Conditions: Hyper-low-density Lipoprotein (LDL) Cholesterolemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 96
Healthy volunteers: no

Brief summary:
The purpose of this study is to confirm the superiority of ETC-1002 after 12 weeks of administration at 180 mg/day to placebo in patients with hyper-LDL cholesterolemia who have inadequate control of low-density lipoprotein cholesterol (LDL C).

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: 180mg of ETC-1002(bempedoic acid) intervention 2: Placebo
Intervention descriptions: intervention 1: 180mg, tablet, once daily, for 12 weeks intervention 2: placebo, tablet, once daily, for 12 weeks

Protocol document:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
 
 
NCT Number: NCT05683340 
Protocol No. 346-102-00002 
Approval: 07 Dec 2022 


Otsuka Pharmaceutical Co., Ltd. 
 
Investigational Medicinal Product 
 
ETC-1002 (Nonproprietary name: Bempedoic acid) 
Translation of Japanese Original 
CLINICAL PROTOCOL 
 
A Placebo-controlled, Randomized, Multicenter, Double-blind, Parallel-group Trial to 
Confirm the Superiority of ETC-1002 in Patients With Hyper-LDL Cholesterolemia 
 
A Confirmatory Trial of ETC-1002 in Patients With Hyper-LDL Cholesterolemia 
 
Protocol No. 346-102-00002 
 
CONFIDENTIAL  PROPRIETARY INFORMATION 
 
 
Clinical Development Phase: 
3 
 
Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
 
Immediately Reportable Event  
Office of PV Operations,  
Department of Pharmacovigilance,  
Otsuka Pharmaceutical Co., Ltd. 
 
 
Amendment 1 Approval: 
07 Dec 2022 
Approval: 
04 Oct 2022 
Date of Translation: 
16 Jan 2023 
 
 


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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 
Screening Period ............................................................................................ 24 
1.3.1.1 
Informed Consent ....................................................................................... 24 
1.3.1.2 
Screening Visit: Week −5 .......................................................................... 24 
1.3.2 
Placebo Run-in Period ................................................................................... 25 
1.3.2.1 
Placebo Run-in Period: Week −4 ............................................................... 25 
1.3.2.2 
Observations and Assessments During the Placebo Run-in Period: 
Week −1 ..................................................................................................... 25 
1.3.3 
Treatment Period ........................................................................................... 26 
1.3.3.1 
Day 1 .......................................................................................................... 26 
1.3.3.2 
Observations and Assessments During the Treatment Period: Week 2 
to Week 12 ................................................................................................. 26 
1.3.4 
Follow-up Period ........................................................................................... 26 
1.3.5 
Discontinuation Visit ..................................................................................... 27 
2 
Introduction ........................................................................................28 
2.1 
Trial Rationale .................................................................................................. 30 
2.2 
Background ...................................................................................................... 32 
2.3 
Known and Potential Risks and Benefits ......................................................... 34 
3 
Objectives and Endpoints ..................................................................35 
4 
Trial Design .........................................................................................36 
4.1 
Type/Design of Trial ........................................................................................ 36 
4.2 
Scientific Rationale for Trial Design................................................................ 37 
4.3 
Dosing Rationale .............................................................................................. 38 
4.4 
End of Trial Definition ..................................................................................... 39 


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4.5 
Definition of Completed Subjects .................................................................... 39 
5 
Trial Population ..................................................................................39 
5.1 
Subject Selection and Numbering .................................................................... 39 
5.2 
Eligibility Criteria............................................................................................. 40 
5.2.1 
Inclusion Criteria ........................................................................................... 40 
5.2.2 
Exclusion Criteria .......................................................................................... 43 
5.3 
Lifestyle Considerations ................................................................................... 46 
5.3.1 
Meals and Dietary Restrictions ...................................................................... 46 
5.3.2 
Caffeine, Alcohol, and Tobacco .................................................................... 46 
5.3.3 
Activity .......................................................................................................... 47 
5.4 
Screen Failures ................................................................................................. 47 
6 
Trial Treatments .................................................................................48 
6.1 
Trial Treatments Administered ........................................................................ 48 
6.1.1 
Placebo Run-in Period ................................................................................... 48 
6.1.2 
Treatment Period ........................................................................................... 48 
6.2 
Management of Investigational Medicinal Product ......................................... 49 
6.2.1 
Packaging and Labeling ................................................................................. 49 
6.2.2 
Storage ........................................................................................................... 49 
6.2.3 
Accountability ................................................................................................ 49 
6.2.4 
Returns and Destruction ................................................................................ 50 
6.2.5 
Reporting of Product Quality Complaints ..................................................... 50 
6.2.5.1 
Eliciting and Reporting Product Quality Complaints ................................ 50 
6.2.5.2 
Information Required for Reporting Product Quality Complaints ............ 51 
6.2.5.3 
Return Process in Case of Product Quality Complaints ............................ 51 
6.2.5.4 
Assessment/Evaluation .............................................................................. 51 
6.2.6 
Investigational Medicinal Product Reserve Sample Requirements ............... 51 
6.3 
Measures to Minimize/Avoid Bias ................................................................... 51 
6.4 
Subject Compliance .......................................................................................... 52 
6.5 
Concomitant Medications or Therapies ........................................................... 52 
6.5.1 
Prohibited Medications or Therapies ............................................................. 53 
6.5.1.1 
Prohibited Medications .............................................................................. 53 
6.5.1.2 
Prohibited Therapies .................................................................................. 54 


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6.5.2 
Permitted Medications or Therapies .............................................................. 54 
6.5.3 
Rescue Medications ....................................................................................... 55 
6.6 
Intervention After the End of the Trial ............................................................. 55 
7 
Discontinuation of Trial/Treatment and Subject 
Discontinuation/Withdrawal .............................................................56 
7.1 
Entire Trial or Treatment Discontinuation ....................................................... 56 
7.2 
Individual Site Discontinuation ........................................................................ 56 
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 .................................. 57 
7.3.4 
Withdrawal of Consent .................................................................................. 58 
7.3.5 
Procedures to Encourage Continued Trial Participation ............................... 59 
7.4 
Definition of Subjects Lost to Follow-up ......................................................... 59 
8 
Trial Procedures .................................................................................60 
8.1 
Efficacy Assessments ....................................................................................... 60 
8.2 
Pharmacokinetic Assessments .......................................................................... 61 
8.3 
Pharmacodynamic Assessments ....................................................................... 61 
8.4 
Pharmacogenomic Assessments ....................................................................... 61 
8.5 
Biomarker Assessments ................................................................................... 61 
8.6 
Future Biospecimen Research Samples ........................................................... 61 
8.6.1 
Scope of Future Biospecimen Research ........................................................ 62 
8.6.2 
Summary of Procedures for Future Biospecimen Research Samples ........... 63 
8.6.3 
Storage of Future Biospecimen Research Samples ....................................... 63 
8.6.4 
Genomic/Genetic Analysis and Biomarker Exploration ............................... 63 
8.6.5 
Acquisition and Withdrawal of Informed Consent for Future 
Biospecimen Research ................................................................................... 64 
8.6.6 
Disclosure of Results of Genomic/Genetic Analysis and Biomarker 
Exploration to Subjects .................................................................................. 64 
8.7 
Safety Assessments .......................................................................................... 65 
8.7.1 
Clinical Laboratory Assessments .................................................................. 65 
8.7.2 
Physical Examination .................................................................................... 66 
8.7.3 
Vital Signs ..................................................................................................... 67 


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8.7.4 
Electrocardiogram .......................................................................................... 67 
8.7.5 
Suicidality Monitoring ................................................................................... 67 
8.7.6 
Other Safety Variables ................................................................................... 68 
8.7.6.1 
Body Weight .............................................................................................. 68 
8.8 
Adverse Events ................................................................................................. 68 
8.8.1 
Definitions ..................................................................................................... 68 
8.8.2 
Eliciting and Reporting Adverse Events ........................................................ 70 
8.8.3 
Immediately Reportable Events ..................................................................... 71 
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 .................................................................. 72 
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 ..................................................................................... 74 
8.10 
Subject Assessment Recording ........................................................................ 74 
8.10.1 
Completion of Subject Diary ......................................................................... 74 
8.11 
Other Assessments ........................................................................................... 75 
8.11.1 
Pregnancy Test ............................................................................................... 75 
8.11.2 
Endocrine Test and Virus Test ...................................................................... 75 
9 
Statistical Considerations ..................................................................76 
9.1 
Sample Size ...................................................................................................... 76 
9.2 
Datasets for Analysis ........................................................................................ 76 
9.3 
Handling of Missing Data for Primary Endpoint Analysis .............................. 76 
9.4 
Statistical Analyses........................................................................................... 77 
9.4.1 
Efficacy Analyses .......................................................................................... 77 
9.4.1.1 
Primary Efficacy Endpoint Analysis .......................................................... 77 
9.4.1.2 
Key Secondary Efficacy Endpoint Analysis .............................................. 77 
9.4.1.3 
Secondary Efficacy Endpoint Analysis ...................................................... 77 
9.4.1.4 
Control of Experiment-wise Type 1 Error ................................................. 78 


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9.4.1.5 
Other Efficacy Endpoint Analysis ............................................................. 78 
9.4.1.6 
Subgroup Analyses .................................................................................... 78 
9.4.2 
Safety Analysis .............................................................................................. 78 
9.4.2.1 
Adverse Events........................................................................................... 78 
9.4.2.2 
Clinical Laboratory Data ............................................................................ 79 
9.4.2.3 
Physical Examination and Vital Signs Data............................................... 79 
9.4.2.4 
Electrocardiogram Data ............................................................................. 79 
9.4.2.5 
Other Safety Data ....................................................................................... 80 
9.4.3 
Other Analyses ............................................................................................... 80 
9.4.3.1 
Analysis of Demographic and Baseline Characteristics ............................ 80 
9.4.3.2 
Pharmacokinetic Analysis .......................................................................... 80 
9.4.3.3 
Pharmacodynamic Analysis ....................................................................... 80 
9.4.3.4 
Pharmacokinetic/Pharmacodynamic Analysis ........................................... 80 
9.4.3.5 
Pharmacogenomic Analysis ....................................................................... 80 
9.4.3.6 
Exploratory Endpoint Analysis .................................................................. 81 
9.5 
Interim Analysis and Adaptive Design ............................................................ 81 
10 
Supporting Documentation and Operational Considerations .......82 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations ............ 82 
10.1.1 
Ethics and Responsibility .............................................................................. 82 
10.1.2 
Informed Consent .......................................................................................... 82 
10.1.3 
Confidentiality ............................................................................................... 83 
10.1.4 
Quality Control and Quality Assurance ......................................................... 83 
10.1.4.1 
Monitoring ................................................................................................. 84 
10.1.4.2 
Auditing ..................................................................................................... 84 
10.1.5 
Protocol Deviations ....................................................................................... 84 
10.1.6 
Records Management .................................................................................... 85 
10.1.6.1 
Source Documents ..................................................................................... 85 
10.1.6.2 
Data Collection........................................................................................... 85 
10.1.6.3 
File Management at the Trial Site .............................................................. 86 
10.1.6.4 
Records Retention at the Trial Site ............................................................ 86 
10.1.6.5 
Publication Authorship Requirements ....................................................... 87 
10.2 
Appendix 2: Clinical Laboratory Tests ............................................................ 88 


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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 Amendments ................................................................................ 92 
11 
References ............................................................................................94 
 
 
 


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List of In-text Tables 
Table 1.3-1 
Schedule of Assessments .............................................................. 22 
Table 3-1 
Objectives and Endpoints of This Trial (Primary and 
Secondary) .................................................................................... 35 
Table 6.5.1-1 
List of Prohibited Medications, Food, and Preference 
Products......................................................................................... 54 
Table 6.5.2-1 
List of Medications or Therapies Permitted Before and 
During the Trial............................................................................. 55 
Table 10.2-1 
Clinical Laboratory Assessments .................................................. 88 
 
 


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


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


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Abbreviation 
Definition 
SAE 
Serious adverse event 
TC 
Total cholesterol  
TEAE 
Treatment-emergent adverse event 
TG 
Triglyceride 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
 
 


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1 
Protocol Summary 
1.1 
Synopsis 
Name of Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
Name of Investigational Medicinal Product: 
ETC-1002 (Nonproprietary name: Bempedoic acid) 
Protocol No.: 
346-102-00002 
Protocol Title: 
A placebo-controlled, randomized, multicenter, double-blind, parallel-group trial to 
confirm the superiority of ETC-1002 in patients with hyper-LDL cholesterolemia 
Protocol Lay Person Short Title: 
A confirmatory trial of ETC-1002 in patients with hyper-LDL cholesterolemia 
Clinical Phase/Trial Type: 
Phase 3 trial/Confirmatory trial 
Treatment/Indication: 
Hyper-low-density lipoprotein (LDL) cholesterolemia 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary Objective: 
 
To confirm the superiority of ETC-1002 after 
12 weeks of administration at 180 mg/day to 
placebo in patients with hyper-LDL 
cholesterolemia who have inadequate control 
of low-density lipoprotein cholesterol 
(LDL-C). 
Primary Endpoint: 
 
Percent change in LDL-C from baseline to 
Week 12 
Secondary Objectives: 
 
To assess the effects of ETC-1002 on non-
high-density lipoprotein cholesterol (non-
HDL-C), total cholesterol (TC), 
apolipoprotein B (apo B), high-sensitivity C-
reactive protein (hsCRP), and glycosylated 
hemoglobin (HbA1c). To assess the 
proportion of subjects achieving the lipid 
management goals of LDL-C by treatment 
with ETC-1002. 
Efficacy Assessments: 
 
Percent change in non-HDL-C, TC, apo B, 
hsCRP, and HbA1c from baseline to Week 12 
 
Proportion of subjects whose LDL-C value 
achieves the lipid management goals based on 
the risk assessment (<100 mg/dL [history of 
coronary artery disease or heterozygous 
familial hypercholesterolemia], <120 mg/dL 
[high risk], or <140 mg/dL [intermediate risk]) 
at Week 12 


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Objectives 
Endpoints 
 
To assess the safety of ETC-1002, when 
ETC-1002 at 180 mg/day is administered for 
12 weeks. 
Safety Assessments: 
 
Adverse events (AEs), clinical laboratory 
tests, physical examination, vital signs (blood 
pressure, pulse rate, and body temperature), 
12-lead electrocardiogram (ECG), and body 
weight 
Other Efficacy Assessments: 
 
To assess the effects of ETC-1002 on high-
density lipoprotein cholesterol (HDL-C) and 
triglycerides (TG). 
Other Efficacy Assessments: 
 
