A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial to Evaluate the Efficacy and Safety of ETC-1002 in Patients With Hypercholesterolemia
Phase: PHASE2
Conditions: Hypercholesterolemia
Sponsor: Otsuka Pharmaceutical Co., Ltd.

 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A Placebo-controlled, Randomized, Multicenter, Double-blind, Parallel-Group Trial to 
Assess the Efficacy and Safety of ETC-1002 in Patients With Hypercholesterolemia 
 
A Dose-finding Trial of ETC-1002 in Patients With Hypercholesterolemia 
 
 
 
 
 
NCT Number: NCT04784442 
Protocol No. 346-102-00001 
Version Date: 19 Nov 2021 (Version 2.0) 

Protocol 346-102-00001
Otsuka Pharmaceutical Co., Ltd.
Investigational Medicinal Product
ETC-1002 (Nonproprietary name: Bempedoic acid)
CLINICAL PROTOCOL
Translation
A Placebo-controlled, Randomized, Multicenter, Double-blind, Parallel-Group Trial to 
Assess the Efficacy and Safety of ETC-1002 in Patients With Hypercholesterolemia
A Dose-finding Trial of ETC-1002 in Patients With Hypercholesterolemia
Protocol No. 346-102-00001
CONFIDENTIAL  PROPRIETARY INFORMATION
Clinical Development Phase:
2
Sponsor:
Otsuka Pharmaceutical Co., Ltd.
Immediately Reportable Event:
Office of PV Operations Department of 
Pharmacovigilance
Amendment 1 Approval:
19 Nov 2021
Approval:
06 Jan 2021
Date of Translation:
03 Dec 2021

Protocol 346-102-00001
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Table of Contents
Table of Contents ..........................................................................................2
List of In-text Tables.....................................................................................8
List of In-text Figures ...................................................................................9
List of Abbreviations...................................................................................10
1
Protocol Summary .............................................................................12
1.1
Synopsis ............................................................................................................12
1.2
Schema ..............................................................................................................21
1.3
Schedule of Assessments ..................................................................................22
1.3.1
Informed Consent ...........................................................................................26
1.3.2
Screening ........................................................................................................26
1.3.5
Observation and Examinations During the Treatment Period........................27
1.3.6
Observation and Examinations During the Follow-up Period .......................28
1.3.7
Withdrawal Examination................................................................................28
2
Introduction........................................................................................28
2.1
Non-clinical Study Results................................................................................30
2.2
Clinical Trial Results.........................................................................................32
2.3
Trial Rationale...................................................................................................33
2.4
Background .......................................................................................................35
2.5
Known and Potential Risks and Benefits..........................................................36
3
Objectives and Endpoints..................................................................37
4
Trial Design.........................................................................................38
4.1
Type/Design of Trial.........................................................................................38
4.1.2
Treatment Period ............................................................................................39
4.2
Scientific Rationale for Trial Design ................................................................40
4.3
Rationale for Dosage Regimen .........................................................................41
4.4
End of Trial Definition......................................................................................42
4.5
Definition of Completed Subjects.....................................................................42

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Trial Population .................................................................................42
5.1
Subject Selection and Numbering.....................................................................42
5.2
Eligibility Criteria .............................................................................................43
5.2.1
Inclusion Criteria............................................................................................43
5.2.2
Exclusion Criteria...........................................................................................44
5.3
Lifestyle Considerations....................................................................................47
5.3.1
Meals and Dietary Restrictions ......................................................................47
5.3.2
Caffeine, Alcohol, and Tobacco.....................................................................47
5.3.3
Activity...........................................................................................................48
5.4
Screen Failures..................................................................................................48
6
Trial Treatments ................................................................................49
6.1
Trial Treatments Administered .........................................................................49
6.1.2
Treatment Period ............................................................................................49
6.1.3
Medical Devices .............................................................................................50
6.2
Management of Investigational Medicinal Product ..........................................50
6.2.1
Packaging and Labeling .................................................................................50
6.2.2
Storage............................................................................................................50
6.2.3
Accountability ................................................................................................50
6.2.4
Returns and Destruction .................................................................................51
6.2.5
Reporting of Product Quality Complaints......................................................51
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 .............................52
6.2.5.4
Assessment/Evaluation ...............................................................................52
6.3
Measures to Minimize/Avoid Bias....................................................................52
6.4
Subject Compliance ..........................................................................................53
6.5
Concomitant Medications or Therapies ............................................................53
6.5.1
Prohibited Medications...................................................................................54
6.5.2
Prohibited Therapies.......................................................................................54
6.5.3
Permitted Medications or Therapies...............................................................54
6.5.4
Rescue Medications........................................................................................55

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6.6
Intervention After the End of the Trial .............................................................55
7
Withdrawal Criteria and Procedures...............................................55
7.1
Entire Trial or Treatment Discontinuation........................................................55
7.2
Individual Site Discontinuation.........................................................................55
7.3
Individual Subject Discontinuation...................................................................56
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..........................................................59
8
Trial Procedures.................................................................................59
8.1
Efficacy Assessments........................................................................................59
8.2
Pharmacokinetic Assessments ..........................................................................60
8.2.1
Pharmacokinetic Plasma Samples ..................................................................61
8.3
Pharmacodynamic Assessments........................................................................62
8.4
Pharmacogenomic Assessments........................................................................62
8.6
Future Biospecimen Research Samples ............................................................62
8.6.1
Scope of Future Biospecimen Research.........................................................63
8.6.2
Summary of Procedures for Future Biospecimen Research Samples ............64
8.6.3
Storage of Future Biospecimen Research Samples........................................64
8.6.4
Genomic/genetic Analysis and Biomarker Exploration.................................64
8.6.5
Acquisition and Withdrawal of Informed Consent for Future 
Biospecimen Research....................................................................................65
8.6.6
Disclosure of Results of Genomic/genetic Analysis and Biomarker 
Exploration to Subjects...................................................................................65
8.7
Safety Assessments ...........................................................................................66
8.7.1
Clinical Laboratory Assessments ...................................................................66
8.7.2
Physical Examination .....................................................................................67
8.7.3
Vital Signs ......................................................................................................68
8.7.4
Electrocardiogram ..........................................................................................68

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8.7.5
Suicidality Monitoring....................................................................................68
8.7.6
Other Safety Variables ...................................................................................69
8.7.6.1
Height/body Weight....................................................................................69
8.8
Adverse Events..................................................................................................69
8.8.1
Definitions ......................................................................................................69
8.8.2
Eliciting and Reporting Adverse Events ........................................................71
8.8.3
Immediately Reportable Events .....................................................................72
8.8.4
Medical Device Incidents (Including Malfunctions)......................................72
8.8.5
Adverse Events of Special Interest.................................................................72
8.8.6
Potential Serious Hepatotoxicity ....................................................................72
8.8.7
Procedure for Breaking the Blind...................................................................73
8.8.8
Follow-up of Adverse Events.........................................................................73
8.8.8.1
Follow-up of Nonserious Adverse Events..................................................73
8.8.8.2
Follow-up of Immediately Reportable Events............................................73
8.8.8.3
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact....................................................74
8.9
Treatment of Overdose......................................................................................75
8.10
Subject Assessment Recording .........................................................................75
8.10.1
Completion of Subject Diary..........................................................................75
8.11
Other Assessments ............................................................................................75
8.11.1
Pregnancy Test ...............................................................................................75
8.11.2
Endocrine Test and Virus Test .......................................................................76
9
Statistical Considerations..................................................................76
9.1
Sample Size.......................................................................................................76
9.2
Datasets for Analysis.........................................................................................77
9.3
Handling of Missing Data for Primary Endpoint Analysis...............................77
9.4
Statistical Analyses ...........................................................................................77
9.4.1
Efficacy Analyses...........................................................................................77
9.4.1.1
Primary Efficacy Endpoint Analysis ..........................................................78
9.4.1.2
Key Secondary Efficacy Endpoint Analysis...............................................78
9.4.1.3
Secondary Efficacy Endpoint Analysis ......................................................78
9.4.1.4
Control of Experiment-wise Type 1 Error..................................................79
9.4.1.5
Other Efficacy Endpoint Analysis ..............................................................79

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9.4.1.6
Subgroup Analyses .....................................................................................79
9.4.2
Safety Analysis...............................................................................................79
9.4.2.1
Adverse Events ...........................................................................................79
9.4.2.2
Clinical Laboratory Data.............................................................................80
9.4.2.3
Vital Signs Data..........................................................................................80
9.4.2.4
Electrocardiogram Data ..............................................................................81
9.4.2.5
Other Safety Data........................................................................................81
9.4.3
Other Analyses ...............................................................................................81
9.4.3.1
Analysis of Demographic and Baseline Characteristics .............................81
9.4.3.2
Pharmacokinetic Analysis...........................................................................81
9.4.3.3
Pharmacodynamic Analysis........................................................................82
9.4.3.4
Pharmacokinetic/Pharmacodynamic Analysis............................................82
9.4.3.5
Pharmacogenomic Analysis........................................................................82
9.4.3.6
Exploratory Endpoint Analysis...................................................................82
9.5
Interim Analysis and Adaptive Design .............................................................82
9.5.1
Data Monitoring Committee...........................................................................82
10
Supporting Documentation and Operational Considerations .......83
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations ............83
10.1.1
Ethics and Responsibility ...............................................................................83
10.1.2
Informed Consent ...........................................................................................83
10.1.3
Confidentiality................................................................................................84
10.1.4
Quality Control and Quality Assurance .........................................................84
10.1.4.1
Monitoring ..................................................................................................85
10.1.4.2
Auditing ......................................................................................................85
10.1.5
Protocol Deviations ........................................................................................85
10.1.6
Records Management .....................................................................................86
10.1.6.1
Source Documents ......................................................................................86
10.1.6.2
Data Collection ...........................................................................................86
10.1.6.3
File Management at the Trial Site...............................................................87
10.1.6.4
Records Retention at the Trial Site .............................................................87
10.1.6.5
Publication Authorship Requirements........................................................88
10.2
Appendix 2: Clinical Laboratory Tests.............................................................89

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10.3
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information........................................................................................................89
10.4
Appendix 4: Protocol Amendments..................................................................91
10.4.1
Protocol Amendment(s)/Administrative Change(s).......................................92
10.4.1.1
Protocol Amendment 1 ...............................................................................92
11
References...........................................................................................94

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List of In-text Tables
Table 1.3-1
Schedule of Assessments...............................................................22
Table 3-1
Trial Objectives and Endpoints .....................................................37
Table 6.5.1-1
List of Prohibited Medications, Food, and Preference 
Products .........................................................................................54
Table 6.5.3-1
List of Medications or Therapies Permitted Before and 
During the Trial .............................................................................55
Table 10.2-1
Clinical Laboratory Assessments ..................................................89

