR interval, QRS interval, QT interval, and 
QTcF), descriptive statistics of the actual value and change from baseline will be 
calculated at each time point. The number and percentage of subjects with an actual value 
of QTcF of >450 msec, >480 msec, or >500 msec at any postdose time point will be 
calculated. In addition, the number and percentage of subjects with a change from 
baseline in QTcF of >30 msec or >60 msec at any postdose time point will be calculated. 
Similarly, the number and percentage of subjects meeting these criteria at each postdose 
time point will also be calculated. 
For assessment of normality/abnormality, shift tables at baseline and each time point will 
be prepared. 
 
9.4.2.5 
Other Safety Data 
Descriptive statistics of the actual value and change from baseline will be calculated at 
each time point for body weight. 
The number and percentage of subjects meeting Criteria for Identifying Body Weight of 
Potential Clinical Relevance will be calculated. 
 

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9.4.3 
Other Analyses 
9.4.3.1 
Analysis of Demographic and Baseline Characteristics 
Frequency distributions or descriptive statistics of each item for demographic and other 
baseline characteristics will be calculated in each analysis set. The summarization will be 
performed by rollover subjects, newly enrolled subjects, and overall (rollover and newly 
enrolled) subjects. 
 
9.4.3.2 
Pharmacokinetic Analysis 
No pharmacokinetic analysis is planned. 
 
9.4.3.3 
Pharmacodynamic Analysis 
No pharmacodynamic analysis is planned. 
 
9.4.3.4 
Pharmacokinetic/Pharmacodynamic Analysis 
No pharmacokinetic/pharmacodynamic analysis is planned. 
 
9.4.3.5 
Pharmacogenomic Analysis 
No pharmacogenomic analysis is planned. 
 
9.4.3.6 
Exploratory Endpoint Analysis 
Not applicable. 
 
9.5 
Interim Analysis and Adaptive Design 
Not applicable for interim analysis or adaptive design. 
 
9.5.1 
Data Monitoring Committee 
Not applicable. 
 

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10 
Supporting Documentation and Operational Considerations 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight 
Considerations 
10.1.1 
Ethics and Responsibility 
This trial must be conducted in compliance with the protocol, applicable ICH 
(International Council for Harmonisation) GCP guidance, international ethical principles 
derived from the Declaration of Helsinki and Council for International Organizations of 
Medical Science guidelines, and applicable local laws and regulations. Each trial site will 
seek approval by an IRB according to regional requirements, and the trial site will 
provide that documentation to the sponsor. The IRB will evaluate the ethical, scientific, 
and medical appropriateness of the trial. Further, in preparing and handling the eCRF, 
IRE, and any safety information, the investigator, subinvestigator, and their staff will take 
measures to ensure adequate care in protecting subject privacy. To this end, a subject ID 
will be used to identify each subject. 
Financial aspects, subject insurance, and the publication policy for the trial will be 
documented in the agreement between the sponsor and the trial site. 
 
10.1.2 
Informed Consent 
Informed consent will be freely obtained from all subjects (or their guardian or legally 
acceptable representative, as applicable for local laws). The ICF will be approved by the 
same IRB that approves this protocol. 
Each ICF will comply with the ICH GCP Guidelines, and local regulatory requirements. 
In support of the site’s standard process for administering informed consent, this trial will 
also allow for eICF as a tool within applicable regions and trial sites. The eICF utilizes 
the IRB approved site-specific ICF to offer subjects an enhanced platform to review and 
understand their rights as a research subject as well as required trial procedures. When 
possible, trial sites will have subjects review and sign the eICF prior to starting any trial 
procedures; however, if local regulations do not allow for use of the electronic format, 
subjects may continue in the trial utilizing the standard paper and wet ink signature 
process. 
Investigators or subinvestigators may discuss trial availability and the possibility for 
entry with a potential subject without first obtaining consent. However, informed consent 
must be obtained and documented before initiation of any procedures that are performed 