Percent change in HDL-C and TG from 
baseline to Week 12 
 
Trial Design: 
A placebo-controlled, randomized, multicenter, double-blind, parallel-group trial 
Trial Population: 
This trial will enroll subjects with hyper-LDL cholesterolemia between 18 and 85 years 
of age, inclusive, who are at risk for cardiovascular events and who have inadequate 
control of LDL-C with existing hyper-LDL cholesterolemia treatments. 
The target number of subjects is 84 in total (42 in the ETC-1002 180-mg group and 42 in 
the placebo group) as randomized subjects. 
Key Inclusion/Exclusion Criteria: 
Inclusion Criteria 
1) Patients who have the ability to provide informed consent, and who provide 
written informed consent prior to the start of the trial 
2) Patients, either male or female, between 18 and 85 years of age, inclusive, at the 
time of informed consent 
3) Patients with inadequate response to statins or statin intolerance as defined below 
 
[Inadequate response to statins] 
Patients with hyper-LDL cholesterolemia who have been taking statins and cannot 
achieve the lipid management goals of LDL-C based on the risk assessment (see 
inclusion criterion 4)), meeting either of the following a) or b) 


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Category 
LDL-C at Week −5 
and Week −1 
Background lipid-lowering drugs at screening 
Type of 
drugs 
Timing of the start of 
treatment:  
before informed consent 
Dose and regimen 
a) 
The lipid 
management goals of 
LDL-C based on the 
risk assessment 
cannot be achieved 
(see inclusion 
criterion 4)). 
Statins alone 
From at least 4 weeks 
before 
Same dose and 
regimen within the 
approved dose range 
b) 
Statins + 
nonstatins 
 
Fibrates, selective 
peroxisome 
proliferator-activated 
receptor (PPAR)α 
modulators:  
From at least 6 weeks 
before 
 
Statins and drugs other 
than those above:  
From at least 4 weeks 
before 
 
Statins: Same 
dose and regimen 
within the 
approved dose 
range 
 
Nonstatins: Same 
dose and regimen 
 
[Statin intolerance] 
Patients with hyper-LDL cholesterolemia for whom safety problems have occurred while 
taking at least one type of statin, and who experienced resolution of the problems after 
discontinuation or dose reduction, and who cannot achieve the lipid management goals of 
LDL-C based on the risk assessment (see inclusion criterion 4)), meeting any of the 
following a) to c) 


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Category 
LDL-C at Week −5 
and Week −1 
Background lipid-lowering drugs at screening 
Type of 
drugs 
Timing of the start of 
treatment:  
before informed consent 
Dose and regimen 
a) 
The lipid 
management goals of 
LDL-C based on the 
risk assessment 
cannot be achieved 
(see inclusion 
criterion 4)). 
Statins alone 
From at least 4 weeks 
before 
Same dose and 
regimen at (or below) 
the lowest approved 
dose 
b) 
Statins + 
nonstatins 
 
Fibrates, selective 
PPARα modulators: 
From at least 6 weeks 
before 
 
Statins and drugs other 
than those above:  
From at least 4 weeks 
before 
 
Statins: Same 
dose and regimen 
at (or below) the 
lowest approved 
dose 
 
Nonstatins: Same 
dose and regimen 
c) 
Only 
nonstatins 
 
Fibrates, selective 
PPARα modulators: 
From at least 6 weeks 
before 
 
Drugs other than the 
above:  
From at least 4 weeks 
before 
Same dose and 
regimen 
 
4) Patients with a history or current condition meeting any of the following criteria 
1) to 3) 
Category 
History or current condition 
LDL-C at Week −5 
and Week −1 
1) 
History of coronary artery disease 
≥100 mg/dL 
Heterozygous familial hypercholesterolemia (HeFH) 
2) 
Peripheral arterial disease 
≥120 mg/dL 
History of non-cardiogenic cerebral infarction 
Chronic kidney disease (Provided that it does not fall under 
exclusion criterion 12)) 
Type 2 diabetes mellitus (Diagnosed at least 3 months before 
Week −5, without falling under exclusion criterion 7)) 
3) 
The total score in the coronary artery disease risk prediction 
model using the Suita score specified by the Japan 
Atherosclerosis Society is ≥56 points (high risk) 
≥120 mg/dL 
The total score in the coronary artery disease risk prediction 
model using the Suita score specified by the Japan 
Atherosclerosis Society is ≥41 and ≤55 points (intermediate risk) 
≥140 mg/dL 
 
5) Patients with fasting TG levels of <400 mg/dL at screening (Week −5) 
 


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Exclusion Criteria 
1) Females who are pregnant or breast-feeding or who have a positive pregnancy test 
(urine) result at screening (Week −5) or on Day 1 
2) Sexually active and reproductive males or sexually active females of childbearing 
potential who do not agree to practice 2 different approved methods of birth 
control or to maintain complete abstinence (the methods of periodic abstinence 
and withdrawal are not appropriate for contraception) during the trial and for 
30 days after final 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, or condom (all methods are 
approved or certified in Japan). 
3) Patients with homozygous familial hypercholesterolemia (HoFH) 
4) Patients who currently have or who have had within the past 3 months prior to 
screening (Week −5) any of the following cardiovascular diseases, or those who 
have developed any of these AEs during the screening and placebo run-in period 
 Myocardial infarction, severe or unstable angina pectoris, coronary angioplasty, 
coronary artery bypass graft, stroke, transient ischemic attack, symptomatic 
carotid artery stenosis, symptomatic peripheral arterial disease, or decompensated 
heart failure 
 Abdominal aortic aneurysm 
 Patients with risk factors for torsade de pointes, such as unexplained syncope or 
long-QT syndrome, or a family history of long-QT syndrome 
5) Patients with uncontrolled hypertension, defined as follows: sitting systolic blood 
pressure of ≥160 mmHg or diastolic blood pressure of ≥100 mmHg after resting 
5 minutes at screening (Week −5) 
6) Patients with uncontrolled and serious hematologic or coagulation disorders, or 
with hemoglobin of <10.0 g/dL at screening (Week −5) 
7) Patients with uncontrolled diabetes with HbA1c of ≥9% at screening (Week −5) 
8) Patients with uncontrolled hypothyroidism with thyroid-stimulating hormone 
(TSH) of >1.5 × the upper limit of normal (ULN) at screening (Week −5) 
9) Patients with liver disease or dysfunction, including: 
 Positive serology for hepatitis B surface antigen (HBsAg) or a positive hepatitis C 
virus (HCV) antibody test at screening (Week −5) 
 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) of 
≥3 × ULN or total bilirubin of ≥2 × ULN at screening (Week −5) 
10) Patients with a history or current chronic musculoskeletal symptoms that may be 
difficult to differentiate from myalgia 
(eg, fibromyalgia) 
11) Patients with creatine kinase (CK) of >3 × ULN at screening (Week −5) 
12) Patients with a history or current renal dysfunction, nephritic syndrome, or 
nephritis, and with estimated glomerular filtration rate (eGFR) of 
≤30 mL/min/1.73 m2 at screening (Week −5) 


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13) Patients who have had gastrointestinal surgery that may affect drug absorption 
(eg, Lap-Band® or gastric bypass) 
14) Patients who have undergone surgery, chemotherapy, or radiation for active 
malignancy (excluding properly treated nonmetastatic basal or squamous cell 
carcinoma of the skin and cervical carcinoma in situ) within the past 5 years prior 
to screening (Week −5) 
15) Patients with a history of drug, alcohol, or cocaine abuse within the past 2 years 
prior to screening (Week −5) 
16) Patients who have had blood collection (eg, blood donation) in a cumulative 
amount exceeding 200 mL within 4 weeks, 400 mL within 12 weeks, or 1200 mL 
within 1 year prior to screening (Week −5) 
17) Patients who have used any investigational drug not approved in Japan within 
either 4 weeks or 5 times the half-life of the drug, whichever is longer, prior to 
screening (Week −5) 
18) Patients who took the IMP in Trial 346-102-00001 or patients who have used 
ETC-1002 in the past 
19) Patients who used or received the following drugs (including food) or therapies 
within the specified period or who are planning to use or receive them by the end 
of the tests at Week 12 
 
Drugs (including food) or 
therapies 
Prohibition period 
1. 
Systemic corticosteroids 
From 3 months prior to Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
However, the drug may be used concomitantly with no change in 
dose from 3 months prior to Week −5 to the end of the tests at 
Week 12 (or to the completion of the assessments at Discontinuation 
Visit, if applicable). 
2. 
Lomitapide 
From 3 months prior to Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
3. 
Proprotein convertase 
subtilisin/kexin type 9 
(PCSK9) inhibitors 
From 4 months prior to Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
4. 
5. 
Red yeast rice and food 
containing red yeast rice 
From 2 weeks prior to Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
6. 
LDL apheresis 
From 3 months prior to Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
 


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20) Patients in whom the following drugs (therapies) are changed prior to Day 1 or in 
whom initiation of the following drugs (therapies) is planned by the end of the 
tests at Week 12 
 
Drugs or therapies 
Period in which the drug or therapy cannot be changed or  
newly started 
1. 
Female or male hormone 
replacement 
From 6 weeks prior to Day 1 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
2. 
Thyroid replacement 
From 6 weeks prior to Day 1 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
3. 
Diabetes medications 
From 4 weeks prior to Day 1 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
4. 
Obesity medications 
From 3 months prior to Day 1 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
 
21) Patients whose LDL-C level at Week −1 has changed by at least ±20% as 
compared with that at screening (Week −5) 
22) Patients with <80% compliance with the single-blind placebo up to Day 1 during 
the placebo run-in period or who cannot continue drug administration due to 
safety issues 
23) Patients in whom a muscle-related AE other than due to strain, trauma, or other 
obvious etiology newly occurs or is aggravated during the placebo run-in period 
24) Patients otherwise judged inappropriate for participating in the trial in the opinion 
of the investigator or subinvestigator 
 
Trial Sites: 
Approximately 35 sites in Japan 
Investigational Medicinal Product, Dose, Dosage Regimen, Treatment Duration, 
Formulation, and Mode of Administration: 
Description 
Placebo Run-in Period 
Treatment Period 
Investigational 
medicinal products 
Medications 
Placebo tablets 
ETC-1002 180-mg tablets/ 
Placebo tablets 
Dose and 
regimen/  
Mode of 
administration 
1 tablet once daily/oral 
Lipid-lowering drugs 
Medications 
Lipid-lowering drugs used before informed consent 
(Statins and/or nonstatins) 
Dose and 
regimen 
Continue treatment without changing the type or dose and 
regimen 
Treatment duration 
4 weeks 
12 weeks 
 


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Trial Assessments: 
Assessments for Efficacy: LDL-C, non-HDL-C, TC, HDL-C, TG, apo B, hsCRP, and 
HbA1c 
Trial Assessments for Future Biospecimen Research (FBR): DNA sample storage 
(optional) and serum sample storage for biomarker exploration (optional) 
Assessments for Safety: Adverse events, clinical laboratory tests, physical examination, 
vital signs (blood pressure, pulse rate, and body temperature), 12-lead ECG, and body 
weight 
Screening/Other: Demographics, height, medical history, prior medications, virus test 
(HBsAg and HCV antibodies), endocrine test (TSH), and pregnancy test (urine, serum) 
Data Monitoring Committee: No 
Statistical Methods: 
Primary Efficacy Endpoint Analysis 
The primary endpoint is the percent change from baseline to Week 12 in LDL-C 
measured by the direct method. Baseline is defined as the mean of the LDL-C values for 
Day 1 and Week −1. A mixed models repeated measures (MMRM) analysis assuming 
missing at random (MAR) will be performed using observed case (OC) data. The 
treatment comparison will be based on the least-squares mean difference between the 
ETC-1002 group and the placebo group at Week 12. A two-sided significance level of 
5% will be used. The model will include treatment group, stratification factor, time, and 
treatment-by-time interaction as factors, and baseline and baseline-by-time interaction as 
covariates. The error covariance structure will be unstructured. The Kenward-Roger 
method will be used for the approximate degrees of freedom. 
Sample Size 
In the phase 2 trial conducted in Japan, the difference in the percent change from baseline 
in LDL-C to Week 12, between the ETC-1002 180-mg group and the placebo group was 
−19%, and the standard deviation of the percent change from baseline in each group 
ranged from 9% to 17%. Since the between-group difference in the phase 2 trial in Japan 
was comparable to the results estimated from phase 3 trials conducted outside Japan, the 
between-group difference in this trial is assumed to be −19%. Also considering the 
standard deviation (14% to 25%) in the phase 3 trials conducted outside Japan, in which 
similar populations of subjects to this trial were enrolled, the standard deviation in this 
trial is conservatively assumed to be 25%. Under those assumptions, a total of 76 subjects 


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(38 subjects/group) will be required to ensure a power of 90%. Assuming a withdrawal 
rate of 10%, the total number of subjects in this trial is set at 84. 
Trial Duration: 
Each subject in this trial is expected to participate in the following periods of the trial: 
 Screening period (1 week) 
 Placebo run-in period (single-blind, 4 weeks) 
 Treatment period (double-blind, 12 weeks) 
 Follow-up period (4 weeks) 
 
Overall, the trial duration from signing of the first informed consent form (ICF) to the 
end date of the follow-up period of the final subject assessment is expected to be 
approximately 11 months. 
 