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List of In-text Figures
Figure 1.2-1
Trial Design Schematic..................................................................21

Protocol 346-102-00001
List of Abbreviations
Abbreviation
Definition
AE
Adverse event
ACL
Adenosine triphosphate citrate lyase
ALT
Alanine aminotransferase
apo B
Apolipoprotein B
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
BMI
Body mass index
CCDS
Company Core Data Sheet
CK
Creatine kinase
Cmax
Maximum (peak) plasma concentration of the drug
CRO
Contract research organization
CSR
Clinical study report
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
eGFR
Estimated glomerular filtration rate
FAS
Full analysis set
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
HeFH
Heterozygous familial hypercholesterolemia
HMG-CoA
3-hydroxy-3-methylglutaryl coenzyme A
HoFH
Homozygous familial hypercholesterolemia
hsCRP
High-sensitivity C-reactive protein
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
non-HDL-C
Non-high-density lipoprotein cholesterol
OAT
Organic anion transporter

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Abbreviation
Definition
PCSK9
Proprotein convertase subtilisin/kexin type 9
PPAR
Peroxisome proliferator-activated receptor
PQC
Product quality complaint
QTc
Corrected QT interval
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
TC
Total cholesterol
TEAE
Treatment-emergent adverse event
TG
Triglyceride
tmax
Time to maximum plasma concentration
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.:
346-102-00001
Protocol Title:
A placebo-controlled, randomized, multicenter, double-blind, parallel-group trial to 
assess the efficacy and safety of ETC-1002 in patients with hypercholesterolemia
Protocol Lay Person Short Title:
A dose-finding trial of ETC-1002 in patients with hypercholesterolemia
Clinical Phase/Trial Type:
Phase 2 trial/Dose-finding trial
Treatment/Indication:
Patients with hypercholesterolemia
Objectives and Endpoints:
Objectives
Endpoints
Primary Objectives:

To assess the low-density lipoprotein 
cholesterol (LDL-C)-lowering efficacy 
of ETC-1002 at 60 mg, 120 mg, and 
180 mg versus placebo when 
administered for 12 weeks in 
combination with ongoing stable statin 
therapy and/or other lipid-modifying 
therapy in patients with 
hypercholesterolemia who have 
inadequate control of LDL-C

To characterize the dose-response of 
ETC-1002 and investigate the 
appropriate dosage for a phase 3 trial
Primary Endpoint

Percent change in LDL-C from 
baseline to Week 12

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Secondary Objectives:

To assess the effect of ETC-1002 on 
high-density lipoprotein cholesterol 
(HDL-C), non-high-density lipoprotein 
cholesterol (non-HDL-C), total 
cholesterol (TC), triglyceride (TG), 
apolipoprotein B (apoB), high-
sensitivity C-reactive protein (hsCRP), 
and glycosylated hemoglobin (HbA1c)

To assess the proportion of subjects 
achieving the lipid management goals of 
LDL-C by treatment with ETC-1002.

To assess the pharmacokinetic plasma 
trough and near-peak concentrations of 
ETC-1002 and its active metabolite 
(ESP15228)

To characterize the safety and 
tolerability of ETC-1002 versus placebo 
in patients with hypercholesterolemia 
when administered in combination with 
ongoing stable statin therapy and/or 
other lipid-modifying therapy
Secondary Endpoints

Percent change in HDL-C, non-
HDL-C, TC, TG, apo B, hsCRP and 
HbA1c from baseline to Week 12

Proportion of subjects whose 
LDL-C value achieve the lipid 
management goals based on 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]) and the 
proportion of subjects whose LDL-C 
value achieve <70 mg/dL at 
Week 12
Other Assessments

Time course of LDL-C, HDL-C, 
non-HDL-C, TC, TG, apo B, 
hsCRP, and HbA1c at each time 
point during the treatment period
Pharmacokinetic Assessments

Plasma concentrations of ETC-1002 
and its active metabolite, ESP15228
Safety Assessments
Adverse events (AEs), clinical 
laboratory tests, physical examination, 
vital signs (blood pressure, pulse rate, 
and body temperature), body weight, 
and 12-lead electrocardiogram (ECG)
Trial Design:
A placebo-controlled, randomized, multicenter, double-blind, parallel-group trial
Trial Population:
This trial will enroll subjects with hypercholesterolemia aged 20 years or older and 
younger than 75 years who are at risk for cardiovascular events and who have inadequate 
control of LDL-C by the existing hypercholesterolemia drugs.
The target number of subjects is 176 in total (44 in the ETC-1002 60-mg/day group, 44 in 
the 120-mg/day group, 44 in the 180-mg/day group, and 44 in the placebo group) as 
randomized subjects.

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Inclusion/Exclusion Criteria:
Inclusion Criteria
1) Patients from whom written informed consent is obtained prior to start of the trial
2) Patients, either male or female, age 20 years or older and younger than 75 years at 
the time of informed consent
3) Patients who meet the following criteria for inadequate response to statins (statin 
tolerance) or statin intolerance

Statin tolerance
Patients with hypercholesterolemia who have been taking statins (atorvastatin, 
pitavastatin, rosuvastatin, pravastatin, simvastatin, or fluvastatin), and 
hypercholesterolemia drugs other than statins if necessary, at the same dose 
and regimen from at least 4 weeks prior to Week −5 (Visit S1) (at least 
6 weeks, for fibrates and selective peroxisome proliferator-activated receptor 
[PPAR] α modulators) to Week −5 (Visit S1) according to the approved 
dosage regimen, but fail to achieve the lipid management goals of LDL-C 
based on risk assessment shown in the inclusion criteria 4) at both Week −5 
(Visit S1) and Week −1 (Visit S3)

Statin intolerance
Patients with hypercholesterolemia in whom safety problems occurred when 
administration of statins was started or increased in dose and were resolved 
after discontinuation or dose reduction of statin administration, and who have 
been taking statins at (or below) the lowest approved daily dose and/or who 
have been taking at least one hypercholesterolemia drug other than statins at 
the same dose and regimen from at least 4 weeks prior to Week −5 (Visit S1) 
(at least 6 weeks, for fibrates and selective PPAR α modulators) to Week −5 
(Visit S1) according to the approved dosage regimen, but fail to achieve the 
lipid management goals of LDL-C based on risk assessment shown in the 
inclusion criteria 4) at both Week −5 (Visit S1) and Week −1 (Visit S3)
4) Patients considered to be at risk of developing cardiovascular events who meet 
any of the following conditions a), b), or c)
a) Patients with either of the following medical histories or complications and in 
whom LDL-C at Week −5 (Visit S1) and Week −1 (Visit S3) is ≥100 mg/dL

History of coronary artery disease

Diagnosed with heterozygous familial hypercholesterolemia (HeFH)
b) Patients with any of the following medical histories or complications and in 
whom LDL-C at Week −5 (Visit S1) and Week −1 (Visit S3) is ≥120 mg/dL

Diagnosed with peripheral arterial disease

History of non-cardiogenic cerebral infarction

Diagnosed with chronic kidney disease and does not fall under the 
exclusion criteria 12)

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
Diagnosed with type 2 diabetes mellitus more than 3 months prior to 
Week −5 (Visit S1) and does not fall under the exclusion criteria 7)
c) Patients who do not meet inclusion criteria a) or b), but whose 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) and in whom each LDL-C level at Week −5 (Visit S1) and 
Week −1 (Visit S3) is ≥140 mg/dL, or whose total score is ≥56 (high risk) and 
in whom each LDL-C level at Week −5 (Visit S1) and Week −1 (Visit S3) is 
≥120 mg/dL
5) Patients with fasting TG level of <400 mg/dL at Week −5 (Visit S1)
6) Patients with body mass index (BMI) of ≥18 kg/m2 and <35 kg/m2 at Week −5 
(Visit S1)
Exclusion Criteria
1) Women who are pregnant or breastfeeding or who have a positive pregnancy test 
(urine) result at Week −5 (Visit S1) or Day 1 (Visit T1)
2) Sexually active male subjects or sexually active female subjects 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 Investigational Medicinal Product (IMP) administration. If 
employing birth control, 2 of the following methods must be used: vasectomy, 
tubal ligation, intrauterine device, birth control pill, and condoms (all methods are 
approved or certified in Japan).
3) Patients with homozygous familial hypercholesterolemia (HoFH)
4) Patients with a history or current symptoms of any of the following cardiovascular 
diseases within 3 months prior to Week −5 (Visit S1)
 

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 long-QT syndrome, family history of long-QT 
syndrome, or risk factors for Torsade de Pointes, such as persistent 
hypokalemia or second- or third-degree atrioventricular block (except when 
controlled by medication, etc)
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 Week −5 (Visit S1)
6) Patients with uncontrolled and serious hematologic or coagulation disorders or 
with Hgb of <10.0 g/dL at Week −5 (Visit S1)

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7) Patients with type 1 diabetes or uncontrolled type 2 diabetes with HbA1c of ≥9% 
at Week −5 (Visit S1)
8) Patients with uncontrolled hypothyroidism with thyroid-stimulating hormone 
(TSH) of >1.5 × the upper limit of normal (ULN) at Week −5 (Visit S1)
9) Patients with liver disease or dysfunction, including:

Positive serology for hepatitis B surface antigen (HBsAg) or hepatitis C 
(HCV) antibodies at Week −5 (Visit S1)

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) of 
≥3 × ULN or total bilirubin of ≥2 × ULN at Week −5 (Visit S1)
10) Patients with a history or complication of chronic musculoskeletal symptoms that 
may be difficult to differentiate from myalgia 
(eg, fibromyalgia)
11) Patients with creatine kinase (CK) of >3 × ULN at Week −5 (Visit S1)
12) Patients with renal dysfunction or nephritic syndrome or a history or complication 
of nephritis and with estimated glomerular filtration rate (eGFR) of 
≤30 mL/min/1.73m2 at Week −5 (Visit S1)
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 Week −5 (Visit S1)
15) Patients with a history of drug, alcohol, or cocaine abuse within the past 2 years 
prior to Week −5 (Visit S1)
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 Week −5 (Visit S1)
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 
Week −5 (Visit S1)
18) Patients who used or received the following drugs (including food) or therapies 
within the specified period or who are expected to use or receive them by the end 
of tests at Week 12 (Visit T6)
1.
Initiation of administration or change in dose of a systemic corticosteroid (from 3 months prior to 
Week −5 [Visit S1] to the end of tests at Week 12 [Visit T6] [or to the completion of the withdrawal 
examination, if applicable])
2.
Lomitapide (from 3 months prior to Week −5 [Visit S1] to the end of tests at Week 12 [Visit T6] [or 
to the completion of the withdrawal examination, if applicable])
3.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (from 4 weeks prior to Week −5 
[Visit S1] to the end of tests at Week 12 [Visit T6] [or to the completion of the withdrawal 
examination, if applicable])
4.
 