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solely for the purpose of determining eligibility for this trial, including withdrawal from 
current medication(s). 
Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care. 
Prospective trial subjects will be provided with controlled access to the eICF application 
by trial site staff. When the trial site staff and the subject agree that the subject has 
enough information to make an informed decision to participate, the subject will 
electronically sign in the eICF application of the trial site and an electronic date and 
timestamp will be applied to the signature. The subject will be given a printed, signed 
copy of the ICF. Any other parties required by the IRB (trial site staff, witnesses, or 
legally authorized representative) are also required to sign electronically and these 
signatures will be stored with the eICF in accordance with the ICH GCP Guideline and 
local regulatory requirements/guidelines. These signatures cannot be altered, removed, or 
copied. After the completion of the trial, the investigator or subinvestigator will store the 
electronic original (PDF) output from the eICF application. 
For the paper ICF, once appropriate essential information has been provided and fully 
explained in layman’s terms to the subject by the investigator/subinvestigator (or a 
qualified designee), and it has been documented that the subject has had the opportunity 
to ask questions, the IRB approved written ICF will be signed and dated by both the 
subject and the person obtaining consent (investigator/subinvestigator or designee), as 
well as by any other parties required by the IRB. The subject will receive a copy of the 
signed ICF; the original shall be kept on file by the investigator or subinvestigator. 
Subjects may be asked to sign additional ICFs if the protocol is amended and the changes 
to the protocol result in additional information that needs to be provided to the subjects, 
so that they can make a knowledgeable and voluntary decision on continued trial 
participation. Female partners of male subjects who become pregnant during the course 
of the trial may be asked to sign additional ICFs in order to collect additional information 
regarding the non-subject partner and fetus. 
A separate and similar consent process will be followed for the optional blood samples 
for FBR. Consent must be obtained before the blood sample is collected. Sample storage 
for FBR is optional and will not affect the subject’s participation in the trial if the subject 
does not consent to the FBR sample storage. 
 

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10.1.3 
Confidentiality 
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region(s) where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. All IMPs, subject bodily fluids, and/or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor. 
Subjects will be identified only by unique subject ID in the eCRF. If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations. 
 
10.1.4 
Quality Control and Quality Assurance 
The sponsor will perform quality management activities for this trial in accordance with 
the ICH GCP guidance and standard operating procedures. 
 
10.1.4.1 
Monitoring 
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the applicable ICH GCP guidance, and applicable 
regulatory requirements and local laws. As part of a concerted effort to fulfill these 
obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor’s monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications. In addition, all 
investigators/subinvestigators and trial site personnel will undergo initial and ongoing 
training for this particular trial, and this training will be clearly documented. 
 
10.1.4.2 
Auditing 
The sponsor’s Quality Assurance Unit (or representative) may conduct trial site audits. 
Audits will include, but are not limited to, IMP supply, presence of required documents, 
the informed consent process, site operations, delegation of authority and training, and a 
review of the eCRF with source documents, as applicable. The investigator will agree to 
cooperate and participate with audits. 

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Regulatory authorities may inspect the trial site during or after the trial. The investigator 
will cooperate with such inspections and will contact the sponsor immediately if such an 
inspection occurs. 
 
10.1.5 
Protocol Deviations 
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, subject enrolled in violation of eligibility criteria or concomitant medication 
criteria), the investigator/subinvestigator or designee will contact the sponsor at the 
earliest possible time by telephone or via e-mail. The investigator/subinvestigator and 
sponsor (or designee) will come as quickly as possible to a joint decision regarding the 
subject’s continuation in the trial. This decision will be documented by the 
investigator/subinvestigator and the sponsor (or designee) and reviewed by the site 
monitor. 
Any major protocol deviation will be recorded in the eCRF along with the start date and 
details of the deviation. 
 
10.1.6 
Records Management 
10.1.6.1 
Source Documents 
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include but are not limited to medical 
records, electronic data, logs, and recorded data from automated instruments or 
applications. All source documents pertaining to this trial (excluding FBR documents) 
will be maintained by the trial sites and made available for direct inspection by 
authorized persons. 
Investigators/trial sites will permit trial-related monitoring, audits, IRB review, and 
regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF. In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements. 
 