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1.2 
Schema 
 
Figure 1.2-1 
Trial Design Schematic 
 
 
Screening Period
(1 week)
Follow-up Period
(4 weeks)
Modifiable
Visit
Placebo
Randomized
Lipid-lowering drugs: Type and dose/regimen fixed
Placebo Run-in Period
(single blind) (4 weeks)
Treatment Period
(double blind) (12 weeks)
ETC-1002  180 mg (N = 42)
Placebo (N = 42)
R
Week−5
Week−4
Week−1
Day 1 (Start day of the treatment period)
Week 2
Week 4
Week 12
Week 16
(End of trial: 28 days after the 
final IMP administration)
Week 8
Day1
P
Start of IMP dosing
(Start of trial)
End of treatment
P
R


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1.3 
Schedule of Assessments 
Table 1.3-1 
Schedule of Assessments 
 
Screening 
Period 
Placebo Run-in 
Period 
Treatment Period 
Follow-up 
Period 
Visit (Week) 
Week −5 
Week −4 Week −1 
Day 1 
Week 2 
Week 4 
Week 8 
Week 12/ 
Discontinuationa 
Week 16 
Trial Day 
Day  
−35 ± 3 
Day  
−28 ± 3 
Day  
−7 ± 2 
Day  
15 ± 3 
Day  
29 ± 3 
Day  
57 ± 3 
Day  
85 ± 3 
28 days ±7 days 
after the final 
IMP 
administration 
Informed consentb 
● 
 
 
 
 
 
 
 
 
Eligibility assessment 
● 
● 
● 
● 
 
 
 
 
 
Demographics 
● 
 
 
 
 
 
 
 
 
Endocrine test (TSH) 
Virus test (HBsAg, HCV antibody) 
● 
 
 
 
 
 
 
 
 
Placebo administration for  
the placebo run-in period 
 
● 
● 
 
 
 
 
 
 
Randomization 
 
 
 
● 
 
 
 
 
 
IMP administration for  
the treatment period 
 
 
 
● 
● 
● 
● 
 
 
Fasting lipidsc, d 
● 
 
● 
● 
● 
● 
● 
● 
● 
HbA1cd 
● 
 
 
● 
 
 
 
● 
 
hsCRP, apo Bd 
 
 
 
● 
 
 
 
● 
 
Physical examination 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Body weight 
● 
 
● 
● 
 
● 
● 
● 
 
Vital signse 
● 
● 
● 
● 
● 
● 
● 
● 
● 
12-Lead ECGf 
● 
 
 
● 
 
● 
 
● 
 
Clinical laboratory testsg 
● 
 
● 
● 
 
● 
● 
● 
● 
Provision of subject diary 
 
● 
● 
● 
● 
● 
● 
 
 
Collection of subject diary 
 
 
● 
● 
● 
● 
● 
● 
 


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Table 1.3-1 
Schedule of Assessments 
 
Screening 
Period 
Placebo Run-in 
Period 
Treatment Period 
Follow-up 
Period 
Visit (Week) 
Week −5 
Week −4 Week −1 
Day 1 
Week 2 
Week 4 
Week 8 
Week 12/ 
Discontinuationa 
Week 16 
Trial Day 
Day  
−35 ± 3 
Day  
−28 ± 3 
Day  
−7 ± 2 
Day  
15 ± 3 
Day  
29 ± 3 
Day  
57 ± 3 
Day  
85 ± 3 
28 days ±7 days 
after the final 
IMP 
administration 
Confirmation of use of concomitant 
medications/therapies 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
Pregnancy testh 
● 
 
 
● 
 
 
 
● 
 
Blood sampling for biomarker storagei 
 
 
 
○ 
○ 
○ 
 
○ 
○ 
Blood sampling for DNA storage i 
 
 
 
○ 
 
 
 
 
 
● Mandatory; ○ Optional 
aIn cases of early discontinuation during the placebo run-in period or treatment period, “Discontinuation Visit” is to be performed within 2 days after the last 
dose of the IMP as far as possible. With regard to termination during the placebo run-in period, blood sampling for biomarker sample storage, DNA sample 
storage, hsCRP, and apo B measurement is not to be performed. 
bWritten informed consent will be obtained from the patient himself/herself prior to any trial-related assessments. Written consent will be obtained by Week −5. 
cFasting lipid assessments include LDL-C, HDL-C, non-HDL-C, TC, and TG. 
dOn scheduled visit days, subjects are to be instructed to come to the trial site without taking the IMP and reminded to take the IMP after tests are completed. 
eBody temperature, blood pressure, and pulse measurements are to be performed after resting for at least 5 minutes and prior to blood sampling to the extent 
possible. 
f12-Lead ECG is to be performed after resting for at least 10 minutes and prior to blood sampling whenever possible. 
gClinical laboratory tests include hematology, blood chemistry (except for HbA1c, fasting lipid assessments), and urinalysis. 
hPregnancy test is to be performed only for females of childbearing potential. If urine test is positive, the serum test will be performed (except Week −5). 
iBlood sampling is to be performed only for subjects who provide written consent for DNA sample storage and biomarker sample storage. Blood sampling for 
DNA sample storage will be performed before IMP administration on Day 1 in principle. If blood sampling cannot be performed or needs to be performed 
again, it will be performed at a feasible time during the trial period. 


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1.3.1 
Screening Period 
1.3.1.1 
Informed Consent 
Prior to starting any assessments at screening, written informed consent will be obtained 
from the patients themselves. After informed consent is obtained, each subject will be 
given a subject identification number and registered in the Interactive Web Response 
System (IWRS). Operation of the IWRS after the initial registration will be separately 
specified in the procedure as a system to manage the registration status of subjects and 
the investigational medicinal product (IMP). The investigator or subinvestigator will 
enter the subject identification number and the date of informed consent in the subject 
screening log. The subject identification number and the date of informed consent will 
also be recorded in the source document and the electronic case report form (eCRF). 
For DNA sample storage and biomarker sample storage, written informed consent will be 
obtained from the subjects themselves using a separate informed consent form (ICF), and 
the date of informed consent will be recorded in the source document and the eCRF. 
DNA and biomarker sample 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 sample 
storage. 
 
1.3.1.2 
Screening Visit: Week −5 
After obtaining informed consent, the investigator or subinvestigator will perform the 
observation and assessments at Week −5 specified in Table 1.3-1, record the results in the 
source document and the eCRF with the visit date, and enter the required information in 
the IWRS. After judging the eligibility for participation in the trial, the investigator or 
subinvestigator will record the eligibility for enrollment, date of enrollment, and reasons 
in the case of non-enrollment in the subject screening log. 
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, and country) 
 Height (in units of 0.1 cm [if measured to the second decimal place or less, the second 
decimal place will be rounded.]) 
 Past medical history (within 1 year before informed consent, but this limitation is not 
applicable to those related to the inclusion and exclusion criteria) 
 Current condition (at the time of informed consent) 
 History of hypercholesterolemia 


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History of Hypercholesterolemia: Investigation Item 
 
Name of diagnosis 
 
Date of diagnosis 
 
Presence or absence of familial hypercholesterolemia 
 
Classification and details of classification (according to the flowchart using the Suita score in the 
Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 
2017,1 and according to the flowchart using the score of the Hisayama Study in the Guidelines 
20222) 
 
Statin response (inadequate response to statins, statin intolerance) 
 
For patients with statin intolerance: Cause of statin intolerance and the name/daily dose of the statin 
 
 Prior lipid-lowering drugs received within 6 weeks prior to informed consent 
 Therapeutic drugs for diabetes mellitus used within 7 weeks prior to informed consent 
 All prior medications and prior therapies received within 4 weeks prior to informed 
consent 
 Result of eligibility assessment 
 
1.3.2 
Placebo Run-in Period 
1.3.2.1 
Placebo Run-in Period: Week −4 
The investigator or subinvestigator will perform the observations and assessments at 
Week −4 at the start of the placebo run-in period specified in Table 1.3-1, record the 
results in the source document and the eCRF with the visit date. Subject eligibility will be 
determined, and the result of the determination will be recorded in the source document 
and the eCRF and entered in the IWRS. If the subject is judged to be eligible, the date of 
enrollment in the placebo run-in period will be recorded in the source document and the 
eCRF and entered in the IWRS. 
 
1.3.2.2 
Observations and Assessments During the Placebo Run-in 
Period: Week −1 
Subjects who meet the eligibility criteria based on the observation and assessments at 
Week −4 will proceed to the 4-week placebo run-in period, continue taking any lipid-
lowering drugs that they have been taking from before informed consent at the same dose 
and regimen, and receive placebo tablets for 4 weeks. The investigator or subinvestigator 
will perform the observation and assessments specified in Table 1.3-1, record the visit 
date in the source document and the eCRF, and enter the result of the determination in the 
IWRS. On and after Week −4, subjects not meeting the eligibility criteria based on the 


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observations and examinations at Week −1 will be withdrawn from the trial, as subjects 
withdrawn from the placebo run-in period. 
 
1.3.3 
Treatment Period 
1.3.3.1 
Day 1 
The investigator or subinvestigator will determine whether or not a subject can proceed to 
the treatment period based on the results of the observations and assessments on Day 1 
specified in Table 1.3-1, record the result in the source document and the eCRF, and enter 
the determination result in the IWRS. If the subject is judged to be eligible for proceeding 
to the treatment period, the subject will be randomly assigned to either the ETC-1002 
180-mg group or the placebo group in a ratio of 1:1. The date and randomization number 
will be recorded in the source document and the eCRF. 
 
1.3.3.2 
Observations and Assessments During the Treatment Period: 
Week 2 to Week 12 
If a subject who has been determined to be eligible for proceeding to the treatment period 
has received a lipid-lowering drug since before informed consent, the subject should 
continue to receive the drug at the same dose and regimen in addition to taking the IMP 
(ETC-1002 at 180 mg/day or placebo) for 12 weeks. 
The observation and assessments specified in Table 1.3-1 will be performed during the 
treatment period, and the results will be recorded in the source document and the eCRF 
with the visit date. The investigator or subinvestigator will enter the required information 
in the IWRS at each visit for each subject. 
 
1.3.4 
Follow-up Period 
The investigator or subinvestigator will perform the observation and assessments 
specified in Table 1.3-1 at the visit 28 days (±7 days) after the last IMP administration to 
all the subjects who proceed to the treatment period and record the results in the source 
document and the eCRF with the visit date. The investigator or subinvestigator will enter 
the required information in the IWRS at the end of the follow-up period for each subject. 
The tests during the follow-up period will not be performed for subjects who are 
proceeding to the treatment period in the 52-week (open-label) long-term trial. 
Proceeding to the long-term trial is optional. 


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1.3.5 
Discontinuation Visit 
When the subject discontinues during the placebo run-in period or the treatment period, 
the investigator or subinvestigator will perform the same assessments at Week 12 (see 
Table 1.3-1) at Discontinuation Visit within 2 days after the last dose of the IMP as much 
as possible and record the results in the source document and the eCRF with the visit 
date. The investigator or subinvestigator will enter the required information in the IWRS 
at the time of discontinuation for each subject. 
 


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2 
Introduction 
Dyslipidemia is defined as a condition in which low-density lipoprotein cholesterol 
(LDL-C), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) in the 
blood are outside the reference values. Since these abnormalities are primarily associated 
with the incidence of coronary artery disease, prophylaxis and subsequent treatment are 
considered critical. In addition, with the recent westernization of food, the number of 
patients with dyslipidemia is increasing each year in Japan, and currently stands at 
approximately 2.2 million.3 Hyper-LDL cholesterolemia, which is one of the forms of 
dyslipidemia, refers to the state of having high LDL-C levels in the blood. If left 
untreated, this condition is considered as one of the most significant risk factors 
associated with the development and progression of arteriosclerosis. Drugs currently 
launched in Japan for the treatment of hyper-LDL cholesterolemia include 3 hydroxy-3-
methylglutaryl-coenzyme A reductase inhibitors (various statins), small intestine 
cholesterol transporter inhibitors (ezetimibe), and human anti-proprotein convertase 
subtilisin/kexin type 9 (PCSK9) monoclonal antibody formulations (evolocumab). 
Several large-scale clinical trials have demonstrated the usefulness of these drugs for the 
primary and secondary prevention of coronary artery disease.4,5,6,7,8 Japanese and non-
Japanese guidelines1,9,10 place statins as the first-line drug, and statins have been used for 
the treatment of hyper-LDL cholesterolemia. LDL-C can be controlled with statins in 
many patients. However, in some patients with a history of coronary artery disease or 
patients with familial hypercholesterolemia who require strict control of LDL-C, 
treatment with statins alone is often not able to achieve the lipid management goals of 
LDL-C based on the risk assessment for the primary and secondary prevention of 
coronary artery disease specified in Japan Atherosclerosis Society Guidelines for 
Prevention of Atherosclerotic Cardiovascular Diseases 2017,1 posing an issue with drug 
therapy for patients with inadequate control of LDL-C. In such cases, combination 
therapy using drugs with mechanisms of action different from statins is performed, the 
issue of drug therapy still remains. Statin intolerance, which requires a dose reduction or 
interruption of statins due to myopathy or hepatic impairment caused by statin therapy, is 
observed in some patients. According to the Statin Intolerance Clinical Guide,11 statin 
intolerance is defined as “in the individual case treated with statins for the first time, in 
whom statin continuation becomes difficult due to an adverse event upon initial statin 
administration, and those adverse events were again observed by at least one another 
statin”. The guideline recommends dose reduction or discontinuation of statins, switching 
to other statins, or administration of nonstatins, depending on the severity of adverse 
events (AEs), if myopathy (subjective symptoms such as myalgia, twitching, stiffness, 


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Approval: 07 Dec 2022 
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 because of the inability of statin 
administration due to statin intolerance. 
ETC-1002 (nonproprietary name: bempedoic acid) is a drug with a new mechanism of 
action that inhibits cholesterol and fatty acid synthetic pathways by acting on adenosine 
triphosphate citrate lyase, an enzyme degrading citric acid in the cholesterol biosynthetic 
pathway in the liver. Esperion Therapeutics, Inc. has been developing the drug in 
countries other than Japan. In clinical trials conducted outside Japan in patients with 
hyper-LDL cholesterolemia, administration of add-on ETC-1002 to patients who are not 
adequately controlled with their maximally tolerated statins resulted in a significant 
decrease in LDL-C levels compared with the placebo group. Treatment with ETC-1002 
also significantly reduced LDL-C levels in patients with statin-intolerant hyper-LDL 
cholesterolemia compared with placebo. No particular safety concern has been identified 
in the clinical trials that have been conducted to date. Based on the results of clinical 
trials conducted outside Japan, the efficacy of ETC-1002 at 180 mg/day was confirmed in 
combination with statins and/or nonstatins in patients who are not able to achieve 
adequate control with their maximally tolerated statins in the US. As no particular safety 
concerns were identified, ETC-1002 was approved in February 2020 and has already 
been marketed. In Europe, since the efficacy and safety of ETC-1002 at 180 mg/day 
alone was demonstrated in patients with statin intolerance in addition to patients with an 
inadequate response to the maximally tolerated statins in whom ETC-1002 was used in 
combination with statins and/or nonstatins, ETC-1002 was approved in April 2020, and 
has already been marketed in some European countries. In addition, a large-scale 
cardiovascular outcome trial is currently ongoing to assess whether long-term treatment 
with ETC-1002 at 180 mg reduces the risk of major adverse cardiovascular events 
(MACE) in statin-intolerant patients with or at a high risk of atherosclerotic 
cardiovascular disease. 
Otsuka Pharmaceutical Co., Ltd. (hereinafter referred to as “Otsuka”) considers that 
ETC-1002 can be a new treatment option for Japanese patients with hyper-LDL 
cholesterolemia in whom LDL-C values cannot be adequately controlled with existing 
statin-based therapy. Otsuka has obtained the development and marketing right in Japan 
from Esperion Therapeutics, Inc. and started development in Japan. A phase 2 dose-
finding trial (Protocol No. 346-102-00001) conducted to assess the efficacy, dose-


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response, and safety in Japanese patients and determine the dose used in the phase 3 trial 
has already been concluded. 
For further information, please refer to the ETC-1002 Investigator’s Brochure (IB). 
 