5.
Red yeast rice and food containing red yeast rice (from 2 weeks prior to Week −5 [Visit S1] to the 
end of tests at Week 12 [Visit T6] [or to the completion of the withdrawal examination, if applicable])

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6.
LDL apheresis (from 3 months prior to Week −5 [Visit S1] to the end of tests at Week 12 [Visit T6] 
[or to the completion of the withdrawal examination, if applicable])
19) Patients in whom the following drugs (therapies) are changed prior to Day 1 
(Visit T1) or in whom initiation of the following drugs (therapies) is planned by 
the end of tests at Week 12 (Visit T6)

Hormone replacement: Within 6 weeks prior to Day 1 (Visit T1)

Thyroid replacement: Within 6 weeks prior to Day 1 (Visit T1)

Diabetes medications: Within 4 weeks prior to Day 1 (Visit T1)

Obesity medications: Within 3 months prior to Day 1 (Visit T1)
20) Patients 
 
 who cannot continue drug 
administration due to safety issues
21)
 
22) Patients otherwise judged inappropriate for participating in the trial in the opinion 
of the investigator or subinvestigator
Trial Sites:
Approximately 50 sites in Japan
Investigational Medicinal Products and Mandatory Concomitant Medications, Dose, 
Dosage Regimen, Treatment Duration, Formulation, and Mode of Administration:
 
 
 
 
 
 
 
 

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[Treatment period (double-blind)]
1) Medications

Mandatory concomitant medications: 
Hypercholesterolemia drugs (statins and/or drugs other than statins) that have 
been taken from before informed consent

Investigational medicinal products:

ETC-1002 60 mg tablets

Placebo tablets
2) Dose and regimen

Mandatory concomitant medications: 
Hypercholesterolemia drugs 
 will be 
continued without changing the type and the dose and regimen during the 
treatment period.

Investigational medicinal products:

180-mg/day group: Three ETC-1002 60-mg tablets will be administered 
orally once daily.

120-mg/day group: Two ETC-1002 60-mg tablets and one placebo tablet 
will be administered orally once daily.

60-mg/day group: One ETC-1002 60-mg tablet and two placebo tablets 
will be administered orally once daily.

Placebo group: Three placebo tablets will be administered orally once 
daily.
3) Treatment duration: 12 weeks
Trial Assessments:
Assessments for Efficacy: LDL-C, HDL-C, non-HDL-C, TC, TG, apo B, hsCRP, and 
HbA1c
Assessments for Pharmacokinetics: Plasma concentrations of ETC-1002 and its active 
metabolite, ESP15228
Assessments for Safety: Adverse events, clinical laboratory tests, 12-lead ECG, vital 
signs, physical examination, body weight
Screening/Other: demographics, height, virus test (HBsAg and HCV antibodies), 
endocrine test (TSH), pregnancy test (urine, serum), deoxyribonucleic acid (DNA) 
storage (optional), biomarker storage (optional)
Data Monitoring Committee: No

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Statistical Methods:
[Statistical methods for the primary efficacy endpoint]
The primary efficacy endpoint is the percent change in LDL-C from baseline to Week 12. 
Analysis of covariance will be performed using treatment group and the randomization 
stratification factor (statin tolerance or statin intolerance) as factors and baseline value of 
LDL-C as a covariate at a two-sided significance level of 0.05. Comparisons versus the 
placebo group will be performed starting from the highest ETC-1002 dose group. 
Baseline is defined as the mean of the LDL-C values for Day 1 (Visit T1) and Week −1 
(Visits S3).
[Sample size justification]
Differences in the percent change in LDL-C from baseline to Week 12 in the ETC-1002 
group versus the placebo group in non-Japanese phase 3 trials were −18.1% and −17.42% 
in trials in statin tolerant subjects and −21.41% and −28.45% in trials in statin intolerant 
subjects. Base on the results, the difference between the ETC-1002 group and the placebo 
group in the subjects with statin tolerance was assumed to be 17%, and the difference 
between the ETC-1002 group and the placebo group in the subjects with statin 
intolerance was assumed to be 25%. For the present trial it was assumed that the 
percentage of statin intolerant subjects enrolled would be 20% and that the difference in 
the endpoint between the ETC-1002 group and the placebo group would be 19% in the 
overall trial population. Based on the results of the phase 3 trials, assuming a difference 
of 19% with standard deviation of 25% between the ETC-1002 groups and the placebo 
group in the percent change in LDL-C from baseline to Week 12, 38 subjects per group 
are required to achieve a power of 90% or higher in a two-tailed test with a 5% 
significance level. Assuming a withdrawal rate of 12.5%, the target number of subjects to 
be randomized was set at 44 per group.
Trial Duration:
Each subject in this trial is expected to participate in the following periods of the trial:

Screening period (1 week)

Treatment period (double-blind, 12 weeks)

Follow-up period (4 weeks)

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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 15 months.

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-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
-
 
 

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1.3.1
Informed Consent
Prior to all screening tests, written informed consent will be obtained from subjects 
himself/herself. After informed consent is obtained, each subject will be registered in the 
Interactive Web Response System (IWRS), given a subject identification number, and 
recorded. 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 IMP. 
The investigator or subinvestigator enters 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 be also recorded in the source document and the 
electronic case report form (eCRF).
For DNA storage and biomarker storage, written informed consent will be obtained from 
subjects himself/herself using a separate ICF, and the date of informed consent will be 
recorded in the source document and the eCRF. DNA and biomarker storage are optional 
and will not impact the subject’s participation in the trial if the subject does not consent 
to DNA and/or biomarker storage.
1.3.2
Screening
After obtaining informed consent, the investigator or subinvestigator will perform the 
observation and examinations at Week −5 (Visit S1) specified in Table 1.3-1, record 
them in the source document and the eCRF with the visit date, and register the visit date 
in the IWRS. After judging the eligibility for participation in the trial, the investigator or 
subinvestigator will describe the eligibility for enrollment, date of enrollment, and 
reasons in case of non-enrollment in the subject screening log.
The investigator or subinvestigator will investigate the following information and record 
it in the source document and the eCRF.

Demographics (collection date, birth date, sex, possibility of pregnancy, race, 
ethnicity, country)

Medical history (within 1 year before informed consent, but this limitation is not 
applicable to those related to the inclusion and exclusion criteria)

Complications (at informed consent)

History of hypercholesterolemia (name of diagnosis, date of diagnosis, presence or 
absence of familial hypercholesterolemia, classification and details of classification 
according to the flowchart using Suita score in the Japan Atherosclerosis Society 
Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017,1 statin 
response [statin tolerance/statin intolerance], cause of statin intolerance and 
name/daily dose of statin, if statin intolerance)

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
Prior medications for hypercholesterolemia received within 6 weeks prior to informed 
consent

All prior medications and prior therapies received within 4 weeks prior to informed 
consent

Result of eligibility assessment
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.3.5
Observation and Examinations During the Treatment Period
Subjects who are judged to be eligible for proceeding to the treatment period based on the 
assessment on Day 1 (Visit T1) 
 
 

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 and receive the IMP (ETC-1002 60 mg/day, 120 mg/day, 
180 mg/day, or placebo) for 12 weeks. After each subject proceeds to the treatment 
period, the investigator or subinvestigator performs the observation and examinations 
specified in Table 1.3-1 and records them in the source document and the eCRF with the 
visit date. The investigator or subinvestigator will register necessary items in the IWRS at 
each visit for each subject.
1.3.6
Observation and Examinations During the Follow-up Period
The investigator or subinvestigator will perform the observation and examinations 
specified in Table 1.3-1 at the visit 28 days (±7 days) after the last date of IMP 
administration to all the subjects who proceed to the treatment period, and record them in 
the source document and the eCRF with the visit date. The investigator or subinvestigator 
will register necessary items in the IWRS at the end of the follow-up period for each 
subject.
1.3.7
Withdrawal Examination
When the subject is withdrawn during 
 the treatment period, 
the investigator or subinvestigator will perform the withdrawal examination specified in 
Table 1.3-1 and record them in the source document and the eCRF with the visit date. 
The investigator or subinvestigator will register necessary items in the IWRS at the time 
of withdrawal for each subject.
2
Introduction
Hypercholesterolemia is one of key risk factors associated with the development and 
progression of arteriosclerosis, and several large-scale clinical trials have demonstrated 
the usefulness of drug therapy for primary and secondary prevention of coronary artery 
disease.2,3,4,5,6 Drugs currently launched in Japan and overseas for the treatment of 
hypercholesterolemia include 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) 
reductase inhibitors (various statins), small intestine cholesterol transporter inhibitors 
(ezetimibe), and human anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) 
monoclonal antibody formulations (evolocumab). Among these drugs, Japanese and 
overseas guidelines1,7,8 place statins as the first-line drug. Statins have been used for the 
treatment of hypercholesterolemia and have become able to control low-density 
lipoprotein cholesterol (LDL-C) 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 

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the lipid management goals of LDL-C based on 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]) 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 patients who have inadequate control of 
LDL-C by combination therapy of statins and other drugs remains an issue of drug 
therapy for patients with hypercholesterolemia. Statin intolerance, which requires 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 2018,9 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 other drugs other than statins, 
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 (ACL), 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 non-Japanese clinical trials in patients with 
hypercholesterolemia, 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 
hypercholesterolemia compared with placebo. No particular safety concern has been 
identified in the clinical trials conducted to date. Based on the results of non-Japanese 
clinical trials, ETC-1002 was approved for the treatment of hypercholesterolemia in the 
US in February 2020 and in Europe in April 2020.