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10.1.6.2 
Data Collection 
During each subject’s visit to the site, an investigator/subinvestigator or their designee 
participating in the trial will record information to document all significant observations. 
At a minimum, these notes will contain: 
 Documentation of the informed consent process, including any revised consents; 
 Documentation of the investigator/subinvestigator’s decision to enroll the subject into 
the trial, the review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial; 
 The date of the visit and the corresponding Visit or Day in the trial schedule; 
 General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator/subinvestigator’s assessment of relationship to IMP must also be 
recorded; 
 Any changes in concomitant medications or dosages; 
 A general reference to the procedures completed, including dosing and IMP 
compliance; 
 The signature (or initials) and date of the investigator/subinvestigator (or designee) 
who made an entry in the medical record. 
 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above. 
 
Information from medical records and other source documents will be entered by 
investigative site personnel onto eCRFs in the sponsor’s electronic data capture (EDC) 
system that is 21 CFR Part 11 compliant. Changes to the data will be captured by an 
automatic audit trail in the EDC system. 
Electronic data not entered on eCRF, such as data received from central laboratories, will 
be reconciled using key data fields by the sponsor or designee with the eCRF data to 
ensure consistency. 
 
10.1.6.3 
File Management at the Trial Site 
The head of the trial site will ensure that the trial site file is maintained in accordance 
with applicable ICH guidance and as required by applicable local regulations. The trial 
site will take measures to prevent accidental or premature destruction of these documents. 
 

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10.1.6.4 
Records Retention at the Trial Site 
The trial site will retain all documents and records related to this trial for the longest of 
the following 3 periods. However, if the sponsor requires a longer storage period, the 
storage period and method will be discussed with the sponsor. 
 A period of at least 2 years after the date on which approval to market the IMP is 
obtained; However, in the case that development is discontinued or a notification to 
inform that the trial results will not be attached to the approval application is 
received, a period of at least 3 years after the decision date of stopping development, 
or the receiving date of the notification informing that the trial results will not be 
attached to the approval application. 
 A period of at least 3 years after date of trial discontinuation/completion; OR 
 The period of FBR sample storage. 
 
The trial site must not dispose of any records relevant to this trial without either (1) 
written permission from the sponsor or (2) provision of an opportunity for the sponsor to 
collect such records. The trial site will be responsible for maintaining adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
during this trial including any data clarification forms received from the sponsor. Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities. 
 
10.1.6.5 
Publication Authorship Requirements 
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 
criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met: 
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND 
2) Drafting the work or revising it critically for important intellectual content; AND 
3) Final approval of the version to be published; AND 
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved. 
 
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors. 
Investigators or other trial subjects who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 

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trial, investigators or other trial subjects consent to such acknowledgement in any 
publications resulting from its conduct. 
 

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10.2 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 10.2-1 will be performed. 
 
Table 10.2-1 
Clinical Laboratory Assessments 
Hematology: 
Red blood cell count 
Hemoglobin 
Hematocrit 
Mean corpuscular hemoglobin concentration 
Mean corpuscular volume 
White blood cell (WBC) count 
WBC count with differential (neutrophils, 
eosinophils, basophils, monocytes, and 
lymphocytes) 
Platelets 
 
Urinalysis (parameters other than pH and specific 
gravity will be included in the qualitative 
urinalysis) 
pH 
Protein 
Glucose 
Occult blood 
Bilirubin 
Urobilinogen 
Specific gravity 
Ketones 
Serum Chemistry: 
Alkaline phosphatase 
ALT 
AST 
Total bilirubin 
Gamma glutamyl transferase 
Total protein 
Albumin 
Lactate dehydrogenase 
Blood urea nitrogen 
Creatinine 
Uric acid 
CK 
Serum electrolytes (sodium, potassium, chloride, 
calcium, bicarbonate) 
Glucose* 
*Testing will be performed in the fasting state. 
 