2.1 
Trial Rationale 
Thus far, the efficacy of ETC-1002 on hyper-LDL cholesterolemia has been 
demonstrated in phase 3 placebo-controlled, double-blind trials conducted outside Japan 
in patients with hyper-LDL cholesterolemia (Trials 1002-040, 1002-046, 1002-047, and 
1002-048), and it has been confirmed that there are no particular safety concerns. 
Adverse events that occurred 
in 5% or more of subjects in the ETC-1002 group were pyrexia (7.1% [10/141 subjects]), 
malaise (5.0% [7/141 subjects]), hepatic function abnormal (5.0% [7/141 subjects]), 
arthralgia (5.0% [7/141 subjects]), and headache (5.0% [7/141 subjects]).


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The subgroup analysis by statin response (inadequate response to statins, statin 
intolerance) demonstrated that the percent change (least squares mean) in LDL-C from 
baseline to Week 12 was −5.48%, −18.13%, and −16.31% in the ETC-1002 60, 120, and 
180-mg groups, respectively, versus −0.29% in the placebo group among subjects with 
inadequate response to statins; and  −20.43%, −27.44%, and −31.25% in the ETC-1002 
60, 120, and 180-mg groups, respectively, versus +1.00% in the placebo group among 
subjects with statin intolerance
There was no considerable 
difference in the tendency of the incidence of AEs between subjects with inadequate 
response to statins and those with statin intolerance. 
Meanwhile, a large-
scale cardiovascular outcomes trial is currently ongoing to evaluate the effect of ETC-
1002 at 180 mg on lowering the risk of MACE in patients with hyper-LDL 
cholesterolemia, and the results will be available in the future. 


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The primary endpoint is the percent change from baseline to Week 12 in LDL-C. The 
duration of the treatment period for the evaluation in this trial is set at 12 weeks, because 
the evaluation time point for the primary endpoint in the phase 2 trial is at 12 weeks after 
the start of administration, and also because the trial duration should persist for at least 3 
months according to the Guidelines on Clinical Evaluation of Medicinal Products for 
Treatment of Dyslipidemia.12 In addition, this trial will include patients who cannot 
achieve the lipid management goals specified in the Japan Atherosclerosis Society 
Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017,1 even after 
taking existing therapeutics for hyper-LDL cholesterolemia.
The concomitant lipid-lowering drugs will be continued without 
changing the type, dose, and regimen from at least 4 weeks before informed consent (at 
least 6 weeks before, for fibrates and selective peroxisome proliferator-activated receptor 
[PPAR]α modulators). 
Taken together, it is judged to be ethically appropriate to conduct this trial to confirm the 
superiority of ETC-1002 at 180 mg/day to placebo in patients with hyper-LDL 
cholesterolemia. 
 
2.2 
Background 
Efficacy data supporting the indication of LDL-C reduction have been obtained from 4 
phase 3 
trials of ETC-1002 in clinical trials conducted outside Japan. In 
these trials, the once-daily administration of ETC-1002, added to a maximum tolerated 


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Approval: 07 Dec 2022 
dose of statins (including no statin) and/or other therapeutics for hyper-LDL 
cholesterolemia (ezetimibe or PCSK9 inhibitors) resulted in a significant reduction of 
LDL-C from baseline in patients with hyper-LDL cholesterolemia (including those at 
high cardiovascular risk). 
Overall, ETC-1002 has an acceptable safety profile in 
combination with other LDL-C lowering therapies (including statins, ezetimibe, or 
PCSK9 inhibitors) in a variety of patient populations. 
In Japan, a dose-finding trial (Protocol No. 346-102-00001) of ETC-1002 as a phase 2 
trial was conducted in patients with hyper-LDL cholesterolemia to investigate the 
efficacy and safety of ETC-1002 at 60 mg/day, 120 mg/day, 180 mg/day, and placebo. 
The results verified the efficacy and safety of ETC-1002 at up to 180 mg/day in Japanese 
patients with hyper-LDL cholesterolemia. 
Therefore, this clinical trial has been planned to confirm the superiority of ETC-1002 to 
placebo in patients with inadequate response to statins or statin intolerance in whom the 
target LDL-C level cannot be achieved by drug therapy with statin alone or in 
combination with other drugs. (See Section 2.1 for details.) 
 


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2.3 
Known and Potential Risks and Benefits 
The results of the clinical trials conducted outside Japan and the Japanese phase 2 trial 
have demonstrated that ETC-1002 at 180 mg/day was effective in patients with 
inadequate response to statins or statin intolerance. For safety, ETC-1002 was tolerated at 
up to 180 mg/day with no tendency for an increased incidence of AEs in a dose-
dependent manner in the Japanese phase 2 trial.
ETC-1002 can be a useful treatment for patients with hyper-LDL cholesterolemia 
who need to continue long-term therapy for hyper-LDL cholesterolemia. 


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Approval: 07 Dec 2022 
Once the IB is revised, the revised version will be provided to the trial sites. The trial 
sites should refer to the most current version provided as needed. 
 
3 
Objectives and Endpoints 
The objectives and endpoints of this trial are shown below. 
 
Table 3-1 
Objectives and Endpoints of This Trial (Primary and 
Secondary) 
Objectives 
Endpoints 
Primary Objective: 
 
To confirm the superiority of ETC-1002 after 
12-week of administration at 180 mg/day to 
placebo in patients with hyper-LDL 
cholesterolemia who have inadequate control 
of low-density lipoprotein cholesterol 
(LDL-C). 
Primary Endpoint: 
 
Percent change in LDL-C from baseline to 
Week 12 
Secondary Objectives: 
 
To assess the effects of ETC-1002 on non-
high-density lipoprotein cholesterol (non-
HDL-C), total cholesterol (TC), 
apolipoprotein B (apo B), high-sensitivity 
C-reactive protein (hsCRP), and glycosylated 
hemoglobin (HbA1c). To assess the 
proportion of subjects achieving the lipid 
management goals of LDL-C by treatment 
with ETC-1002. 
 
To assess the safety of ETC-1002, when 
ETC-1002 at 180 mg/day is administered for 
12 weeks. 
Efficacy Assessments: 
 
Percent change in non-HDL-C, TC, apo B, 
hsCRP, and HbA1c from baseline to Week 12 
 
Proportion of subjects whose LDL-C value 
achieves the lipid management goals based on 
the risk assessment (<100 mg/dL [history of 
coronary artery disease or heterozygous 
familial hypercholesterolemia], <120 mg/dL 
[high risk], or <140 mg/dL [intermediate risk]) 
at Week 12 
Safety Assessments: 
 
Adverse events, clinical laboratory tests, 
physical examination, vital signs (blood 
pressure, pulse rate, and body temperature), 
12-lead ECG, and body weight 
Other Efficacy Assessments: 
 
To assess the effects of ETC-1002 on high-
density lipoprotein cholesterol (HDL-C) and 
triglycerides (TG). 
Other Efficacy Assessments: 
 
Percent change in HDL-C and TG from 
baseline to Week 12 
 
Section 9.4 describes the statistical analysis of the endpoints. 
 


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4 
Trial Design 
4.1 
Type/Design of Trial 
This is a placebo-controlled, randomized, multi-center, double-blind, parallel-group trial 
to confirm the efficacy and assess the safety of 12-week administration of ETC-1002 at 
180 mg/day in patients with hyper-LDL cholesterolemia who are being treated for hyper-
LDL cholesterolemia but have inadequate control and cannot achieve the lipid 
management goals. The trial population will include patients with an inadequate response 
to statins who cannot achieve the lipid management goals despite statin therapy, and 
patients with statin intolerance who cannot achieve the lipid management goals because 
they have experienced safety problems caused by statin administration which resolved 
after discontinuation or dose reduction. 
A schematic of the trial design is presented in Figure 1.2-1. 
This trial consists of the screening period, the placebo run-in period, the treatment period, 
and the follow-up period. Subjects determined to be eligible in the screening period will 
proceed to the placebo run-in period, continue the treatment without changing the type or 
dose and regimen of lipid-lowering drugs that have been taken from before informed 
consent, and receive placebo in a single-blind manner. Subjects with noncompliance with 
less than 80% compliance with the single-blind placebo during the 4-week placebo run-in 
period will be withdrawn at the end of the placebo run-in period. Subjects who do not 
have safety problems or muscle-related AEs in the 4-week placebo run-in period, or who 
do not fall under the exclusion criteria as judged by the investigator or subinvestigator, 
will be assigned to either the ETC-1002 180-mg group or the placebo group, and proceed 
to the treatment period. Statin response (inadequate response to statins/statin intolerance) 
is set as a randomization stratification factor so that subjects with inadequate response to 
statins and statin intolerance will be equally allocated to each treatment group. 
During the treatment period, subjects should continue to take the lipid-lowering drugs 
that they have taken from before informed consent and receive either ETC-1002 at 
180 mg or placebo for 12 weeks. The medications to be administered in the placebo run-
in period and the treatment period are as follows: 


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Description 
Placebo Run-in Period 
Treatment Period 
Investigational 
medicinal products 
Medications 
Placebo tablets 
ETC-1002 180-mg tablets/ 
Placebo tablets 
Dose and 
regimen/  
Mode of 
administration 
1 tablet once daily/oral 
Lipid-lowering drugs 
Medications 
Lipid-lowering drugs used before informed consent 
(Statins and/or nonstatins) 
Dose and 
regimen 
Continue treatment without changing the type or dose and 
regimen 
Treatment duration 
4 weeks 
12 weeks 
 
4.2 
Scientific Rationale for Trial Design 
This clinical trial has been planned to confirm the superiority of ETC-1002 to placebo in 
patients with inadequate response to statins or statin intolerance who cannot achieve the 
lipid management goals specified in the Japan Atherosclerosis Society Guidelines for 
Prevention of Atherosclerotic Cardiovascular Diseases 2017.1 The primary endpoint is 
the percent change from baseline to Week 12 in LDL-C. This trial consists of the 
screening period, the placebo run-in period, the treatment period, and the follow-up 
period. Subjects who are determined to meet the inclusion criteria and do not fall under 
the exclusion criteria in the screening period are to proceed to the placebo run-in period 
from 4 weeks before randomization and receive placebo for 4 weeks in a single-blind 
manner. 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.11,13 Some patients have been reported to experience a reverse placebo effect 
(nocebo effect) and complain of events such as muscle symptoms, even with nonstatin 
drugs such as placebo.14,15 To evaluate the safety of ETC-1002 more appropriately, a 
placebo run-in period is set in the same manner as in the Japanese phase 2 trial and the 
clinical trials conducted outside Japan of ETC-1002. Subjects who show the nocebo 
effect during the placebo run-in period will be excluded. 
In the treatment period, the lipid-lowering drugs will be continued without changing the 
type or dose and regimen from at least 4 weeks before informed consent (at least 6 weeks 
before, for fibrates and selective PPARα modulators), and ETC-1002 or placebo will be 
added in a double-blind manner. As described above, placebo is selected as a comparator 
to appropriately assess the efficacy in this trial. 
As for the treatment duration, the percent change in LDL-C from baseline to 12 weeks 
after the start of administration was selected as the primary endpoint in all 4 phase 3 trials 
conducted outside Japan as well as in the Japanese phase 2 trial. 


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In addition, a period 
of 12 weeks is set as the duration necessary to evaluate the efficacy of ETC-1002, 
because the trial duration should persist for at least 3 months according to the Guidelines 
on Clinical Evaluation of Medicinal Products for Treatment of Dyslipidemia.12 The 
primary endpoint is set as the percent change in LDL-C from baseline to Week 12. 
 
4.3 
Dosing Rationale 
 


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4.4 
End of Trial Definition 
The “end of trial date” is defined as the “last date of visit/contact” or the “date of final 
contact attempt” recorded on the page of the post-treatment follow-up in the eCRF for the 
last subject completing or withdrawing from the trial. For subjects who will proceed to 
the long-term trial (Trial 346-102-00003), the end of trial date in this trial is defined as 
the date of the Week 12 assessment. 
 
4.5 
Definition of Completed Subjects 
The treatment period is defined as the time period during which subjects are evaluated for 
the primary and/or secondary objectives of the trial irrespective of whether or not the 
subject was administered all doses of the IMP. For purposes of this trial, subjects who 
complete the Week 12 assessment will be defined as trial completers. 
 
5 
Trial Population 
This trial will include Japanese patients with hyper-LDL cholesterolemia between 18 and 
85 years of age, inclusive, at the time of informed consent and with an inadequate 
response to statins or statin intolerance, who cannot achieve the lipid management goals 
specified in the Japan Atherosclerosis Society Guidelines for Prevention of 
Atherosclerotic Cardiovascular Diseases 2017.1 Subjects who are determined to be 
eligible by the investigator or subinvestigator in the screening period will proceed to the 
placebo run-in period. Among the subjects with no safety problems and no muscle-
related AEs in the placebo run-in period, those confirmed by the investigator or 
subinvestigator not to fall under the exclusion criteria will be randomized. The target 
number of subjects is 84 in total (42 in the ETC-1002 180-mg group and 42 in the 
placebo group) as randomized subjects. In addition to patients with inadequate response 
to statins, patients with statin intolerance is planned to be enrolled at ≥20% of the total 
population in this trial. Statin response (inadequate response to statins/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 who have the ability to provide informed consent and who provide 
written informed consent prior to the start of the trial 
2) Patients, either male or female, between 18 and 85 years of age, inclusive, at the 
time of informed consent 
3) Patients with inadequate response to statins or statin intolerance as defined below 
Statins refer to atorvastatin, pitavastatin, rosuvastatin, pravastatin, simvastatin, or 
fluvastatin. 
 Inadequate response to statins: Patients with hyper-LDL cholesterolemia who 
have been taking statins and cannot achieve the lipid management goals of 
LDL-C based on the risk assessment (see inclusion criterion 4)), meeting either of 
the following a) or b) 
a) Patients who have been taking statins (within the approved dose range) alone 
at the same dose and regimen from at least 4 weeks before informed consent 
b) Patients who have been taking statins (within the approved dose range) and 
nonstatins at the same dose and regimen from at least 4 weeks before 
informed consent (at least 6 weeks before, for fibrates and selective PPARα 
modulators) 
 


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[Inadequate response to statins] 
Category 
LDL-C at Week −5 
and Week −1 
Background lipid-lowering drugs at screening 
Type of 
drugs 
Timing of the start of 
treatment:  
before informed consent 
Dose and regimen 
a) 
The lipid 
management goals of 
LDL-C based on the 
risk assessment 
cannot be achieved 
(see inclusion 
criterion 4)). 
Statins alone 
From at least 4 weeks 
before 
Same dose and 
regimen within the 
approved dose range 
b) 
Statins + 
nonstatins 
 