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Otsuka Pharmaceutical Co., Ltd. (hereinafter referred to as “Otsuka”) considers that 
ETC-1002 can be a new treatment option for Japanese patients with hypercholesterolemia 
in whom LDL-C values cannot be adequately controlled by existing statin-based therapy. 
Otsuka has obtained the development and marketing right in Japan from Esperion 
Therapeutics, Inc. and started development in Japan.
For further information on results from the nonclinical and clinical trials of ETC-1002, 
please refer to the ETC-1002 Investigator’s Brochure. The outline is described below.
2.1
Non-clinical Study Results
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2.2
Clinical Trial Results
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2.3
Trial Rationale
Statins are recommended as the first-line drug for the treatment of hypercholesterolemia 
in Japanese and overseas guidelines.1,7,8 Although statins enabled control in accordance 
with the lipid management goals in many patients, some patients with a history of 
coronary artery disease or patients with familial hypercholesterolemia who require strict 
control of LDL-C have not often achieved the target LDL-C level by treatment with 
statins alone. Despite the concomitant use of statins and drugs with other mechanisms of 
action in such patients, the fact that there are patients who cannot achieve the lipid 
management goals remains an issue of drug therapy. In addition, some patients are 
intolerant to statins and dose reduction or interruption of statins is required due to 
myopathy or hepatic impairment caused by statins. The guidelines recommend dose 
reduction or discontinuation of statins, switching to other statins, or administration of 
other drugs other than statins depending on the severity of AEs. Thus, there is a need for 

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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.
The efficacy of ETC-1002 has been verified in several phase 3 placebo-controlled, 
double-blind trials in patients with hypercholesterolemia conducted in non-Japanese 
countries (Trials 1002-040, 1002-046, 1002-047, and 1002-048), and it has been 
confirmed that there was no particular safety concern. 
 
 
 
 
 It has also been 
confirmed that there is no safety problem and that ETC-1002 is well tolerated when 
administered to healthy Japanese adults. Therefore, there is a high possibility that 
treatment with ETC-1002 is also effective in Japanese patients with 
hypercholesterolemia.
This trial has been planned to confirm the efficacy and dose-response of ETC-1002 and 
determine the dose of ETC-1002 to be used in the phase 3 trial, as well as to assess the 
safety in Japanese patients with hypercholesterolemia who have had inadequate responses 
to statins and/or hypercholesterolemia drugs other than statins. 
 
 
 
 
 
 
 
 The type, dose and regimen of concomitant 
hypercholesterolemia drugs will be unchanged from at least 4 weeks before Week −5 
(Visit S1) (at least 6 weeks before, for fibrates and selective PPARα modulators). The 
duration of the treatment period to compare with the placebo group is 12 weeks as with 
the period to evaluate the primary endpoint in non-Japanese trials.
The primary endpoint is the percent change from baseline in LDL-C to Week 12, as in 
the non-Japanese trials. A total of 4 treatment groups, ETC-1002 60-mg/day group, 
120-mg/day group, 180-mg/day group, and placebo group, are set to investigate the 
efficacy and dose-response of ETC-1002.

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Based on the above, it is judged to be scientifically and ethically appropriate to 
investigate the efficacy and safety of ETC-1002 by the combination of 
hypercholesterolemia drugs with ETC-1002 or placebo once daily for 12 weeks in 
Japanese patients with hypercholesterolemia.
2.4
Background
For patients in whom the onset risk of the cardiovascular event is high and who require 
strict control of LDL-C but cannot achieve the management goal with monotherapy of 
statins, the first-line drug for hypercholesterolemia, combination therapy of statins and 
drugs with other mechanism of action has been performed. In addition, in patients who 
have to reduce the dose of statins or interrupt statins due to statin intolerance, there are 
many cases in which LDL-C cannot be adequately controlled by combination therapy of 
the reduced statins and drugs of other mechanism of action, or by treatment with drugs 
other than statins. Therefore, a drug with a new mechanism of action is required for 
patients who cannot adequately control LDL-C by the existing hypercholesterolemia 
drugs, primarily statins.
ETC-1002 is a compound with a new mechanism of action different from that of existing 
hypercholesterolemia drugs and can become a new therapeutic option for patients who 
have inadequate control of LDL-C with these existing hypercholesterolemia drugs. On 
the basis of the results of non-Japanese clinical trials in patients with 
hypercholesterolemia, the efficacy of ETC-1002 at 180 mg/day was confirmed in 
combination of statins and/or hypercholesterolemia drugs other than statins. As no 
particular safety concerns have been identified, ETC-1002 was approved in the US in 
February, 2020 and in Europe in April, 2020. Based on the above, ETC-1002 is 
considered to be a promising therapeutic drug for Japanese patients with 
hypercholesterolemia and therefore this clinical trial is planned.

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2.5
Known and Potential Risks and Benefits
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In the non-Japanese clinical trials of ETC-1002, efficacy was confirmed in patients with 
statin tolerance or statin intolerance, and there were no AEs with significantly different 
incidence from those in the placebo group in terms of safety. 
 
 
ETC-1002 can be a useful treatment for patients with hypercholesterolemia who need to 
continue long-term therapy with hypercholesterolemia drugs.
Once the Investigator’s Brochure 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.

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3
Objectives and Endpoints
The objectives and endpoints of this trial are shown in Table 3-1.
Table 3-1
Trial Objectives and Endpoints
Objectives
Endpoints
Primary Objectives:

To assess the LDL-C-lowering efficacy 
of ETC-1002 at 60 mg, 120 mg, and 
180 mg versus placebo when 
administered for 12 weeks in 
combination with ongoing stable statin 
therapy and/or other lipid-modifying 
therapy in patients with 
hypercholesterolemia who have 
inadequate control of LDL-C

To characterize the dose-response of 
ETC-1002 and investigate the 
appropriate dosage for a phase 3 trial
Primary Endpoint

Percent change in LDL-C from 
baseline to Week 12
Secondary Objectives:

To assess the effect of ETC-1002 on 
HDL-C, non-HDL-C, TC, TG, apo B, 
hsCRP and HbA1c

To assess the proportion of subjects 
achieving the lipid management goals of 
LDL-C by treatment with ETC-1002.

To assess the pharmacokinetic plasma 
trough and near-peak concentrations of 
ETC-1002 and its active metabolite 
(ESP15228)

To characterize the safety and 
tolerability of ETC-1002 versus placebo 
in patients with hypercholesterolemia 
when administered in combination with 
ongoing stable statin therapy and/or 
other lipid-modifying therapy
Secondary Endpoints

Percent change in HDL-C, non-
HDL-C, TC, TG, apo B, hsCRP and 
HbA1c from baseline to Week 12

Proportion of subjects whose 
LDL-C value achieve the lipid 
management goals based on 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]) and the 
proportion of subjects whose 
LDL-C value achieve <70 mg/dL at 
Week 12
Other Assessments

Time course of LDL-C, HDL-C, 
non-HDL-C, TC, TG, apo B, 
hsCRP, and HbA1c at each time 
point during the treatment period
Pharmacokinetic Assessments

Plasma concentrations of ETC-1002 
and its active metabolite, ESP15228
Safety Assessments

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Adverse events, clinical laboratory tests, 
physical examination, vital signs (blood 
pressure, pulse rate, and body 
temperature), body weight, and 12-lead 
electrocardiogram (ECG)
Section 9.4 describes the statistical analysis of the endpoints.
4
Trial Design
4.1
Type/Design of Trial
This is a placebo-controlled, randomized, multi-center, double-blind, parallel-group trial 
to assess the efficacy and safety of ETC-1002 in patients with hypercholesterolemia who 
are being treated with hypercholesterolemia drugs but have inadequate control and cannot 
achieve the lipid management goals. The trial population will include patients with statin 
tolerance who do not sufficiently respond to statins and cannot achieve the lipid 
management goals despite being treated with statins, and patients with statin intolerance 
who have experienced safety problems at the time of starting or increasing the dose of 
statins, have been successfully resolved after stopping or reducing the dose of statins, and 
cannot achieve the lipid management goals in spite of taking statins at (or below) the 
lowest approved daily dose and/or hypercholesterolemia drugs other than statins.
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 determined to be eligible in the screening period will proceed to 
 the treatment without changing the type and the dose and regimen 
of hypercholesterolemia drugs that have been taken from before informed consent, and 
receive placebo tablets in a single-blind manner. 
 
 
 Subjects who do not have safety problems 
and muscle-related AEs 
 and who do not fall under 
the exclusion criteria as judged by the investigator or subinvestigator will be assigned 
either to the ETC-1002 60-mg/day, 120-mg/day, 180-mg/day, or placebo group and 
proceed to the treatment period. Statin response (statin tolerance/statin intolerance) is set 
as a randomization stratification factor so that subjects with statin intolerance will be 
equally allocated to each treatment group.

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During the treatment period, subjects will continue to take the hypercholesterolemia 
drugs that have been taken from before informed consent and receive either placebo or 
ETC-1002 (60 mg/day, 120 mg/day, or 180 mg/day) for 12 weeks. 
 
 
 
 
 
 
 
 
 
4.1.2
Treatment Period
1) Medications

Mandatory concomitant medications: 
Hypercholesterolemia drugs (statins and/or drugs other than statins) that have 
been taken from before informed consent

Investigational medicinal products:

ETC-1002 60 mg tablets

Placebo tablets
2) Dose and regimen

Mandatory concomitant medications: 
Hypercholesterolemia drugs 
 will be 
continued without changing the type and the dose and regimen during the 
treatment period.

Investigational medicinal products:

180-mg/day group: Three ETC-1002 60-mg tablets will be administered 
orally once daily.

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
120-mg/day group: Two ETC-1002 60-mg tablets and one placebo tablet 
will be administered orally once daily.

60-mg/day group: One ETC-1002 60-mg tablet and two placebo tablets 
will be administered orally once daily.

Placebo group: Three placebo tablets will be administered orally once 
daily.
3) Treatment duration
12 weeks
4.2
Scientific Rationale for Trial Design
 
 
 Patients 
with statin intolerance are known to experience muscle-related AEs such as muscle pain, 
or AEs associated with hepatic impairment when treated with statins.9,10 Some patients 
have been reported to experience a reverse placebo effect (nocebo effect) to complain of 
events such as muscle symptoms, even with non-statin drugs such as placebo.11,12 
 
 
 
In the treatment period, the hypercholesterolemia drugs will be continued without 
changing the type and the dose and regimen from at least 4 weeks before Week −5 (Visit 
S1) (at least 6 weeks before, for fibrates and selective PPARα modulators), and 
ETC-1002 or placebo will be added in a double-blind manner. Since the primary 
objective of this trial is to confirm the efficacy of ETC-1002 and determine the dose used 
in the phase 3 trial, placebo is considered to be an appropriate comparator to be 
administered in the treatment period.
As for the treatment duration, the percent change in LDL-C from baseline to Week 12 
was selected as the primary endpoint in all 4 non-Japanese phase 3 trials, and LDL-C 
decreased from baseline at Week 2 to 4 after start of administration. Therefore, a period 
of 12 weeks is set as the duration necessary to evaluate the efficacy of ETC-1002. The 
primary endpoint is set as the percent change in LDL-C from baseline to Week 12, as in 
the non-Japanese trials.