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10.3 
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information 
Females of childbearing potential (FOCBP) are females whose menstruation has started 
and who are not documented as sterile (eg, have had a bilateral oophorectomy, or 
hysterectomy, or who have been postmenopausal for at least 12 months). Females of 
nonchildbearing potential do not meet definition of FOCBP. 
For males and FOCBP, or their partners, who are sexually active, there must be a 
documented agreement that the subject and their partner will take effective measures (ie, 
2 different approved methods of birth control or remains abstinent) to prevent pregnancy 
during the course of the trial and for 30 days after the last dose of IMP. Unless the subject 
or his/her partner is sterile (ie, females who have had a bilateral oophorectomy, have had 
a hysterectomy, or have been postmenopausal for at least 12 consecutive months; or 
males who have had a bilateral orchiectomy) or remains abstinent during the trial and for 
30 days after the last dose of IMP, 2 of the following approved methods of birth control 
must be used: (vasectomy, tubal ligation, intrauterine device, birth control pill, or condom 
[all methods are approved or certificated in Japan]). Any single method of birth control, 
including vasectomy and tubal ligation, may fail, leading to pregnancy. Male subjects 
must agree not to donate sperm from the time of screening through the trial and until 
30 days after the last dose of IMP. 
Before enrolling males and females in this clinical trial, investigators or subinvestigators 
must review the below information about trial participation as part of the ICF process. 
The topics should generally include: 
 General information 
 The informed consent form 
 Pregnancy prevention information 
 Contraceptives in current use 
 Follow-up of a reported pregnancy 
 
Before trial enrollment, males and FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. Subjects must sign the ICF confirming that the above-mentioned risk factors 
and the consequences were discussed. 
A urine pregnancy test will be performed on all FOCBP. If a urine test is performed and 
is positive, the investigator or subinvestigator will follow-up with a confirmatory serum 
test (for human chorionic gonadotropin) (except at screening). 

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During the trial, all FOCBP should be instructed to contact the investigator or 
subinvestigator immediately if they suspect they might be pregnant (eg, missed or late 
menstrual cycle). Male subjects must be instructed to contact the investigator 
immediately, during the trial, if their partner suspects that they might be pregnant (eg, 
missed or late menstrual cycle). 
If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum pregnancy tests are available. If the pregnancy 
is confirmed, the subject must not receive the IMP and must not be enrolled in the trial. If 
pregnancy is suspected while the subject is taking IMP, the IMP must be withheld 
immediately (if reasonable, taking into consideration any potential withdrawal risks) until 
the result of the pregnancy test is known. If pregnancy is confirmed, the IMP will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for 
subject safety) and the subject will be withdrawn from the trial. Exceptions to trial 
discontinuation may be considered for life-threatening conditions only after consultations 
with the IRE contact (see the title page of this protocol for contact information). 
The investigator or subinvestigator must immediately notify the sponsor (within 
24 hours) of any pregnancy associated with IMP exposure during the trial and for at least 
30 days after the last dose of IMP, and record the event on the IRE form or other 
documentation and forward it to the sponsor. The sponsor will forward the Pregnancy 
Surveillance Form(s) to the investigator or subinvestigator for monitoring the outcome of 
the pregnancy. 
Protocol required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. In addition, the 
investigator or subinvestigator must report to the sponsor, on the Pregnancy Surveillance 
Form(s), follow-up information regarding the course of the pregnancy, including 
perinatal and neonatal outcome. Infants will be followed for a minimum of 6 months 
from the date of birth. 
 

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10.4 
Appendix 4: Protocol Amendments 
The investigator or subinvestigator will not make any changes to this protocol without the 
sponsor’s prior written consent and subsequent approval by the IRB. Any permanent 
change to the protocol, whether an overall change or a change for specific trial site(s), 
must be handled as a protocol amendment. Any amendment will be written by the 
sponsor. Each amendment will be submitted to the IRB, as required by local regulations. 
Except for “administrative” or “nonsubstantial” amendments, investigators or 
subinvestigator will wait for IRB approval of the amended protocol before implementing 
the change(s). Administrative amendments are defined as having no effect on the safety 
of subjects, conduct or management of the trial, trial design, or the quality or safety of 
IMPs used in the trial. A protocol change intended to eliminate an apparent immediate 
hazard to subjects should be implemented immediately, followed by IRB notification 
within local applicable timelines. If required, the sponsor will submit protocol 
amendments to the applicable regulatory agencies within local applicable timelines. 
When the IRB, investigators, and/or the sponsor conclude that the protocol amendment 
substantially alters the trial design and/or increases the potential risk to the subject, the 
currently approved written ICF will require similar modification. In such cases, after 
approval of the new ICF by the IRB, repeat written informed consent will be obtained 
from subjects enrolled in the trial before expecting continued participation and before the 
amendment-specified changes in the trial are implemented. 
 