Fibrates, selective 
PPARα modulators:  
From at least 6 weeks 
before 
 
Statins and drugs other 
than those above:  
From at least 4 weeks 
before 
 
Statins: Same 
dose and regimen 
within the 
approved dose 
range 
 
Nonstatins: Same 
dose and regimen 
 
 Statin intolerance: Patients with hyper-LDL cholesterolemia for whom safety 
problems occurred while taking at least one type of statin, and who experienced 
resolution of problems after discontinuation or dose reduction, and who cannot 
achieve the lipid management goals of LDL-C based on the risk assessment (see 
inclusion criterion 4)), meeting any of the following a) to c) 
a) Patients who have been taking statins (at or below the lowest approved dose) 
alone at the same dose and regimen from at least 4 weeks before informed 
consent 
b) Patients who have been taking statins (at or below the lowest approved dose) 
and nonstatins at the same dose and regimen from at least 4 weeks before 
informed consent (at least 6 weeks before, for fibrates and selective PPARα 
modulators) 
c) Patients who have been taking only nonstatins at the same dose and regimen, 
from at least 4 weeks before informed consent (at least 6 weeks before, for 
fibrates and selective PPARα modulators) 
 


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[Statin intolerance] 
Category 
LDL-C at Week −5 
and Week −1 
Background lipid-lowering drugs at screening 
Type of 
drugs 
Timing of the start of 
treatment:  
before informed consent 
Dose and regimen 
a) 
The lipid 
management goals of 
LDL-C based on the 
risk assessment 
cannot be achieved 
(see inclusion 
criterion 4)). 
Statins alone 
From at least 4 weeks 
before 
Same dose and 
regimen at (or below) 
the lowest approved 
dose 
b) 
Statins + 
nonstatins 
 
Fibrates, selective 
PPARα modulators: 
From at least 6 weeks 
before 
 
Statins and drugs other 
than those above:  
From at least 4 weeks 
before 
 
Statins: Same 
dose and regimen 
at (or below) the 
lowest approved 
dose 
 
Nonstatins: Same 
dose and regimen 
c) 
Only 
nonstatins 
 
Fibrates, selective 
PPARα modulators: 
From at least 6 weeks 
before 
 
Drugs other than the 
above:  
From at least 4 weeks 
before 
Same dose and 
regimen 
 
4) Patients with a history or current condition meeting any of the following criteria 
1) to 3) 
Category 
History or current condition 
LDL-C at Week −5 
and Week −1 
1) 
History of coronary artery disease 
≥100 mg/dL 
Heterozygous familial hypercholesterolemia (HeFH) 
2) 
Peripheral arterial disease 
≥120 mg/dL 
History of non-cardiogenic cerebral infarction 
Chronic kidney disease (Provided that it does not fall under 
exclusion criterion 12)) 
Type 2 diabetes mellitus (Diagnosed at least 3 months before 
Week −5, without falling under exclusion criterion 7)) 
3) 
The total score in the coronary artery disease risk prediction 
model using the Suita score specified by the Japan 
Atherosclerosis Society is ≥56 points (high risk) 
≥120 mg/dL 
The total score in the coronary artery disease risk prediction 
model using the Suita score specified by the Japan 
Atherosclerosis Society is ≥41 and ≤55 points (intermediate risk) 
≥140 mg/dL 
 
5) Patients with fasting TG level of <400 mg/dL at screening (Week −5) 
 


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[Rationale for the inclusion criteria] 
1) This criterion is set based on ethical considerations. 
2) The lower limit of age is set as adults with sufficient ability to provide informed 
consent. The upper limit of age is set at 85 years in consideration of safety. 
3) to 4) These criteria are set to appropriately evaluate the efficacy. 
5) This criterion is set in consideration of safety. It is also considered that it will be 
difficult to appropriately calculate LDL-C values using the Friedewald formula. 
 
5.2.2 
Exclusion Criteria 
Subjects will be excluded if they meet any of the following exclusion criteria when 
assessed: 
1) Females who are pregnant or breast-feeding or who have a positive pregnancy test 
(urine) result at screening (Week −5) or on Day 1 
2) Sexually active and reproductive males or sexually active females of childbearing 
potential who do not agree to practice 2 different approved methods of birth 
control or to maintain complete abstinence (the methods of periodic abstinence 
and withdrawal are not appropriate for contraception) during the trial and for 
30 days after final IMP administration. If employing birth control, 2 of the 
following methods must be used: vasectomy, tubal ligation, intrauterine device, 
birth control pill, or condom (all methods are approved or certified in Japan). 
3) Patients with homozygous familial hypercholesterolemia (HoFH) 
4) Patients who currently have or who have had within the past 3 months prior to 
screening (Week −5) any of the following cardiovascular diseases, or those who 
had developed any of these AEs during the screening and placebo run-in period 
 Myocardial infarction, severe or unstable angina pectoris, coronary angioplasty, 
coronary artery bypass graft, stroke, transient ischemic attack, symptomatic 
carotid artery stenosis, symptomatic peripheral arterial disease, or decompensated 
heart failure 
 Abdominal aortic aneurysm 
 Patients with risk factors for torsade de pointes, such as unexplained syncope, or 
long-QT syndrome or a family history of long-QT syndrome 
5) Patients with uncontrolled hypertension, defined as follows: sitting systolic blood 
pressure of ≥160 mmHg or diastolic blood pressure of ≥100 mmHg after resting 
5 minutes at screening (Week −5) 
6) Patients with uncontrolled and serious hematologic or coagulation disorders or 
with hemoglobin of <10.0 g/dL at screening (Week −5) 
7) Patients with uncontrolled diabetes with HbA1c of ≥9% at screening (Week −5) 
8) Patients with uncontrolled hypothyroidism with thyroid-stimulating hormone 
(TSH) of >1.5 × the upper limit of normal (ULN) at screening (Week −5) 
9) Patients with a liver disease or dysfunction, including: 


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 Positive serology for hepatitis B surface antigen (HBsAg) or a positive hepatitis C 
virus (HCV) antibody test at screening (Week −5) 
 Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) of 
≥3 × ULN or total bilirubin of ≥2 × ULN at screening (Week −5) 
10) Patients with a history or current chronic musculoskeletal symptoms that may be 
difficult to differentiate from myalgia 
(eg, fibromyalgia) 
11) Patients with CK of >3 × ULN at screening (Week −5) 
12) Patients with a history or current renal dysfunction, nephritic syndrome, or 
nephritis and with estimated glomerular filtration rate (eGFR) of 
≤30 mL/min/1.73 m2 at screening (Week −5) 
13) Patients who have had gastrointestinal surgery that may affect drug absorption 
(eg, Lap-Band® or gastric bypass) 
14) Patients who have undergone surgery, chemotherapy, or radiation therapy for 
active malignancy (excluding properly treated nonmetastatic basal or squamous 
cell carcinoma of the skin and cervical carcinoma in situ) within the past 5 years 
prior to screening (Week −5) 
15) Patients with a history of drug, alcohol, or cocaine abuse within the past 2 years 
prior to screening (Week −5) 
16) Patients who have had blood collection (eg, blood donation) in a cumulative 
amount exceeding 200 mL within 4 weeks, 400 mL within 12 weeks, or 1200 mL 
within 1 year prior to screening (Week −5) 
17) Patients who have used any investigational drug not approved in Japan within 
either 4 weeks or 5 times the half-life of the drug, whichever is longer, prior to 
screening (Week −5) 
18) Patients who took the IMP in Trial 346-102-00001, or patients who have used 
ETC-1002 in the past 
19) Patients who used or received the following drugs (including food) or therapies 
within the specified period or who are planning to use or receive them by the end 
of the tests at Week 12 
 
Drugs (including food) or 
therapies 
Prohibited period 
1. 
Systemic corticosteroids 
From 3 months prior to Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
However, the drug may be used concomitantly with no change in 
dose from 3 months prior to Week −5 to the end of the tests at 
Week 12 (or to the completion of the assessments at Discontinuation 
Visit, if applicable). 
2. 
Lomitapide 
From 3 months prior to Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
3. 
PCSK9 Inhibitors 
From 4 months prior to Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 


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Drugs (including food) or 
therapies 
Prohibited period 
4. 
5. 
Red yeast rice and food 
containing red yeast rice 
From 2 weeks prior to Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
6. 
LDL apheresis 
From 3 months prior to Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
 
20) Patients in whom the following drugs (therapies) are changed prior to Day 1 or in 
whom initiation of the following drugs (therapies) is planned by the end of the 
tests at Week 12 
 
Drugs or therapies 
Period in which the drug or therapy cannot be changed or  
newly started 
1. 
Female or male hormone 
replacement 
From 6 weeks prior to Day 1 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
2. 
Thyroid replacement 
From 6 weeks prior to Day 1 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
3. 
Diabetes medications 
From 4 weeks prior to Day 1 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
4. 
Obesity medications 
From 3 months prior to Day 1 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
 
21) Patients whose LDL-C level at Week −1 has changed by at least ±20% as 
compared with that at screening (Week −5) 
22) Patients with <80% compliance with the single-blind placebo up to Day 1 during 
the placebo run-in period or who cannot continue drug administration due to 
safety issues 
23) Patients in whom a muscle-related AE other than due to strain, trauma, or other 
obvious etiology newly occurs or is aggravated during the placebo run-in period 
24) Patients otherwise judged inappropriate for participating in the trial in the opinion 
of the investigator or subinvestigator 
 
A definition of childbearing potential can be found in Section 10.3. 
Subjects must agree to the restrictions on medications and lifestyle described in 
Section 6.5.1 and Section 5.3, respectively. 
 
[Rationale for the exclusion criteria] 


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1) to 2) These criteria are set in consideration of the safety because the safety of 
administration of ETC-1002 during pregnancy and breast-feeding has not been 
established. 
3) to 9), 12), 15), 24) These criteria are set in consideration of safety. 
10) to 11), 14), 18), 22) to 23) These criteria are set to appropriately evaluate the 
safety of ETC-1002. 
13) This criterion is set to avoid the influence of such a surgery on ETC-1002 
absorption, etc. 
16) This criterion is set according to the Blood Sampling Criteria of the New Blood 
Program Advisory Committee to ensure the safety of subjects. 
17), 19) to 20) These criteria are set to appropriately evaluate the efficacy and safety 
of ETC-1002. 
21) This criterion is set to appropriately evaluate the efficacy of ETC-1002. 
 
5.3 
Lifestyle Considerations 
5.3.1 
Meals and Dietary Restrictions 
To properly evaluate the efficacy and safety of ETC-1002, diet therapy receiving since 
before informed consent should not be changed from Week −5 to the end of the tests at 
Week 12 (or to the completion of the assessments at Discontinuation Visit, if applicable). 
For dietary supplements that may affect cholesterol levels including LDL-C, the 
investigator or subinvestigator will explain to the subjects at each visit so that the intake 
status will not change from Week −4 to the end of the tests at Week 12 (or to the 
completion of the assessments at Discontinuation Visit, if applicable), and record the 
intake status in the source document. 
 
5.3.2 
Caffeine, Alcohol, and Tobacco 
For alcohol and tobacco, the usual amount of alcohol consumed and the number of 
cigarettes smoked prior to participation in the trial will be checked with the subject and 
documented in the source document. The investigator or subinvestigator will instruct 
subjects not to significantly increase the amount of alcohol consumed or the number of 
cigarettes smoked from Week −5 to the end of the tests at Week 12 (or to the completion 
of the assessments at Discontinuation Visit, if applicable). 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 that has been 
received since before informed consent should not be changed from Week −5 to the end 
of the tests at Week 12 (or to the completion of the assessments at Discontinuation Visit, 
if applicable). 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), but who is not enrolled in the placebo run-in period. 
All AEs must be reported after subject informed consent has been obtained, including 
screening failures due to AEs, irrespective of IMP administration. 
If the subject meets the definition of a screen failure in this trial, the following 
information will be recorded in the eCRF: 
 Date of informed consent 
 Visit date (screening visit) 
 Demographics (collection date, birth date, sex, race, ethnicity, country) 
 History of hypercholesterolemia 
History of Hypercholesterolemia: Investigation Item 
 
Name of diagnosis 
 
Date of diagnosis 
 
Presence or absence of familial hypercholesterolemia 
 
Classification and details of classification (according to the flowchart using the Suita score in the 
Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 
2017,1 and according to the flowchart using the score of the Hisayama Study in the Guidelines 
20222) 
 
Statin response (inadequate response to statins, statin intolerance) 
 
For patients with statin intolerance: Cause of statin intolerance and the name/daily dose of the statin 
 
 Result of eligibility assessment 
 Screen failure date 
 Reason for screen failure 
 Adverse events 
 


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Subjects who sign an ICF but do not enter the placebo run-in period (screen failure) will 
be allowed to re-screen. In the event that the subject is re-screened for trial participation, 
a new ICF must be signed. 
 
6 
Trial Treatments 
Trial interventions used in this trial are a test product and a placebo. No trial interventions 
are used in this trial other than the IMP. 
 
6.1 
Trial Treatments Administered 
6.1.1 
Placebo Run-in Period 
Subjects who are judged to be eligible at screening will proceed to the placebo run-in 
period, continue the treatment without changing the type or dose and regimen of lipid-
lowering drugs that have been taken from before informed consent, and receive placebo 
once daily orally in a single-blind manner. The time of IMP administration should be 
same to the extent possible. The following information will be recorded in the eCRF: for 
the IMP, the number of tablets taken per day, start and end dates of administration; for 
lipid-lowering drugs, the name of the drug, route of administration, dose and frequency, 
daily dose, start and end dates of administration. 
Subjects who are unable to fix the type or dose and regimen of lipid-lowering drugs will 
be withdrawn from the trial. Subjects with noncompliance with less than 80% compliance 
with the single-blind placebo throughout the placebo run-in period will be withdrawn 
from the trial. The IMP compliance rate will be calculated using the following formula. 
See Section 7.3.2 for treatment discontinuation. 
IMP compliance rate (%) = 
Actual number of days of taking single-blind placebo tablets 
× 100 
Number of days specified to take single-blind placebo tablets 
throughout the placebo run-in perioda 
aNumber of days from the start day of administration of the single-blind placebo (on the day of 
Week −4) to the day before Day 1 
 
6.1.2 
Treatment Period 
Subjects who are randomized and proceed to the treatment period should continue to 
receive the lipid-lowering drugs that have been taken from before informed consent 
without changing the type or dose and regimen as in the placebo run-in period, and will 


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also receive ETC-1002 at 180 mg or placebo once daily orally. The time of IMP 
administration should be same to the extent possible. The following information will be 
recorded in the eCRF: for the IMP, the number of tablets taken per day, start and end 
dates of administration; for lipid-lowering drugs, the name of the drug, route of 
administration, dose and frequency, daily dose, start and end dates of administration. For 
information regarding the dose regimen and treatment period, see Section 4.1. 
 