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4.3
Rationale for Dosage Regimen
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4.4
End of Trial Definition
The end of trial date is defined as the following date from the eCRF page for the last 
subject completing or withdrawing from the trial: the “completion of trial date or 
withdrawal date” from the page of trial completion, or the “last date of visit/contact” or 
the “date of final contact attempt” from the page of the post-treatment observation or 
follow-up.
4.5
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
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 compete 
the Week 12 (Visit T6) assessment will be defined as trial completers.
5
Trial Population
This trial will be conducted in Japanese patients with hypercholesterolemia who are aged 
20 years or older and younger than 75 years at the time of informed consent and who are 
being treated with hypercholesterolemia drugs but have inadequate control and cannot 
achieve the lipid management goals. 
 
 
 
 
 The target number of subjects is 176 in 
total (44 in the ETC-1002 60-mg/day group, 44 in the 120-mg/day group, 44 in the 
180-mg/day group, and 44 in the placebo group) as randomized subjects. In addition to 
patients with statin tolerance, patients with statin intolerance will be enrolled at ≥20% of 
the total. Statin response (statin tolerance/statin intolerance) is set as a randomization 
stratification factor so that subjects with statin intolerance will be equally allocated to 
each treatment group.
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:
1) Patients from whom written informed consent is obtained prior to start of the trial
2) Patients, either male or female, age 20 years or older and younger than 75 years at 
the time of informed consent
3) Patients who meet the following criteria for statin tolerance or statin intolerance

Statin tolerance
Patients with hypercholesterolemia who have been taking statins (atorvastatin, 
pitavastatin, rosuvastatin, pravastatin, simvastatin, or fluvastatin) and 
hypercholesterolemia drugs other than statins if necessary, at the same dose 
and regimen from at least 4 weeks prior to Week −5 (Visit S1) (at least 
6 weeks, for fibrates and selective PPAR α modulators) to Week −5 (Visit S1) 
according to the approved regimen, but fail to achieve the lipid management 
goals of LDL-C based on risk assessment shown in the inclusion criteria 4) at 
both Week −5 (Visit S1) and Week −1 (Visit S3)

Statin intolerance
Patients with hypercholesterolemia in whom safety problems occurred when 
administration of statins was started or increased in dose and were resolved 
after discontinuation or dose reduction of statin administration, and who have 
been taking statins at (or below) the lowest approved daily dose and/or who 
have been taking at least one hypercholesterolemia drug other than statins at 
the same dose and regimen from at least 4 weeks prior to Week −5 (Visit S1) 
(at least 6 weeks, for fibrates and selective PPAR α modulators) to Week −5 
(Visit S1) according to the approved dosage regimen, but fail to achieve the 
lipid management goals of LDL-C based on risk assessment shown in the 
inclusion criteria 4) at both Week −5 (Visit S1) and Week −1 (Visit S3)
4) Patients considered to be at risk of developing cardiovascular events who meet 
any of the following conditions a), b), or c)
a) Patients with either of the following medical histories or complications and in 
whom LDL-C at Week −5 (Visit S1) and Week-1 (Visit S3) is ≥100 mg/dL

History of coronary artery disease

Diagnosed with heterozygous familial hypercholesterolemia (HeFH)

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b) Patients with any of the following medical histories or complications and in 
whom LDL-C at Week −5 (Visit S1) and Week-1 (Visit S3) is ≥120 mg/dL

Diagnosed with peripheral arterial disease

History of non-cardiogenic cerebral infarction

Diagnosed with chronic kidney disease and does not fall under the 
exclusion criteria 12)

Diagnosed with type 2 diabetes mellitus more than 3 months prior to 
Week −5 (Visit S1) and does not fall under the exclusion criteria 7)
c) Patients who do not meet inclusion criteria a) or b), but whose 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) and in whom each LDL-C level at Week −5 (Visit S1) and 
Week −1 (Visit S3) is ≥140 mg/dL, or whose total score is ≥56 (high risk) and 
in whom each LDL-C level at Week −5 (Visit S1) and Week −1 (Visit S3) is 
≥120 mg/dL
5) Patients with fasting TG level of <400 mg/dL at Week −5 (Visit S1)
6) Patients with body mass index (BMI) of ≥18 kg/m2 and <35 kg/m2 at Week −5 
(Visit S1)
[Rationale for inclusion criteria]
1)
This criterion is set from ethical considerations.
2)
Since elderly patients generally have reduced physiological function and 
ETC-1002 is administered to Japanese patients with hypercholesterolemia 
for the first time, the trial is to be conducted in patients aged <75 years in 
consideration of safety. The lower limit of age is set at 20 years from ethical 
considerations.
3) to 4) These criteria are set to appropriately evaluate the efficacy.
5)
This criterion is set in consideration of the difficulty in accurate calculation 
of LDL-C using the Friedewald formula and subject safety.
6)
This is set to minimize the inter-individual variation in pharmacokinetics 
due to body size.
5.2.2
Exclusion Criteria
Subjects will be excluded if they meet any of the following exclusion criteria when 
assessed:
1) Women who are pregnant or breastfeeding or who have a positive pregnancy test 
(urine) result at Week −5 (Visit S1) or Day 1 (Visit T1)
2) Sexually active male subjects or sexually active female subjects of childbearing 
potential who do not agree to practice 2 different approved methods of birth 

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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, and condoms (all methods are approved or certified in Japan). A 
definition of childbearing potential can be found in Section 10.3.
3) Patients with homozygous familial hypercholesterolemia (HoFH)
4) Patients with a history or current symptoms of any of the following cardiovascular 
diseases within 3 months prior to Week −5 (Visit S1), or with 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

Unexplained syncope or long-QT syndrome, family history of long-QT 
syndrome, or risk factors for Torsade de Pointes, such as persistent 
hypokalemia or second- or third-degree atrioventricular block (except when 
controlled by medication, etc)
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 Week −5 (Visit S1)
6) Patients with uncontrolled and serious hematologic or coagulation disorders or 
with Hgb of <10.0 g/dL at Week −5 (Visit S1)
7) Patients with type 1 diabetes or uncontrolled type 2 diabetes with HbA1c of ≥9% 
at Week −5 (Visit S1)
8) Patients with uncontrolled hypothyroidism with thyroid-stimulating hormone 
(TSH) of >1.5 × the upper limit of normal (ULN) at Week −5 (Visit S1)
9) Patients with liver disease or dysfunction, including:

Positive serology for hepatitis B surface antigen (HBsAg) or hepatitis C 
(HCV) antibodies at Week −5 (Visit S1)

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) of 
≥3 × ULN or total bilirubin of ≥2 × ULN at Week −5 (Visit S1)
10) Patients with a history or complication of chronic musculoskeletal symptoms that 
may be difficult to differentiate from myalgia (eg, fibromyalgia)
11) Patients with CK of >3 × ULN at Week −5 (Visit S1)
12) Patients with renal dysfunction or nephritic syndrome or a history or complication 
of nephritis and with estimated glomerular filtration rate (eGFR) of 
≤30 mL/min/1.73m2 at Week −5 (Visit S1)
13) Patients who have had gastrointestinal surgery that may affect drug absorption 
(eg, Lap-Band® or gastric bypass)

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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 Week −5 (Visit S1)
15) Patients with a history of drug, alcohol, or cocaine abuse within the past 2 years 
prior to Week −5 (Visit S1)
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 Week −5 (Visit S1)
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 
Week −5 (Visit S1)
18) Patients who used or received the following drugs (including food) or therapies 
within the specified period or who are expected to use or receive them by the end 
of tests at Week 12 (Visit T6)
1.
Initiation of administration or change in dose of a systemic corticosteroid (from 3 months prior to 
Week −5 [Visit S1] to the end of tests at Week 12 [Visit T6] [or to the completion of the 
withdrawal examination, if applicable])
2.
Lomitapide (from 3 months prior to Week −5 [Visit S1] to the end of tests at Week 12 [Visit T6] 
[or to the completion of the withdrawal examination, if applicable])
3.
PCSK9 inhibitors (from 4 weeks prior to Week −5 [Visit S1] to the end of tests at Week 12 [Visit 
T6] [or to the completion of the withdrawal examination, if applicable])
4.
 
5.
Red yeast rice and food containing red yeast rice (from 2 weeks prior to Week −5 [Visit S1] to the 
end of tests at Week 12 [Visit T6] [or to the completion of the withdrawal examination, if 
applicable])
6.
LDL apheresis (from 3 months prior to Week −5 [Visit S1] to the end of tests at Week 12 [Visit T6] 
[or to the completion of the withdrawal examination, if applicable])
19) Patients in whom the following drugs (therapies) are changed prior to Day 1 
(Visit T1) or in whom initiation of the following drugs (therapies) is planned by 
the end of tests at Week 12 (Visit T6)

Hormone replacement: Within 6 weeks prior to Day 1 (Visit T1)

Thyroid replacement: Within 6 weeks prior to Day 1 (Visit T1)

Diabetes medications: Within 4 weeks prior to Day 1 (Visit T1)

Obesity medications: Within 3 months prior to Day 1 (Visit T1)
20) Patients 
 
 who cannot continue drug 
administration due to safety issues
21)
 
22) Patients otherwise judged inappropriate for participating in the trial in the opinion 
of the investigator or subinvestigator

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[Rationale for exclusion criteria]
1) to 2)
These criteria are set in consideration of the safety because the safety of 
administration of ETC-1002 during pregnancy and breastfeeding has not 
been established.
3) to 9)
These criteria are set in consideration of the safety.
10) to 11) These criteria are set to appropriately evaluate the safety of ETC-1002.
12)
This criterion is set in consideration of the safety.
13)
This criterion is set to avoid influence on pharmacokinetics.
14)
This criterion is set to appropriately evaluate the safety of ETC-1002.
15)
This criterion is set in consideration of the safety.
16)
This criterion is set according to the Blood Sampling Criteria of New 
Blood Program Advisory Committee to ensure the safety of subjects.
17) to 19) These criteria are set to appropriately evaluate the efficacy and safety of 
ETC-1002.
20) to 21) These criteria are set to appropriately evaluate the safety of ETC-1002.
22)
This criterion is set in consideration of the safety.
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 will not be changed during the trial period. For supplements and 
dietary supplements that may affect cholesterol levels including LDL-C, the investigator 
or subinvestigator will explain the subjects at each visit so that the intake status will not 
change from Week −4 (Visit S2) to the end of tests at Week 12 (Visit T6), and record the 
intake status in the source document.
5.3.2
Caffeine, Alcohol, and Tobacco
For alcohol and tobacco, the amount of alcohol consumed and the number of cigarettes 
smoked will be checked with the subject prior to participation in the trial 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 during the trial to record the results in the source document. No caffeine 
restrictions will be applied.