10.4.1 
Protocol Amendment(s)/Administrative Change(s) 
Not applicable. 
 
 
 

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11 
References 
1 
Japan Atherosclerosis Society. Guidelines for Prevention of Atherosclerotic 
Cardiovascular Diseases 2017. 2017. 
2 
Japan Atherosclerosis Society. Guidelines for Prevention of Atherosclerotic 
Cardiovascular Diseases 2022. 2022. 
3 
Ministry of Health, Labour and Welfare. An Outline of the Patient Survey in Japan 
2017. [internet] https://www.mhlw.go.jp/toukei/saikin/hw/kanja/17/index.html 
4 
Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al. 
Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events. N 
Engl J Med. 2015;372(16):1500-9. 
5 
Yusuf S, Bosch J, Dagenais G, Zhu J, Xavier D, Liu L, et al. Cholesterol Lowering in 
Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 
2016;374(21):2021-31. 
6 
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. 
Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 
2015;372(25):2387-97. 
7 
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. 
Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl 
J Med. 2017;376(18):1713-22. 
8 
Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab 
and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 
2018;379(22):2097-107. 
9 
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA 
Guideline on the Management of Blood Cholesterol: A Report of the American 
College of Cardiology/American Heart Association Task Force on Clinical Practice 
Guidelines. Circulation. 2019;139(25):e1082-143. 
10 Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 
ESC/EAS Guidelines for the Management of Dyslipidaemias: Lipid Modification to 
Reduce Cardiovascular Risk. Eur Heart J. 2020;41(1):111-88. 
11 Japan Atherosclerosis Society. Statin Intolerance Clinical Guide 2018. 2018. 
12 Ministry of Health, Labour and Welfare. Clinical Trials That Use Pharmacogenomics. 
PFSB/ELD Notification No. 0930007. 2008. 
13 Ministry of Health, Labour and Welfare. Guideline on Genomic Sampling and 
Management of Genomic Data, PSEHB/PED Notification No. 0118-1. 2018. 
 
 
 
 

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Agreement 
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator’s Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor’s (or designee’s) Clinical Trial Agreement. 
 
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, ETC-1002, the concurrent medications, 
the efficacy and safety parameters and the conduct of the trial in general. I am aware that this protocol 
must be approved by the Institutional Review Board (IRB) responsible for such matters in the clinical 
trial facility where ETC-1002 will be tested prior to commencement of this trial. I agree to adhere 
strictly to the attached protocol (unless amended in the manner set forth in the sponsor’s Clinical Trial 
Agreement, at which time I agree to adhere strictly to the protocol as amended). 
 
I understand that this IRB-approved protocol will be submitted to the appropriate regulatory 
authority/ies by the sponsor. I agree that clinical data entered on eCRF by me or subinvestigator, and 
my staff will be utilized by the sponsor in various ways, such as for submission to governmental 
regulatory authorities and/or in combination with clinical data gathered from other research sites, 
whenever applicable. I agree to allow sponsor and designee monitors and auditors full access to all 
medical records at the research facility for subjects screened or enrolled in the trial. 
 
I agree to await IRB approval before implementation of any substantial amendments to this protocol. 
If, however, I do not comply with the protocol to avoid an immediate hazard to subjects, I will provide 
the information to the IRB within the required local applicable timelines. Administrative changes to 
the protocol will be transmitted to the IRB for informational purposes only, if required by local 
regulations. 
 
I agree to provide all subjects with informed consent forms, as required by the applicable regulations 
and by ICH guidelines. I agree to report to the sponsor any adverse experiences in accordance with the 
terms of the sponsor’s Clinical Trial Agreement and the relevant regional regulation(s) and 
guideline(s). I further agree to provide all required information regarding financial certification or 
disclosure to the sponsor for all investigators and subinvestigators in accordance with the terms of the 
relevant regional regulation(s). I understand that participation in the protocol involves a commitment 
to publish the data from this trial in a cooperative publication before publication of efficacy and safety 
results on an individual basis may occur, and I consent to be acknowledged in any such cooperative 
publications that result. 
 
 
 
 
 
Principal Investigator Print Name 
Name of the Trial Site 
 
 
 
DD Mon YYYY 
 
Signature 
 
Date 
 
The sponsor’s signature on this agreement has been electronically signed. The electronic signature 
page is attached to this agreement.