6.2 
Management of Investigational Medicinal Product 
For full details on IMP management, please refer to the IB and the separate procedures. 
 
6.2.1 
Packaging and Labeling 
The IMP will be provided by the sponsor or designated agent to the IMP storage 
manager. The IMP will be supplied as blister cards. Each blister card used in the dosing 
period will be labeled to clearly disclose the compound ID, trial number, sponsor’s name 
and address, storage temperature, route of administration, appropriate precautionary 
statements, etc. 
 
6.2.2 
Storage 
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited 
to the IMP storage manager. 
The IMP will be stored according to the conditions indicated on the IMP label. 
The trial site staff will maintain a temperature log in the IMP storage area to record the 
temperature. 
 
6.2.3 
Accountability 
The IMP storage manager must maintain an inventory record of IMP (including test 
product, 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 the product 
 
6.2.5.1 
Eliciting and Reporting Product Quality Complaints 
The investigator, subinvestigator, or designee must record each PQC identified through 
any means from the receipt of the IMP from the sponsor or sponsor’s designee, through 
and including reconciliation and up to destruction, including subject dosing. The 
investigator, subinvestigator, or designee must notify the sponsor (or sponsor’s designee) 
by e-mail 
of the 
information specified in Section 6.2.5.2 immediately after becoming aware of the PQC. 
Identification of a PQC by the subject should be reported to the site investigator or 
subinvestigator, who should then follow the reporting procedure above. 
 


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6.2.5.2 
Information Required for Reporting Product Quality Complaints 
 Description of the complaint 
 Reporter identification (eg, subject, investigator, subinvestigator, trial site, etc.) 
 Reporter contact information (eg, address, phone number, e-mail address) 
 ID of the material (product/compound name, kit number) 
 Clinical protocol reference (protocol number and/or trial name) 
 Dosage form/strength (if known) 
 Pictures of complaint sample (if available) 
 Availability of the complaint sample for return 
 
6.2.5.3 
Return Process in Case of Product Quality Complaints 
Indicate during the report of the PQC if the complaint sample is available for return. If 
the complaint sample is available for return, the sponsor will provide return instructions, 
when applicable. 
It must be documented in the site accountability record that the complaint sample has 
been forwarded to the sponsor for complaint investigation. 
 
6.2.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor. 
 
6.2.6 
Investigational Medicinal Product Reserve Sample Requirements 
Not applicable. 
 
6.3 
Measures to Minimize/Avoid Bias 
In this trial, the placebo run-in period will be conducted in a single-blind manner while 
the treatment period will be conducted in a double-blind manner. In the treatment period, 
stratified randomization by statin response (inadequate response to statins/statin 
intolerance) will be performed to minimize the influence on the evaluation. Subjects will 
be randomized to each group in a ratio of 1:1. Details of randomization will be provided 
in a separate procedure. Neither the subjects nor the investigator/subinvestigator will be 
informed of the IMP randomization code. The persons involved in the trial of the 


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sponsor, including the contract research organization (CRO) cannot know the IMP 
randomization code during the trial. 
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. 
Procedures for breaking the blind can be found in Section 8.8.7. 
Maintenance of blinding for the efficacy endpoints is described 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 or to the completion of the 
assessments at Discontinuation Visit. 
 Comply with the dosage regimen, duration, and frequency of administration of the 
IMP and, if any, concomitant lipid-lowering drugs taken since before informed 
consent. Subjects with less than 80% compliance with the single-blind placebo tablets 
throughout the placebo run-in period will be withdrawn from the trial. 
 Use appropriate contraceptive methods. 
 Note the lifestyle considerations (see Section 5.3). 
 Fill in the subject diary (see Section 8.10.1) every day while taking the IMP, and 
bring it to the visit. 
 
6.5 
Concomitant Medications or Therapies 
The investigator or subinvestigator will record all of the following drugs (therapies) in 
the eCRF during the specified collection period. 
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. 
Drug (therapy) 
Collection period 
Lipid-lowering drugs 
From 6 weeks prior to the date of informed consent 
to Week 12 or discontinuation 


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Drug (therapy) 
Collection period 
Diabetes medications 
From 7 weeks prior to the date of informed consent 
to Week 12 or discontinuation 
All concomitant medications other than lipid-
lowering drugs and diabetes medications or 
concomitant therapies 
From 4 weeks prior to the date of informed consent 
to Week 12 or discontinuation 
Concomitant medications or therapies that have 
caused AEs or been used for the treatment of AEs 
From the first day of use to the final observation 
day of the subject 
 
6.5.1 
Prohibited Medications or Therapies 
6.5.1.1 
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. 
 


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Table 6.5.1-1 
List of Prohibited Medications, Food, and Preference 
Products 
 
Drugs (including food) 
Prohibited period 
1. 
Systemic corticosteroids 
From 3 months prior to Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
However, the drug may be used concomitantly without a change in 
dose from 3 months prior to Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable). 
2. 
Lomitapide 
From 3 months prior to Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
3. 
PCSK9 Inhibitors 
From 4 months prior to Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
4. 
 
 
5. 
Red yeast rice and food 
containing red yeast rice 
From 2 weeks prior to Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
 
6.5.1.2 
Prohibited Therapies 
LDL apheresis is prohibited from 3 months prior to Week −5 to the end of the tests at 
Week 12 (or to the completion of the assessments at Discontinuation Visit, if applicable). 
If performed, the subject will discontinue the trial. 
 
6.5.2 
Permitted Medications or Therapies 
Lipid-lowering drugs (excluding PCSK9 inhibitors) used from before informed consent 
should be continued without changing the type or dose and regimen until the end of tests 
at Week 12 of the treatment period (or to the completion of the assessments at 
Discontinuation Visit, if applicable). If any medication or therapy shown in Table 6.5.2-1 
has been taken or used from before informed consent, the type or dose and regimen of the 
concomitant medications or the details of the concomitant therapy should not be changed 
during the applicable period. These medications or therapies cannot be newly started 
during the applicable period. 
 


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Table 6.5.2-1 
List of Medications or Therapies Permitted Before and 
During the Trial 
 
Drugs or therapies 
Period in which the drug or therapy cannot be changed or  
newly started 
1. 
Female or male hormone 
replacement 
From 6 weeks prior to Day 1 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
2. 
Thyroid replacement 
From 6 weeks prior to Day 1 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
3. 
Diabetes medications 
From 4 weeks prior to Day 1 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
4. 
Obesity medications 
From 3 months prior t Day 1 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
5. 
Diet therapy 
From Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
6. 
Exercise therapy 
From Week −5 to the end of the tests at Week 12 
(or to the completion of the assessments at Discontinuation Visit, if 
applicable) 
 
6.5.3 
Rescue Medications 
Not applicable. 
 
6.6 
Intervention After the End of the Trial 
At sites that are conducting a separately planned long-term trial (Trial 346-102-00003), 
subjects who complete this trial may be allowed to participate in the long-term trial. 
When participating in the long-term trial, the subjects must meet the eligibility 
requirements specified in the protocol, and provide a new written informed consent based 
on their voluntary decision during the enrollment period of the long-term trial. The 
subjects should be enrolled in the long-term trial after the completion of all observations, 
tests, and assessments at Week 12, and their records in the source document and the 
eCRF must be completed within 5 days after the completion of Week 12 in principle and 
by the day before the next visit date after Day 1 of the long-term trial, at the latest. 
 


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7 
Discontinuation of Trial/Treatment and Subject 
Discontinuation/Withdrawal 
7.1 
Entire Trial or Treatment Discontinuation 
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to the head of the trial site and regulatory authorities in accordance with regulatory 
requirements. 
 
7.2 
Individual Site Discontinuation 
Individual trial site participation may be discontinued by the sponsor, investigator, or 
Institutional Review Board (IRB) if judged necessary for medical, safety, regulatory, 
ethical, or other reasons consistent with applicable laws, regulations, and the Good 
Clinical Practice (GCP). The head of the trial site will notify the sponsor promptly if the 
trial is terminated by the investigator or IRB at the site. 
 
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 trial discontinuation to be necessary 
during the placebo run-in period or the treatment period, the assessments at 
Discontinuation Visit specified in Table 1.3-1 will be performed within 2 days after the 
last dose of IMP to the extent possible. In the case of the trial discontinuation of subjects 
who have proceeded to the treatment period, such subjects should additionally receive the 
same tests as in the follow-up period (Week 16). 


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7.3.3 
Documenting Reasons for Treatment Discontinuation 
A subject may discontinue IMP for the reasons listed below: Only one reason for 
treatment discontinuation (primary reason) will be recorded in the source document and 
eCRF with the date of discontinuation and entered in the IWRS. 
 Adverse event 
 Death 
 Worsening of underlying disease 
 Subject decides to discontinue because of annoyance or discomfort due to a 
nonserious AE which is not otherwise determined to be an undue hazard 
 Continuing IMP places the subject at undue risk as determined by the investigator 
or subinvestigator (eg, a safety concern that is related to IMP) 
 Serious adverse event 
 Other potentially IMP-related safety concerns or AEs 
 Failure to meet the eligibility criteria 
 Assessed as ineligible based on the eligibility assessment at Week −1 and Day 1 
 Significant 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 or dose and regimen of lipid-lowering drugs concomitantly 
used with the IMP (including adding a new lipid-lowering drug) 
 Lost to follow-up 
 Pregnancy (see Section 10.3) 
 Site terminated by the sponsor 
 Trial terminated by the sponsor 
 Withdrawal by the subject’s request 
 Judgment by the investigator 
 Other 
 
If the subject discontinues IMP due to an AE, the investigator/subinvestigator or other 
trial personnel, will make every effort to follow the event until it has resolved or 
stabilized. Follow-up procedures in Section 7.3.2 must be followed. 
 


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


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schedule of assessments can be accommodated. Only subjects who withdraw their 
permission for all of the above methods of follow-up are considered to have completely 
withdrawn their consent to participate in the trial. 
Details on the withdrawal of consent for the optional 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. 
 
7.4 
Definition of Subjects Lost to Follow-up 
Subjects who cannot be contacted on or before the tests at Week 12, 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?”, “Date of contact/Date of final contact attempt” and “Contact method” will be 
recorded in the eCRF. 
 


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8 
Trial Procedures 
The 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 for LDL-C, non-HDL-C, TC, 
HDL-C, TG, apo B, hsCRP, and HbA1c will be collected. 
 Blind items: LDL-C, non-HDL-C, TC, apo B, and hsCRP 
 
The investigator or subinvestigator will instruct subjects to visit the trial site according to 
the schedule specified in Table 1.3-1 under fasting conditions and collect blood samples. 
The investigator or subinvestigator will record the date and time of blood sampling and 
the fasting state at the time of blood sampling in the source document and the eCRF. The 
test results will be directly reported to the sponsor by the central laboratory selected by 
the sponsor in electronic files. Therefore, it is not necessary to record the results in the 
source document and eCRF. The fasting state is defined as a state in which a subject has 
fasted (including abstaining from sugar-containing beverages such as juice) for 10 hours 
or more. If a subject cannot visit the trial site in a fasting state, the subject should not 
undergo blood sampling but visit the trial site again in a fasting state for blood sampling 
within the visit window for the same evaluation time point. If the subject cannot visit in 
the fasting state again within the visit window for the same evaluation time point, this 
case will be recorded as a protocol deviation and the blood sample will be submitted as a 
sample in a fed state to the central laboratory. Each subject will visit the trial site without 
taking the IMP on the visit day. 
Samples will be sent to the central laboratory, the results of which will be used for 
analysis. LDL-C values will be measured using the direct method and calculated using 
the Friedewald formula (TC−HDL-C−TG/5). Proper sample collection, handling, and 
shipping procedures will be provided to the trial sites in a separate manual prior to the 
start of the trial. 
To maintain the blind of the trial, the results of the assessments of the blind items 
obtained from the start of IMP administration on Day 1 to Week 12 (or to the completion 
of the assessments at Discontinuation Visit, if applicable) will not be reported to the trial 


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site and the sponsor. The test results will be stored strictly by the central laboratory, 
disclosed to the trial site after unblinding, and provided to the sponsor in electronic files. 
In addition, the measurement of the blind items at the laboratory of trial sites is not 
allowed for the samples obtained from the start of IMP administration on Day 1 to 
Week 12 (or to the completion of the assessments at Discontinuation Visit, if applicable). 
 
8.2 
Pharmacokinetic Assessments 
Not applicable. 
 
8.3 
Pharmacodynamic Assessments 
Not applicable. 
 
8.4 
Pharmacogenomic Assessments 
Not applicable. 
 
8.5 
Biomarker Assessments 
Not applicable. 
 
8.6 
Future Biospecimen Research Samples 
Future Biospecimen Research (FBR) samples will be collected at the time points 
described in the Schedule of Assessments (Table 1.3-1). 
[Rationale of sample storage for FBR] 
Storage of DNA will be done to perform genomic/genetic analysis for cases in which 
additional explanation about the pharmacokinetics of ETC-1002 is required or new 
findings on genes and pharmacokinetics are obtained, and/or genomic/genetic analysis 
related to drug response (efficacy or safety) to the IMP or disease is judged to be useful. 
Regarding the collection and storage of DNA samples during the trial period, the 
Ministry of Health, Labour and Welfare states in the Q&A 1 of “Clinical Trials That Use 
Pharmacogenomics (PFSB/ELD Notification No. 0930007 dated 30 Sep 2008)” that it is 
possible to collect samples for genomic/genetic analysis related to the evaluation of the 
IMP (pharmacokinetics, efficacy, safety, etc.) from subjects in either of following cases: 


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1) the samples for which the targets and timing of genomic/genetic analysis have been 
specifically identified at the time of the trial, 2) the samples for which the targets and 
timing of genomic/genetic analysis have not been specifically identified at the time of the 
trial and analysis related to the evaluation of the IMP will be conducted in the future. In 
the same Q&A 2, it is stated that samples for genomic/genetic analysis with the 
objectives including the search for disease-related genes unrelated to the evaluation of the 
IMP can be obtained from subjects.16 In addition, the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
states in Section 1.4. General Principles of ICH E18 Guideline on Genomic Sampling and 
Management of Genomic Data, “With advances in science and increased awareness of 
the impact of genomics, there is a need and an opportunity to maximize the value of the 
collected samples and the data generated from them. Therefore, genomic sample 
acquisition is strongly encouraged in all phases and studies of clinical development.”17 In 
addition to the above, since the sample will be collected at the same timing as other tests 
to reduce the burden on subjects as much as possible, it is considered appropriate to 
collect and store optional DNA samples. 
Serum samples for biomarker exploration will be also stored to conduct a biomarker 
exploration study when biomarker discovery related with drug response (eg, efficacy and 
safety) to the IMP or with disease is considered useful. The sample collection will be 
performed only at trial sites that have agreed in advance to store samples for biomarker 
exploration and only for subjects who have provided written consent for biomarker 
sample storage. Since biomarkers are expected to improve the R&D productivity of drugs 
and the sample will be collected at the same timing as other tests to reduce the burden on 
subjects as much as possible, it is judged appropriate to collect optional samples for 
biomarker exploration and store them. 
 