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5.3.3
Activity
To properly evaluate the efficacy and safety of ETC-1002, exercise therapy for 
hypercholesterolemia since before informed consent will not be changed during the trial 
period. In addition, the investigator or subinvestigator will instruct subjects at each visit 
to refrain from strenuous exercise 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)
. 
All AEs must be reported after subject informed consent has been obtained, including 
screening failures due to AEs, irrespectively 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 (name of diagnosis, date of diagnosis, presence or 
absence of familial hypercholesterolemia, classification and details of classification 
according to the flowchart using Suita score in the Japan Atherosclerosis Society 
Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017,1 statin 
response [statin tolerance/statin intolerance], cause of statin intolerance and 
name/daily dose of statin, if statin intolerance)

Result of eligibility assessment

Screen failure date

Reason for screen failure

Adverse Events
Subjects who sign ICF 
 (screen failure) will be 
allowed to rescreen. 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
6.1
Trial Treatments Administered
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1.2
Treatment Period
Subjects who are randomized and proceed to the treatment period will continue to receive 
hypercholesterolemia drugs that have been taken from before informed consent without 
changing the type or the dose and regimen 
. Subjects will 
also orally receive ETC-1002 60 mg/day, 120 mg/day, 180 mg/day, or placebo. The time 
of IMP administration should be same to the extent possible. The following information 
will be recorded in the eCRF: number of tablets taken per day, start and end dates of 
administration as for the IMP; and name of the drug, route of administration, dose and 
frequency, daily dose, start and end dates of administration as for hypercholesterolemia 
drugs. Subjects with less than 80% compliance with IMP between scheduled visits will 
be withdrawn from the trial. The IMP compliance rate will be calculated using the 

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following formula. For information regarding the dose regimen and treatment period for 
each treatment group of the trial, see Section 4.1.
Actual number of days of taking 3 tablets of the IMP
IMP compliance rate (%) =
Number of days from the previous visit to the day before the 
current visit
× 100
6.1.3
Medical Devices
Not applicable.
6.2
Management of Investigational Medicinal Product
For full details on IMP management, please refer to the ETC-1002 Investigator’s 
Brochure and the separate procedures.
6.2.1
Packaging and Labeling
Investigational medicinal product will be provided by the sponsor or designated agent to 
the IMP storage manager. The IMP will be supplied as the blister cards. Each blister card 
used in the dosing period will be labeled to clearly disclose the subject ID, compound ID, 
trial number, sponsor’s name and address, instructions for use, route of administration, 
and appropriate precautionary statements.
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 (including 
investigational, or placebo) received, dispensed, administered, and returned. The IMP 
storage manager must not provide IMP to any subject not participating in this protocol.

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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 
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 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 complaint

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
Reporter identification (eg, subject, investigator, subinvestigator, trial site, etc.)

Reporter contact information (eg, address, phone number, e-mail address)

ID of material (product/compound name, IMP number)

Clinical protocol reference (protocol number and/or trial name)

Dosage form/strength (if known)

Pictures of complaint sample (if available)

Availability of 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.
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.
6.3
Measures to Minimize/Avoid Bias
In this trial
 
the treatment period will be conducted in a double-blind manner. 
 
 
 
In the treatment period, stratified randomization by statin response (statin tolerance /statin 
intolerance) will be performed to minimize influence on evaluation. Subjects will be 
randomized to each group in a ratio of 1:1:1:1. Details of randomization will be provided 
in a separate procedure. Neither the subject nor the investigator/subinvestigator will be 
informed of the IMP randomization code. The persons involved in the trial of the 
sponsor, including the contract research organization (CRO) (except the bioanalytical 
laboratory), cannot know the IMP randomization code during the trial period.
Indistinguishability of the IMP will be confirmed by the IMP packaging company and the 
sponsor before the start of the trial.
The randomization table will be stored securely until unblinding after all eCRFs and 
database lock.

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The emergency code will be managed by the Interactive Web Response System (IWRS) 
until the end of the trial. If a medical emergency occurs to a subject and it is determined 
that knowledge of the IMP randomization code is important for the treatment of the 
subject, emergency code will be obtained according to Section 8.8.7.
Plasma drug concentrations will not be disclosed until unblinding at the end of the trial. 
These measurements will be performed at a specific bioanalytical laboratory and will not 
be performed at the clinical laboratory of the trial site.
Maintenance of blinding for efficacy endpoints will be found in Section 8.1.
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 12 (Visit T6) or to the 
completion of the withdrawal examination.

Comply with the dosage regimen, duration, and frequency of administration of the 
IMP and mandatory concomitant medications for hypercholesterolemia. A subject 
will be withdrawn from the trial if the compliance rate 
 
 
 is less than 80% between the scheduled visits in the treatment period.

Use appropriate contraceptive methods.

Note the lifestyle considerations (see Section 5.3).
6.5
Concomitant Medications or Therapies
The investigator or subinvestigator will record hypercholesterolemia drugs from 6 weeks 
before the day of informed consent to Week 12 (Visit T6) or at withdrawal, and all drugs 
other than those for hypercholesterolemia (including Chinese herbal medicines that affect 
cholesterol levels such as LDL-C) and therapies from 4 weeks before the day of informed 
consent to Week 12 (Visit T6) or at withdrawal in the eCRF. The investigator or 
subinvestigator will also record all medications and therapies taken by the subject for 
treatment of an AE or which caused an AE until the final observation day for that 
individual subject 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.
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. The subject will be withdrawn from the trial if 
any of these medications, food, and preference products are used or taken.
Table 6.5.1-1
List of Prohibited Medications, Food, and Preference 
Products
1.
Initiation of administration or change in dose of a systemic corticosteroid (from 3 months prior 
to Week −5 [Visit S1] to the end of tests at Week 12 [Visit T6] [or to the completion of the 
withdrawal examination, if applicable])
2.
Lomitapide (from 3 months prior to Week −5 [Visit S1] to the end of tests at Week 12 [Visit T6] 
[or to the completion of the withdrawal examination, if applicable])
3.
PCSK9 inhibitors (from 4 weeks prior to Week −5 [Visit S1] to the end of tests at Week 12 
[Visit T6] [or to the completion of the withdrawal examination, if applicable])
4.
 
5.
Red yeast rice and food containing red yeast rice (from 2 weeks prior to Week −5 [Visit S1] to 
the end of tests at Week 12 [Visit T6] [or to the completion of the withdrawal examination, if 
applicable])
6.5.2
Prohibited Therapies
LDL apheresis is prohibited from 3 months prior to Week −5 (Visit S1) to the end of tests 
at Week 12 (Visit T6) (or to the completion of the withdrawal examination, if applicable). 
If performed, the subject will be withdrawn from the trial.
6.5.3
Permitted Medications or Therapies
Hypercholesterolemia drugs (excluding PCSK9 inhibitors) used from before informed 
consent will be continued without changing the type and the dose and regimen until the 
end of tests at Week 12 (Visit T6) (or to the completion of the withdrawal examination, 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 and the dose and regimen of the concomitant 
medications or the details of the concomitant therapy should not be changed during the 
applicable period. These medications or therapies cannot be newly started during the 
applicable period.

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Table 6.5.3-1
List of Medications or Therapies Permitted Before and 
During the Trial
1.
Hormone replacement (from 6 weeks before Day 1 [Visit T1] to the end of tests at Week 12 
[Visit T6] [or to the completion of the withdrawal examination, if applicable])
2.
Thyroid replacement (from 6 weeks before Day 1 [Visit T1] to the end of tests at Week 12 [Visit 
T6] [or to the completion of the withdrawal examination, if applicable])
3.
Diabetes medications (from 4 weeks before Day 1 [Visit T1] to the end of tests at Week 12 
[Visit T6] [or to the completion of the withdrawal examination, if applicable])
4.
Obesity medications (from 3 months before Day 1 [Visit T1] to the end of tests at Week 12 
[Visit T6] [or to the completion of the withdrawal examination, if applicable])
5.
Diet therapy (during the trial)
6.
Exercise therapy (during the trial)
6.5.4
Rescue Medications
Not applicable.
6.6
Intervention After the End of the Trial
Not applicable.
7
Withdrawal Criteria and Procedures
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 treatment assignment, 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 the trial discontinuation necessary 
during 
 the treatment period, the withdrawal examination 
specified in Table 1.3-1 will be performed to the extent possible. In case of the trial 
discontinuation of subjects who proceed to the treatment period, the same tests as at 
Week 16 (Visit FU) will be performed as the tests in 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 registered 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

Failure to meet randomization criteria

Assessed as ineligible based on the eligibility assessment at Week −1 (Visit S3) 
and Day 1 (Visit T1)

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
Non-compliance with IMP (subjects with an IMP compliance rate of <80% between 
scheduled visits during the treatment period will be withdrawn from the trial. See 
Section 6.1.2 for calculation of the IMP compliance rate.)

Protocol deviations

Randomized by mistake

Revealed to have not met the inclusion criteria or fall under the exclusion criteria

Use of prohibited medications (including food and preference products) or 
prohibited therapies

Changes in the type and the dose and regimen of hypercholesterolemia drugs 
concomitantly used with the IMP (except for worsening of the underlying disease)

Lost to follow-up

Pregnancy (see Section 10.3)

Site terminated by sponsor

Trial terminated by sponsor

Withdrawal by subject’s request (including withdrawal of consent by subject)

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 anonymously 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).

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
Participation in a subset of protocol specified follow-up procedures (by a frequency 
schedule and method, as agreed by subject and trial site staff).

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).

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 from the optional storage of DNA and biomarker 
samples are provided in the ICF for the storage of DNA and biomarker samples.
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.