8.6.1 
Scope of Future Biospecimen Research 
Future Biospecimen Research samples will be collected from subjects who consent to this 
sample collection. Research performed on these samples may include genetic analyses 
(DNA), gene expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics, 
and/or the measurement of other analytes. Such research is for biomarker testing to 
address emergent questions not described elsewhere in the protocol (as part of the main 
trial) and will only be conducted on specimens from subjects who have provided 
appropriate consent. The objective of collecting specimens for FBR is to explore and 


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identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. 
 
8.6.2 
Summary of Procedures for Future Biospecimen Research 
Samples 
All subjects enrolled in the clinical trial will be considered for enrollment in the optional 
FBR substudy. 
After obtaining informed consent, the following FBR specimens will be obtained: 
 Blood for DNA analysis (2 mL whole blood; includes ethylenediaminetetraacetic acid 
as an anticoagulant) 
 Serum for measurements of proteins, sugars, and other molecules (volume of blood 
sampling: 2 mL) 
 
The presence or absence of blood collection for DNA sample storage and the date of the 
sample collection will be recorded in the eCRF. The date and time of collecting samples 
for biomarker exploration will be recorded in the eCRF. Additional information will be 
provided in a manual prepared separately. If an FBR substudy is planned, a separate 
document describing the analysis may be prepared, and the results may be reported 
separately from the clinical study report (CSR). 
 
8.6.3 
Storage of Future Biospecimen Research Samples 
Biospecimen research samples will be retained in the biorepository for potential analysis 
until: 1) genomic/genetic analysis and biomarker exploration are deemed unnecessary; 2) 
15 years (DNA samples) or 5 years (biomarker samples) have passed since the informed 
consent of the first subject; or 3) the subject withdraws consent to storage of FBR 
samples, whichever comes first. 
 
8.6.4 
Genomic/Genetic Analysis and Biomarker Exploration 
Genomic/genetic analysis will be conducted only if it is considered useful as an 
exploratory investigation regarding variations in DNA characteristics related to 
individual differences in drug response (including efficacy, safety, or PK) to the IMP 
and/or variations in disease-related DNA characteristics, or as a basic investigation for 
development to treat disease or promote health. Biomarker exploration will be conducted 


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only if it is considered useful to explore a biomarker related to drug response (including 
efficacy and safety) to the IMP and/or a disease-related biomarker. 
If the conduct of the research is determined, a protocol will be separately prepared and 
approved by the sponsor’s research review committee. Then, the research will be 
conducted in accordance with the local regulations to be followed for analysis. Results 
will not be included in the CSR, but will be reported separately. 
The target of genomic/genetic analysis cannot be identified at present, and genome-wide 
association analysis using DNA chip, microarray, or next-generation sequencer may be 
performed. Biomarkers for measurement and analyses may include proteins, lipids, or 
RNA in the samples, but cannot be identified at this time, including any analytical 
methods. However, the results will not be used for purposes other than the above. 
 
8.6.5 
Acquisition and Withdrawal of Informed Consent for Future 
Biospecimen Research 
Written information for the storage of FBR samples and exploratory research using the 
samples will be prepared separately from that for the trial, and the informed consent form 
will be signed. The date of informed consent will be recorded in the source document and 
the eCRF. 
If the subject withdraws consent to storage of FBR samples during the storage period, the 
sponsor will request the biorepository to destroy the samples and the biorepository will 
destroy the samples in such a way that the subject cannot be identified. However, if any 
personal sample cannot be identified, for example, in the case where the information that 
links the sample with the subject’s information (such as the code list) is discarded, the 
sample of the subject who withdrew the consent may not be destroyed as a result. 
Even if the participation in the trial is withdrawn, it does not mean that the storage of 
FBR samples is canceled unless the subject separately withdraws consent to the storage 
of FBR samples. If the results of genomic/genetic analysis and/or biomarker exploration 
have already been obtained by the time of withdrawal of consent, the results will not be 
discarded. 
 
8.6.6 
Disclosure of Results of Genomic/Genetic Analysis and 
Biomarker Exploration to Subjects 
Even if some findings are obtained as a result of analyses, the results are exploratory or at 
an early stage of research, and therefore scientific reliability such as precision and 


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certainty cannot be sufficiently confirmed. In principle, the sponsor will not disclose the 
results of genomic/genetic analysis and biomarker exploration to subjects because 
disclosure of information that has not been established the reliability of scientific 
evaluation will not be beneficial to subjects. 
 
8.7 
Safety Assessments 
If a “new abnormality” or “exacerbation” is observed in the observation/examination 
items shown in the following sections after the start of the IMP administration which is 
judged to be clinically significant for the subject 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 Schedule 
of Assessments (Table 1.3-1) to perform the clinical laboratory assessments described in 
Section 10.2. The total volume of blood to be collected during the trial will be 
documented in the ICF. 
On the day of the tests shown in the Schedule of Assessments (Table 1.3-1), subjects will 
be asked to visit the trial site in a fasting state (at least 10 hours of fasting [including 
abstaining from sugar-containing beverages such as juice]) without taking the IMP, and 
blood and urine samples will be collected from each subject. If a subject cannot visit the 
trial site in a fasting state, the subject should not undergo blood sampling but visit the 
trial site again in a fasting state for blood sampling within the visit window for the same 
evaluation time point. If the subject cannot visit in the fasting state again within the visit 
window for the same evaluation time point, this case will be recorded as a protocol 
deviation and the blood sample will be submitted as a sample in a fed state to the central 
laboratory. 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 


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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. 
 
 
 
 
8.7.2 
Physical Examination 
Physical examinations will be performed at the time points described in the Schedule of 
Assessments (Table 1.3-1). The investigator or subinvestigator will perform physical 
examinations for the following assessments by methods such as interview and record the 
date and results of the assessment in the source document. For consistency of 
assessments, it is recommended that all physical examinations for individual subjects be 
performed by the same physician throughout the trial. At Week −5 and Day 1, the dates 
and results of the examinations will be recorded in the source document and the eCRF. At 
the other time points, only the date of the examination will be recorded. If clinically 
significant physical findings, which are compared with Week −5 during the screening and 


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placebo run-in periods and compared with Day 1 during the treatment and follow-up 
periods, are observed, those findings will be recorded as AEs. 
Assessments:  HEENT (head, eyes, ears, nose, throat), chest, abdomen, genitourinary, 
extremities, nerves, skin/mucosae 
 
8.7.3 
Vital Signs 
Vital signs will be measured at the time points described in the Schedule of Assessments 
(Table 1.3-1) after resting for at least 5 minutes. The vital signs should be measured 
before blood collection whenever possible to minimize the effects on the assessment. 
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 a sitting position after resting for at least 5 minutes according to the procedures 
specified by the trial site. The date and results of body temperature, systolic and diastolic 
blood pressure, and pulse rate measurements will be recorded in the source document and 
the eCRF. 
 
8.7.4 
Electrocardiogram 
Electrocardiograms will be performed at the time points described in the Schedule of 
Assessments (Table 1.3-1) after resting for at least 10 minutes. The 12-lead ECG should 
be performed before blood collection whenever possible to minimize the effects on the 
assessment. Subjects should be monitored for potentially clinically significant ECG 
results. 
The investigator or subinvestigator will perform the ECG according to the procedures 
specified at each trial site and record the date of measurement, heart rate, PR interval, RR 
interval, QRS width, QT interval, and QTcF in the source document and the eCRF. The 
investigator or subinvestigator will determine normality/abnormality by the assessment of 
the measurements, and record the determinations in the source document and the eCRF. 
Any abnormal findings will be recorded in the source document and the eCRF. 
The sponsor may request to provide a copy of the ECG chart for any reason, including 
additional safety analysis. 
 
8.7.5 
Suicidality Monitoring 
Not applicable. 


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8.7.6 
Other Safety Variables 
8.7.6.1 
Body Weight 
Body weight will be measured at the time points described in the Schedule of 
Assessments (Table 1.3-1), and the dates and results of the measurements will be 
recorded in the source document and the eCRF (in units of 0.1 kg [if measured to the 
second decimal place or less, the second decimal place will be rounded.]). 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). 
 
8.8 
Adverse Events 
8.8.1 
Definitions 
An AE is defined as any untoward medical occurrence in a clinical trial subject 
administered a trial intervention* and does not necessarily have a causal relationship with 
this treatment. In this trial, any untoward medical occurrence in a subject not receiving 
the trial intervention will be included. Adverse events would not include information 
recorded as medical history at screening for pre-planned procedures for which the 
underlying condition was known and no worsening occurred. An adverse reaction is any 
untoward and unintended response to a trial intervention related to any dose 
administered. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
trial intervention caused the AE. 
Treatment-emergent AEs (TEAEs) are defined as AEs with an onset date on or after the 
start of IMP treatment. In more detail, TEAEs are all AEs which started after the start of 
IMP treatment; or if the event was continuous from baseline and worsened after the start 
of IMP treatment. 
 
*  Refer to the guidance in Article 2 of the revised GCP. No trial interventions other than the IMP 
will be used in this clinical trial. 


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An SAE includes any event that results in any of the following outcomes: 
 Death 
 Life-threatening; ie, the subject was, in the opinion of the investigator or 
subinvestigator, at immediate risk of death from the event as it occurred. It does not 
include an event that, had it occurred in a more severe form, might have caused death. 
 Persistent or significant incapacity/disability or substantial disruption of the ability to 
conduct normal life functions. 
 Requires inpatient hospitalization or prolongs hospitalization. 
 Hospitalization itself should not be reported as an SAE; whenever possible, the 
reason for hospitalization should be reported. 
 Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other nonmedical need) are not considered 
SAEs. 
 Prescheduled hospitalization to address a condition that has existed prior to the 
signing of the ICF should not be considered an SAE. 
 Congenital anomaly/birth defect. 
 Other medically significant events that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above; eg, allergic bronchospasm requiring 
intensive treatment in an emergency room or home, blood dyscrasias or convulsions 
that do not result in hospitalization, or the development of drug dependency or drug 
abuse. 
 
Nonserious AEs are all AEs that do not meet the criteria for a “serious” AE. 
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 IREs. Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on an IRE form and the 
Pregnancy Surveillance Form(s) to the sponsor. This includes pregnancy of the 
subject or the partner of the subject. Pregnancy will only be documented on the AE 
eCRF if the pregnancy occurs in a female and there is an abnormality or medical 
problem. 
 
Clinical Laboratory Test Value Changes: It is the investigator/subinvestigator’s 
responsibility to review the results of laboratory tests for each individual subject, as they 
become available. This review will be documented by the investigator/subinvestigator’s 
dated signature on the laboratory report. The investigator or subinvestigator may repeat 
the laboratory test or request additional tests to confirm the results of the original 


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laboratory tests. However, the central laboratory should not report the results of any 
repeated or additional tests for the blind items (see Section 8.1) obtained between Day 1 
(the start of IMP treatment) and Week 12 to the trial site and the sponsor to maintain the 
blind. As for LDL-C, 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 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. However, if an abnormal result is found in 
a test performed at the central laboratory and is considered an AE, the course should be 
confirmed with the test results of the central laboratory in principle. 
 
Severity: Adverse events will be graded on a 3-point scale below: 
1 = Mild:  
Discomfort noticed, but no disruption to daily activity. 
2 = Moderate:  
Discomfort sufficient to reduce or affect normal daily activity. 
3 = Severe:  
Inability to work or perform normal daily activity. 
 
IMP Causality: Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows: 
Related:  
There is a reasonable possibility of a temporal and causal 
relationship between the IMP and the AE. 
Not Related:  
There is no temporal or causal relationship between the IMP and 
the AE. 
 
8.8.2 
Eliciting and Reporting Adverse Events 
The investigator or subinvestigator will regularly assess the subjects for the occurrence of 
AEs. To avoid bias in eliciting AEs, subjects should be asked the nonleading question: 
“How have you felt since your last visit?” All AEs (serious and nonserious) reported by 
the subject must be recorded on the source documents and eCRF provided by the 
sponsor. Adverse event collection will begin after a subject signs the ICF and will 
continue until the end of the follow-up period. All AEs must be recorded in the eCRF 
after subject informed consent has been obtained, including screening failures due to 
AEs, irrespective of trial intervention. In this trial, AEs during the screening and placebo 


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run-in periods will be assessed compared to Week −5, and those during the treatment and 
follow-up periods will be assessed compared to Day 1. 
Medical terminology should be used for AE reporting. Adverse events should be reported 
as a single unifying diagnosis whenever possible or, in the absence of a unifying 
diagnosis, as individual signs or symptoms. 
Exacerbation or disease progression should be reported as an AE only if there are unusual 
or severe clinical features that were not present or experienced earlier, or not expected 
based on the course of the condition. A reported AE that undergoes worsening in severity 
or seriousness should be reported as a new AE in the eCRF. However, if worsening of the 
condition is observed on Day 1 or later, the AE should be reported as a new AE in the 
eCRF without limiting to worsening in severity or seriousness. If a subject is suspected to 
have COVID-19 during the trial, the investigator or subinvestigator will confirm the 
results of an antigen test, etc., and take necessary measures such as a determination on the 
necessity for discontinuation of the IMP, in consideration of the safety of the subjects. A 
positive result will be reported as an AE in the eCRF. 
In addition, the sponsor must be notified immediately by e-mail in principle of any IREs 
according to the procedure outlined below, in Section 8.8.3. Special attention should be 
paid to recording hospitalization and concomitant medications. 
The AE, start date, end date, seriousness, severity, relationship to trial treatment (IMP 
causality), action taken with trial treatment, and outcome will be recorded on the source 
documents and in the eCRF. 
 
8.8.3 
Immediately Reportable Events 
The investigator/subinvestigator or designee must immediately report (within 24 hours), 
using forms including an IRE form, after he/she or site personnel become aware of any 
IRE (SAE, AE related to occupational exposure, potential serious hepatotoxicity, or 
confirmed pregnancy), by e-mail in principle, to the sponsor or designee using the contact 
information on the cover page of this protocol (please note that the IRE form is NOT the 
entry column for AEs in the eCRF). Patient confidentiality must be protected and contact 
information such as name, address, phone number or any other protected health 
information as determined by applicable local regulation must be redacted when 
forwarding Safety Information and supporting documentation. Details regarding the 
follow-up of IREs are included in Section 8.8.8.2. 
 