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7.4
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before the tests on Visit 12 (Visit T6), 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 
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?”, “presence/absence of AEs”, “Date of contact/Date of final contact attempt” 
and “Contact method” will be recorded in eCRF.
8
Trial Procedures
The schedule of tests and assessments to be conducted during the trial are summarized in 
Table 1.3-1. The investigator or subinvestigator will perform observation, examinations 
and assessments according to the schedule. The clinical trial associates are allowed to 
perform the tests under the supervision of the investigator, such as investigation of 
subject demographics and laboratory tests.
8.1
Efficacy Assessments
To evaluate the efficacy of ETC-1002, blood samples will be collected for the following 
fasting lipid assessments of 1) to 5) and assessments of 6) to 8).
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 

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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 from the night before. 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 
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.
Samples will be sent to the central laboratory, the results of which will be used for 
analysis. LDL-C values will be calculated using the Friedewald formula 
(TC−HDL-C−TG/5) and measured using the LDL-C direct method. 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 results of the assessments 1) to 7) will not be 
reported to the trial site and the sponsor from the start of IMP administration on Day 1 
(Visit T1) to Week 12 (Visit T6) (or to the completion of the withdrawal examination, if 
applicable). The test results will be stored strictly by the central laboratory, submitted to 
the trial site after unblinding, and provided to the sponsor in electronic files. In addition, 
measurement at the laboratory of trial sites is not allowed from the start of IMP 
administration on Day 1 (Visit T1) to Week 12 (Visit T6) (or to the completion of the 
withdrawal examination, if applicable).
1) LDL-C
2) HDL-C
3) non-HDL-C
4) TC
5) TG
6) apo B
7) hsCRP
8) HbA1c
8.2
Pharmacokinetic Assessments
The investigator or subinvestigator will instruct subjects to visit the trial site according to 
the schedule specified in Table 1.3-1 without taking the IMP and blood sampling will be 
performed before IMP administration. On Day 1 (Visit T1) and Week 4 (Visit T3), 

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subjects will take the IMP at the trial site and blood sampling will be performed 2 to 
4 hours after IMP administration in addition to pre-dose blood sampling.
8.2.1
Pharmacokinetic Plasma Samples
Blood samples (3 mL) will be collected in vacutainers containing 
ethylenediaminetetraacetic acid (EDTA) and processed into plasma to determine the 
concentrations of ETC-1002 and its active metabolite ESP15228. Additional metabolites 
that are not identified in the protocol may also be analyzed, if needed. In addition, PK 
samples may be used for the investigation of analytical methods, if needed.
The actual date and time of the PK sample collection and the date and time of IMP 
administration immediately before the sample collection will be recorded in the eCRF. 
The results of measurement will be reported directly from the bioanalytical laboratory to 
the sponsor, and therefore, recording in the eCRF is not required.
After processing into plasma, aliquots will be placed into appropriately labeled tubes and 
will be placed in a freezer set at −70°C or −20°C, unless otherwise instructed in the 
Operations.
All plasma samples will be shipped to the bioanalytical laboratory. Additional 
information will be provided in the manuals.
The bioanalytical laboratory will measure drug concentrations only in the samples of the 
ETC-1002 group after keeping a record of the use of the allocation table. The contents of 
the allocation table will not be disclosed to any persons other than those who are 
considered necessary for the duties by the bioanalytical study director and strictly store it. 
The bioanalytical laboratory will retain the results strictly and submit the electronic file to 
the sponsor after unblinding.
 
 
 
 
 
 
 

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8.3
Pharmacodynamic Assessments
Pharmacodynamic assessments other than those described for efficacy assessments are 
not planned.
8.4
Pharmacogenomic Assessments
Not applicable.
8.5
Biomarker Assessments
Biomarker assessments other than those described for efficacy and pharmacodynamic 
assessments are not planned.
 
 
 
 
 
 
 
 
 
 
 
 
 

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8.7
Safety Assessments
If a “new abnormality” or “exacerbation” is observed in the following 
observation/examination items after the start of the IMP administration which are judged 
to be clinically significant by the investigator or subinvestigator as compared to before 
administration, appropriate measures will be taken as necessary. 
Details pertaining to the definitions, collection, reporting, and follow-up of AEs are 
described in Section 8.8.
8.7.1
Clinical Laboratory Assessments
Clinical laboratory samples will be collected at the time points described in the Schedules 
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 ICF.
On the day of the tests shown in the Schedules 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. 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 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. 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.
 
 
 

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8.7.2
Physical Examination
Physical examinations will be performed at the time points described in the Schedules of 
Assessments (Table 1.3-1). The investigator or subinvestigator will perform physical 
examinations for the following test items by methods such as interview and record the 
results 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 Week −5 (Visit S1) and Day 1 (Visit T1), the dates and results of 
the examinations will be recorded in the source document and the eCRF. At other time 
points, only the date of the examination will be recorded. If clinically significant physical 
findings, which are compared with Week −5 (Visit S1) during the screening 
 
 and compared with Day 1 (Visit T1) during the treatment and follow-up 
periods, are observed, those findings will be recorded as AEs.
Test items:
HEENT (head, eyes, ears, nose, throat), chest, abdomen, genitourinary, 
extremities, nerves, skin/mucosae

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8.7.3
Vital Signs
Vital signs will be collected at the time points described in the Schedules of Assessments 
(Table 1.3-1) after resting for at least 5 minutes and before blood sampling. Subjects 
should be monitored for potentially clinically significant vital signs values. Body 
temperature, systolic and diastolic blood pressure, and pulse rate will be measured in the 
sitting position after resting for at least 5 minutes according to the procedures specified 
by the trial site. The date, time, and results of body temperature, systolic and diastolic 
blood pressure, and pulse rate measurements will be recorded in the source document and 
the eCRF.
8.7.4
Electrocardiogram
Electrocardiograms will be performed at the time points described in the Schedules of 
Assessments (Table 1.3-1) after resting for at least 10 minutes and before blood 
sampling. Subjects should be monitored for potentially clinically significant ECG results.
The investigator or subinvestigator will record the 12-lead ECG using the 12-lead ECG 
monitor provided by the central ECG measurement facility and record the date and time 
of the measurement in the source document and the eCRF. The original 12-lead ECG 
tracing will be retained in the medical record or investigator file. The central ECG 
measurement facility will collect the 12-lead ECG data, and measure the heart rate, PR 
interval, RR interval, QRS interval, QT interval, and QTc interval [QTcF = QT 
interval/(RR interval)1/3] to be judged by physician in the central ECG measurement 
facility. The central ECG measurement facility will report the analysis results to the 
investigator or subinvestigator who confirms the results. The report on analysis results 
will be officially documented by entering the date of confirmation and signing by the 
investigator or subinvestigator. The investigator or subinvestigator will assess the results 
with reference to the “Report on Analysis Results” prepared by the central ECG 
measurement facility and record the results of normal/abnormal assessment and abnormal 
findings in the source document and the eCRF. The analysis results will be directly 
reported to the sponsor by the central ECG measurement facility in electronic files. 
Therefore, it is not necessary to record the results in the source document and the eCRF.
8.7.5
Suicidality Monitoring
Not applicable.

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8.7.6
Other Safety Variables
8.7.6.1
Height/body Weight
Body weight and height will be measured at the time points described in the Schedules of 
Assessments (Table 1.3-1), and the dates and results of measurements will be recorded in 
the source document and the eCRF (body weight in units of 0.1 kg and height in units of 
0.1 cm). Body weight will be measured using a calibrated and reliable scale. The same 
scale should be used for the same subject as much as possible, and the measurement will 
be done using the standard method (without shoes and with normal clothing). Height will 
be measured only at Week −5 (Visit S1). Body mass index {BMI = body weight 
[kg]/(height [m]) 2} will be calculated using the body weight measured at Week −5 (Visit 
S1) to confirm that the subject meets the inclusion criteria.
8.8
Adverse Events
8.8.1
Definitions
An AE is defined as any untoward medical occurrence in a clinical trial subject 
administered an IMP and which does not necessarily have a causal relationship with this 
treatment. In this trial, any untoward medical occurrence in a subject not receiving the 
IMP 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. An adverse reaction is any untoward and unintended 
response to an IMP related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE.
Treatment-emergent AEs (TEAEs) are defined as AEs with an onset date on or after the 
start of IMP treatment during the treatment period. In more detail, TEAEs are defined as 
all AEs which newly started after the start of IMP treatment during the treatment period; 
or if the AE was continuous at the start of the treatment period and was worsening.
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.

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
Requires inpatient hospitalization or prolongs hospitalization.

Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the 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.
Immediately Reportable Event (IRE):

Any SAE.

Any AE related to occupational exposure.

Potential serious hepatotoxicity (see Section 8.8.6).

Pregnancies are also defined as immediately reportable events (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 subject and there is 
an abnormality or complication.
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 verify the results of the original laboratory 
tests. However, the central laboratory should not report the results of any repeated or 
additional tests for fasting lipid assessments, apo B, and hsCRP between Day 1 (Visit T1) 
and Week 12 (Visit T6) to the trial site and the sponsor to maintain the blind. As for 
LDL-C and TG, an alert email will be sent from the central laboratory to the investigator, 
subinvestigator, or their staff if an abnormality exceeding a certain reference value is 

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observed (details will be specified in a separate procedure). 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.
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.
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 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 final observation day. All AEs must be recorded in the eCRF after 
subject informed consent has been obtained, including screening failures due to AEs, 
irrespective of IMP administration. In this trial, AEs during the screening 
 
 will be assessed compared to Week −5 (Visit S1), and those during the 
treatment and follow-up periods will be assessed compared to Day 1 (Visit T1).
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 

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condition is observed on Day 1 (Visit 1) or later, the AE should be reported as a new AE 
in the eCRF without limiting to worsening in severity or seriousness.
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.
The adverse event, 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.

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8.8.7
Procedure for Breaking the Blind
When the investigator or subinvestigator determines that emergency code breaking is 
necessary to ensure the subject’s safety in the case of a SAE or other events, the 
investigator or subinvestigator can obtain the emergency code of the subject from the 
IWRS in accordance with the separately specified procedure.
The investigator or subinvestigator is encouraged to contact the sponsor/CRO medical 
advisor to discuss their rationale for unblinding. However, to prevent delays to the 
investigator/subinvestigator, or medical personnel responding to a potentially emergent 
situation, unblinding of IMP will not be dependent upon the investigator receiving 
approval from the sponsor/CRO medical advisor (ie, the investigator or subinvestigator 
will be able to obtain the code break information independent of the sponsor/CRO 
medical advisor). The investigator or subinvestigator must contact the sponsor/CRO 
medical advisor by telephone or e-mail with an explanation of the need for opening the 
treatment assignment code within 24 hours of opening the code. If the blind is broken, the 
Global Pharmacovigilance Department must be notified immediately (see the cover page 
of this protocol for contact information). Documentation of breaking the blind should be 
recorded in the subject’s medical record with the date and time the blind was broken and 
the names of the personnel involved. Once the blind is broken for a subject, that subject 
may not reinitiate treatment with the IMP.
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 28 days after the last 
dose of IMP is administered.

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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 are:

Resolved,

Stabilized,

The subject is lost to follow-up, or

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.
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 to be reasonably associated with 
the use of the IMP, 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.

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8.9
Treatment of Overdose
For treatment of overdose, refer to the overdose section of the Investigator’s Brochure. 
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 Subject Diary
The investigator or subinvestigator will instruct the subjects who are able to receive the 
IMP to enter the status of compliance with the IMP and hypercholesterolemia drugs, 
status of diet/exercise therapy and lifestyle (alcohol intake, smoking), presence or 
absence of subjective symptoms, and the date and time of the IMP administration 
immediately before the visit in the subject diary and bring it to the visit. The investigator 
or subinvestigator will record the status of compliance with the IMP and 
hypercholesterolemia drugs and the date and time of the IMP administration immediately 
before the visit for blood sampling for pharmacokinetic evaluation in the eCRF based on 
the contents entered in the subject diary, and also check the status of diet/exercise therapy 
and lifestyle (alcohol intake, smoking) and changes in subjective symptoms. If any 
subjective symptom is observed between visits, the investigator or subinvestigator will 
ask the subject about the symptom, date and time of onset, etc. to determine whether it is 
an AE.
8.11
Other Assessments
8.11.1
Pregnancy Test
A urine test will be performed for female subjects 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. 
 any positive urine test will lead 
to re-test using serum and the date of blood sampling will be recorded in the source 
document and the eCRF. 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 

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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 −5 (Visit S1) to confirm eligibility of subjects 
regarding thyroid and liver function. The date and time 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.
9
Statistical Considerations
The definitions of the analysis set and the statistical methods for the endpoints in the 
treatment period are described below. Details of the analysis plan for the treatment period 
 will be described in the statistical 
analysis plan (SAP).
9.1
Sample Size
Differences in the percent change in LDL-C from baseline to Week 12 in the ETC-1002 
group versus the placebo group in non-Japanese phase 3 trials were −18.1% and −17.42% 
in trials in statin tolerant subjects and −21.41% and −28.45% in trials in statin intolerant 
subjects. Base on the results, the difference between the ETC-1002 group and the placebo 
group in the subjects with statin tolerance was assumed to be 17%, and the difference 
between the ETC-1002 group and the placebo group in the subjects with statin 
intolerance was assumed to be 25%. For the present trial it was assumed that the 

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percentage of statin intolerant subjects enrolled would be 20% and that the difference in 
the endpoint between the ETC-1002 group and the placebo group would be 19% in the 
overall trial population. Based on the results of the phase 3 trials, assuming a difference 
of 19% with standard deviation of 25% between the ETC-1002 groups and the placebo 
group in the percent change in LDL-C from baseline to Week 12, 38 subjects per group 
are required to achieve a power of 90% or higher in a two-tailed test with a 5% 
significance level. Assuming a withdrawal rate of 12.5%, the target number of subjects to 
be randomized was set at 44 per group.
9.2
Datasets for Analysis
The full analysis set (FAS) will include all subjects who receive at least one dose of IMP 
during the treatment period and for whom LDL-C values at baseline and at least one post-
dose (up to 2 days after final IMP administration) are observed. The safety analysis set 
will include subjects who receive at least one dose of IMP during the treatment period. 
The pharmacokinetic analysis set will include subjects who receive ETC-1002 and for 
whom the measured result of plasma drug concentration after ETC-1002 administration is 
observed.
9.3
Handling of Missing Data for Primary Endpoint Analysis
In the primary analysis of the primary endpoint, when LDL-C at Week 12 is missing, the 
missing value will be imputed using the last value observed from after initial IMP 
administration until 2 days after final IMP administration (last observation carried 
forward: LOCF).
A mixed-effects model repeated measures analysis assuming missing at random will be 
performed using observed case data as sensitivity analyses.
9.4
Statistical Analyses
9.4.1
Efficacy Analyses
The following analyses will be performed on the FAS using the values measured by the 
central laboratory.

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9.4.1.1
Primary Efficacy Endpoint Analysis
The primary efficacy endpoint is the percent change in LDL-C from baseline to Week 12. 
Analysis of covariance will be performed using treatment group and the randomization 
stratification factor (statin tolerance/statin intolerance) as factors and baseline value of 
LDL-C as a covariate at a two-sided significance level of 0.05. Comparisons versus the 
placebo group will be performed starting from the highest ETC-1002 dose group. 
Baseline is defined as the mean of the LDL-C values for Day 1 (Visit T1) and Week −1 
(Visits S3). If only one value is observed, the observed value will be used as the baseline.
The percent change in LDL-C from baseline to Week 12 will be tested using a contrast 
between low-dose saturation, medium-dose saturation, and linear to investigate the dose-
response relationship among placebo, low-dose, medium-dose, and high-dose.
9.4.1.2
Key Secondary Efficacy Endpoint Analysis
Not applicable.
9.4.1.3
Secondary Efficacy Endpoint Analysis
Secondary efficacy endpoints are the percent change from baseline to Week 12 in each 
assessment (HDL-C, non-HDL-C, TC, TG, apo B, hsCRP, and HbA1c), the proportion of 
subjects whose LDL-C value achieve the lipid management goals based on risk 
assessment at Week 12, and the proportion of subjects whose LDL-C value achieve 
<70 mg/dL at Week 12.
For the percent change from baseline to Week 12 in each assessment (HDL-C, non-
HDL-C, TC, TG, apo B, hsCRP, and HbA1c), analysis of covariance will be performed 
using treatment group and the randomization stratification factor (statin tolerance/statin 
intolerance) as factors and the baseline value of each assessment as a covariate. The least 
squares mean of each treatment group and differences in mean of least squares between 
each ETC-1002 group and the placebo group as well as their two-sided 95% confidence 
intervals will be calculated. The proportion of subjects whose LDL-C value achieve the 
lipid management goals based on risk assessment at Week 12, and the proportion of 
subjects whose LDL-C value achieve <70 mg/dL at Week 12 will be analyzed by the 
Cochran-Mantel-Haenszel test stratified by statin response (statin tolerance/statin 
intolerance). The proportion in each treatment group and its two-sided 95% interval, as 
well as the differences of proportion between each ETC-1002 group and the placebo 
group and their two-sided 95% confidence intervals will be calculated.

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9.4.1.4
Control of Experiment-wise Type 1 Error
In the primary analysis of the primary endpoint, type 1 error will be controlled by the 
comparative test versus the placebo group using a closed testing procedure, starting from 
the highest dose group.
9.4.1.5
Other Efficacy Endpoint Analysis
Other efficacy endpoints include the actual value, change and percent change from 
baseline at each time point of each assessment (LDL-C, HDL-C, non-HDL-C, TC, TG, 
apo B, hsCRP, and HbA1c). Their descriptive statistics (number of subjects, mean, 
standard deviation, median, minimum, and maximum) by treatment group will be 
calculated at each time point.
9.4.1.6
Subgroup Analyses
Subgroup analyses will be performed for the percent change in LDL-C from baseline to 
Week 12, which is the primary endpoint. The analyses will be performed by the 
following items:

Statin response (statin tolerance, statin intolerance)

Sex (male, female)

Familial hypercholesterolemia (yes, no)

Diabetes mellitus (yes, no)

Age (<65 years, ≥65 years)
9.4.2
Safety Analysis
Tabulation by treatment group (by dose and overall for ETC-1002) will be performed in 
the safety analysis set. 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: If a 
subject experiences the same event more than once, the more severe event will be used.

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
Treatment-emergent AEs

TEAEs by severity

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP

 
TEAEs potentially causally related to the IMP will be summarized in the same manner.
9.4.2.2
Clinical Laboratory Data
Among parameters of the urinalysis in the laboratory tests, the qualitative urinalysis 
includes parameters other than pH and specific gravity.
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.
The number and percentage of subjects meeting Criteria for Identifying Laboratory 
Values of Potential Clinical Relevance will be calculated (the criteria will be specified in 
the SAP).
9.4.2.3
Vital Signs Data
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 (the criteria will be specified in the SAP).

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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 a 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 who have a change in QTcF from baseline of >30 msec or 
>60 msec at any postdose time point will be calculated. The number and percentage of 
subjects meeting these criteria at baseline or each postdose time point will also be 
calculated.
For assessment of normality/abnormality, shift tables at baseline and each time point will 
be prepared.
The number and percentage of subjects meeting Criteria for Identifying ECG 
Measurements of Potential Clinical Relevance will be calculated (the criteria will be 
specified in the SAP).
9.4.2.5
Other Safety Data
9.4.2.5.1
Body weight
Descriptive statistics of the actual value and change from baseline will be calculated at 
each time point.
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 by treatment group (by dose and overall for 
ETC-1002) in each analysis set.
9.4.3.2
Pharmacokinetic Analysis
In the PK analysis set, descriptive statistics (number of subjects, mean, standard 
deviation, coefficient of variation, minimum, median, and maximum) will be calculated 
for the plasma concentrations of ETC-1002 and its active metabolite ESP15228 at each 
dose, visit, and post-dose time point. Population pharmacokinetic analysis of ETC-1002 
will be performed separately.

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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.
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 
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.
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 

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the person obtaining consent (investigator/subinvestigator or designee). 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.
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. The details of quality management activities are described 
separately in the quality management plan.

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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.
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, treatment assignment 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.

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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 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.
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.
Any changes to information in the medical records and other source documents will be 
initialed and dated on the day the change is made by a trial site staff member authorized 

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to make the change. Changes will be made by striking a single line through erroneous 
data (so as not to obliterate the original data), and clearly entering the correct data (eg, 
wrong data right data). If the reason for the change is not apparent, a brief explanation for 
the change will be written in the source documentation by the investigator or 
subinvestigator. If electronic data systems are used, a full audit trail of the change must 
be maintained.
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 and 
central ECG measurement facilities, 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.
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

Date of decision to terminate storage of FBR samples.
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 

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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 
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
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 
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, and condom [all 
methods are approved or certificated in Japan]). Any single method of birth control, 

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including vasectomy and tubal ligation, may fail, leading to pregnancy. The contraceptive 
method will be documented in the source document. 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

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).
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).

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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.
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.

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ADDITIONAL RISK TO THE SUBJECT:  
There is no additional risk to the subjects.

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References
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Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab 
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Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 
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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.
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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.
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Japan Atherosclerosis Society. Statin Intolerance Clinical Guide 2018. 2018.
10 Toth PP, Patti AM, Giglio RV, Nikolic D, Castellino G, Rizzo M, et al. Management 
of Statin Intolerance in 2018: Still More Questions Than Answers. Am J Cardiovasc 
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11 Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, et al. 
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Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial. JAMA. 
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Protocol 346-102-00001
95
Confidential - Proprietary Information
[Amendment 1 Approval]: 19 Nov 2021
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
Signature
Date
The sponsor’s signature on this agreement has been electronically signed. The electronic signature 
page is attached to this agreement.