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8.8.4 
Medical Device Incidents (Including Malfunctions) 
Not applicable. 
 
8.8.5 
Adverse Events of Special Interest 
Not applicable. 
 
8.8.6 
Potential Serious Hepatotoxicity 
For a subject who experiences an elevation in AST or ALT that is ≥3 times the ULN, a 
total bilirubin level should also be evaluated. If the total bilirubin is ≥2 times the ULN, 
complete an IRE form or other documentation with all values listed and also report as an 
AE in the eCRF. 
 
8.8.7 
Procedure for Breaking the Blind 
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. 
 


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8.8.8 
Follow-up of Adverse Events 
8.8.8.1 
Follow-up of Nonserious Adverse Events 
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eCRF with the current status (ongoing or resolved/recovered) noted. All nonserious 
events (that are not IREs) that are ongoing at the last scheduled contact will be recorded 
as ongoing in the eCRF. For any AE having been identified throughout the trial, during 
analysis, additional relevant medical history information may be requested by the sponsor 
to further ascertain causality (including, but not limited to, information such as risk-
related behavior, family history, and occupation). 
 
8.8.8.2 
Follow-up of Immediately Reportable Events 
This trial requires that subjects be actively monitored for IREs up to the last scheduled 
contact (Week 16, 28 days after the last dose of IMP is administered). 
Immediately reportable events that are identified or ongoing at the last scheduled contact 
must be recorded as such on the AE eCRF page and the IRE form or other 
documentation. If updated information (eg, resolved status) on IRE status becomes 
available after a subject’s last scheduled contact (up to last in-clinic visit for the entire 
trial), this must be reported to the sponsor and recorded on the AE eCRF page and the 
IRE form or other documentation, according to the appropriate reporting procedures 
described in Section 8.8.3. 
It is expected that the investigator or subinvestigator will provide or arrange appropriate 
supportive care for the subject and will provide prompt updates on the subject’s status to 
the sponsor. The investigator or subinvestigator will follow IREs until: 
 The events have resolved, 
 The events have stabilized, 
 The subject is lost to follow-up, or 
 The subject has died. 
 
Resolution means that the subject has returned to the baseline state of health and 
stabilized means that the investigator or subinvestigator does not expect any further 
improvement or worsening of the subject’s condition. The investigator or subinvestigator 
will continue to report any significant follow-up information to the sponsor up to the 
point the event has resolved or stabilized, or the subject is lost to follow-up, or has died. 


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Refer to Section 10.3 for additional information regarding the duration of follow-up for 
subjects that become pregnant or for pregnant partners of male subjects. 
 
8.8.8.3 
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact 
Any new IREs reported to the investigator or subinvestigator which occur after the last 
scheduled contact and are determined by the investigator or subinvestigator to be 
reasonably associated with the use of the trial intervention, should be reported to the 
sponsor according to the procedures outlined in Section 8.8.3. This may include IREs that 
are captured on follow-up telephone contact or at any other time point after the defined 
trial period and continue to report any significant follow-up information to the sponsor 
until the events are resolved or stabilized, or the subject is lost to follow-up or has died. 
 
8.9 
Treatment of Overdose 
For treatment of overdose, refer to the overdose section of the IB. There is no specific 
treatment for overdose with ETC-1002. In the event of overdose, symptomatic and 
supportive therapies should be provided as appropriate. 
 
8.10 
Subject Assessment Recording 
8.10.1 
Completion of Subject Diary 
The investigator or subinvestigator will instruct the subjects who are judged able to 
receive the IMP to enter the status of compliance with the IMP and lipid-lowering drugs, 
status of diet/exercise therapy and lifestyle (alcohol intake, smoking), and presence or 
absence of subjective symptoms in the subject diary, and bring it to the visit. The 
investigator or subinvestigator will record the status of compliance with the IMP and 
lipid-lowering drugs in the eCRF based on the contents entered in the subject diary, 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. 
 


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8.11 
Other Assessments 
8.11.1 
Pregnancy Test 
A urine test will be performed for females of childbearing potential according to the 
schedule specified in Table 1.3-1, and the date and result of the test will be recorded in 
the source document and the eCRF. A definition of childbearing potential can be found in 
Section 10.3. Subjects with a positive urine test will be withdrawn from the trial. 
However, any positive urine test on or after the placebo run-in period will lead to a re-test 
using serum to confirm the diagnosis, and the date of blood sampling will be recorded in 
the source document and the eCRF. If the serum test is positive, the investigator or 
subinvestigator will report it to the sponsor as an IRE. 
The serum test will be performed by the central laboratory selected by the sponsor. 
Proper sample collection, handling, and shipping procedures will be provided to the trial 
sites in a separate manual prior to the start of the trial. The central laboratory will report 
the test results to the investigator or subinvestigator who confirms the test results. The 
laboratory report will be officially documented by entering the date of confirmation and 
signing the report by the investigator or subinvestigator. The results of the serum test will 
be directly reported to the sponsor by the central laboratory in electronic files. Therefore, 
it is not necessary to record the results in the source document and the eCRF. 
 
8.11.2 
Endocrine Test and Virus Test 
Samples for the endocrine test (of TSH) and the virus test (of HBsAg and HCV 
antibodies) will be collected at Week −5 to confirm eligibility of subjects regarding 
thyroid and liver function. The date of blood sampling will be recorded in the source 
document and the eCRF. Samples will be shipped to the central laboratory selected by the 
sponsor, and eligibility will be confirmed based on the test results measured by the 
central laboratory. Proper sample collection, handling, and shipping procedures will be 
provided to the trial sites in a separate manual prior to the start of the trial. The central 
laboratory will report the test results to the investigator or subinvestigator who confirms 
the results. The laboratory report will be officially documented by entering the date of 
confirmation and signing the report by the investigator or subinvestigator. The test results 
will be directly reported to the sponsor by the central laboratory in electronic files. 
Therefore, it is not necessary to record the results in the source document and the eCRF. 
 


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9 
Statistical Considerations 
9.1 
Sample Size 
 
 
9.2 
Datasets for Analysis 
The safety analysis set will include subjects who receive at least one dose of the IMP 
during the treatment period. 
The full analysis set will include subjects who receive at least one dose of the IMP during 
the treatment period, and who have LDL-C measurements at baseline and at one or more 
time points after administration of the IMP during the treatment period. 
 
9.3 
Handling of Missing Data for Primary Endpoint Analysis 
In the primary analysis of the primary endpoint, a mixed-effects model repeated measures 
(MMRM) analysis assuming missing at random (MAR) will be performed using 
observed cases (OC) data set without imputation of missing data. Placebo multiple 
imputation, etc. assuming missing not at random will be performed as a sensitivity 
analysis for the handling of missing data. Details will be described in the statistical 
analysis plan. 
 


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9.4 
Statistical Analyses 
9.4.1 
Efficacy Analyses 
9.4.1.1 
Primary Efficacy Endpoint Analysis 
The primary endpoint is the percent change from baseline to Week 12 in LDL-C 
measured by the direct method. Baseline is defined as the mean of the LDL-C values for 
Day 1 and Week −1. The MMRM analysis assuming MAR will be performed using OC 
data. The treatment comparison will be based on differences in the least-squares mean 
between the ETC-1002 group and the placebo group at Week 12. A two-sided 
significance level of 5% will be used. The model will include the treatment group, 
randomization stratification factor, time, and treatment-by-time interaction as factors, and 
baseline and baseline-by-time interaction as covariates. The error covariance structure 
will be unstructured. The Kenward-Roger method will be used for the degrees of freedom 
approximation. If any problem occurs in the convergence status in the estimation of the 
variance components, the following structure will be used in the order of heterogeneous 
toeplitz, heterogeneous autoregressive of order 1, and heterogeneous compound 
symmetry, and the first error covariance structure that converges will be used. If a 
structure other than unstructured is selected, a sandwich estimator of the standard error 
will be used. 
 
9.4.1.2 
Key Secondary Efficacy Endpoint Analysis 
Not applicable. 
 
9.4.1.3 
Secondary Efficacy Endpoint Analysis 
The same MMRM analysis as used for the primary endpoint will be performed for non-
HDL-C and TC. The baseline is defined as the mean of Day 1 and Week −1 for both non-
HDL-C and TC. 
For apo B, hsCRP, and HbA1c, an analysis of covariance will be performed using OC 
data. The model will include the treatment group and the randomization stratification 
factor of statin response (inadequate response to statins/statin intolerance) as factors, and 
the baseline for each endpoint as a covariate. 
The proportion of subjects whose LDL-C value achieves the lipid management goals 
(<100 mg/dL [history of coronary artery disease or heterozygous familial 
hypercholesterolemia], <120 mg/dL [high risk], or <140 mg/dL [intermediate risk]) at 


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Week 12 will be analyzed by the Cochran-Mantel-Haenszel test, stratified by statin 
response (inadequate response to statins/statin intolerance), and the difference in 
proportions between the ETC-1002 group and the placebo group, and the two-sided 95% 
confidence intervals (based on the Cochran-Mantel-Haenszel test) will be calculated. In 
cases where the LDL-C at Week 12 is missing, it will be handled as not achieving the 
lipid management goals. 
 
9.4.1.4 
Control of Experiment-wise Type 1 Error 
Not applicable. 
 
9.4.1.5 
Other Efficacy Endpoint Analysis 
The same MMRM analysis as used for the primary endpoint will be performed for 
HDL-C and TG. 
 
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 (inadequate response to statins, statin intolerance) 
 
9.4.2 
Safety Analysis 
Safety analyses will be performed using the safety analysis set. The same summarization 
will also be performed by randomization stratification factors (statin response). 
 
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 by 
treatment group: 
 Treatment-emergent AEs 
 TEAEs by severity 
 TEAEs causally related to the IMP 
 TEAEs with an outcome of death 


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 Serious TEAEs 
 TEAEs leading to discontinuation of the IMP 
 
 
 
9.4.2.2 
Clinical Laboratory Data 
For parameters other than qualitative urinalysis, descriptive statistics of the actual value 
and change from baseline will be calculated by treatment group at each time point. For 
qualitative urinalysis parameters, shift tables at each time point from baseline will be 
prepared by treatment group. 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 by treatment 
group. 
The number and percentage of subjects meeting Criteria for Identifying Laboratory 
Values of Potential Clinical Relevance will be calculated by treatment group. 
 
9.4.2.3 
Physical Examination and Vital Signs Data 
Physical examination results will be tabulated. 
For vital signs (blood pressure, pulse rate, and body temperature), descriptive statistics of 
the actual value and change from baseline will be calculated at each time point by 
treatment group. 
The number and percentage of subjects meeting Criteria for Identifying Vital Signs of 
Potential Clinical Relevance will be calculated by treatment group. 
 
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 by treatment group. The number and percentage of subjects 
with an actual value of QTcF of >450 msec, >480 msec, or >500 msec at any postdose 
time point will be calculated by treatment group. In addition, the number and percentage 
of subjects with a change from baseline in QTcF of >30 msec or >60 msec at any 
postdose time point will be calculated by treatment group. Similarly, the number and 


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percentage of subjects meeting these criteria at each postdose time point will also be 
calculated by treatment group. 
For assessment of normality/abnormality, shift tables at baseline and each time point will 
be prepared by treatment group. 
The number and percentage of subjects meeting Criteria for Identifying ECG 
Measurements of Potential Clinical Relevance will be calculated by treatment group. 
 
9.4.2.5 
Other Safety Data 
Descriptive statistics of the actual value and change from baseline will be calculated at 
each time point for body weight by treatment group. 
The number and percentage of subjects meeting Criteria for Identifying Body Weight of 
Potential Clinical Relevance will be calculated by treatment group. 
 
9.4.3 
Other Analyses 
9.4.3.1 
Analysis of Demographic and Baseline Characteristics 
Frequency distributions or descriptive statistics of each item for demographic and other 
baseline characteristics will be calculated in each analysis set by treatment group. 
 
9.4.3.2 
Pharmacokinetic Analysis 
No pharmacokinetic analysis is planned. 
 
9.4.3.3 
Pharmacodynamic Analysis 
No pharmacodynamic analysis is planned. 
 
9.4.3.4 
Pharmacokinetic/Pharmacodynamic Analysis 
No pharmacokinetic/pharmacodynamic analysis is planned. 
 
9.4.3.5 
Pharmacogenomic Analysis 
No pharmacogenomic analysis is planned. 


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9.4.3.6 
Exploratory Endpoint Analysis 
Not applicable. 
 
9.5 
Interim Analysis and Adaptive Design 
Not applicable for interim analysis or adaptive design. 
 


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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), as well as by any 
other parties required by the IRB. The subject will receive a copy of the signed ICF; the 
original shall be kept on file by the investigator or subinvestigator. Subjects may be asked 
to sign additional ICFs if the protocol is amended and the changes to the protocol result 
in additional information that needs to be provided to the subjects, so that they can make 
a knowledgeable and voluntary decision on continued trial participation. Female partners 
of male subjects who become pregnant during the course of the trial may be asked to sign 
additional ICFs, in order to collect additional information regarding the non-subject 
partner and fetus. 
A separate and similar consent process will be followed for the optional blood samples 
for FBR. Consent must be obtained before the blood sample is collected. Sample storage 
for FBR is optional and will not affect the subject’s participation in the trial if the subject 
does not consent to the FBR sample storage. 
 
10.1.3 
Confidentiality 
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region(s) where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. All IMPs, subject bodily fluids, and/or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor. 
Subjects will be identified only by unique subject ID in the eCRF. If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations. 
 
10.1.4 
Quality Control and Quality Assurance 
The sponsor will perform quality management activities for this trial in accordance with 
the ICH GCP guidance and standard operating procedures. 
 


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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 (excluding FBR documents) 
will be maintained by the trial sites and made available for direct inspection by 
authorized persons. 
Investigators/trial sites will permit trial-related monitoring, audits, IRB review, and 
regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF. In all cases, subject confidentiality must be 
maintained in accordance with local regulatory requirements. 
 
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. 


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Information from medical records and other source documents will be entered by 
investigative site personnel onto eCRFs in the sponsor’s electronic data capture (EDC) 
system that is 21 CFR Part 11 compliant. Changes to the data will be captured by an 
automatic audit trail in the EDC system. 
Electronic data not entered on eCRF, such as data received from central laboratories, will 
be reconciled using key data fields by the sponsor or designee with the eCRF data to 
ensure consistency. 
 
10.1.6.3 
File Management at the Trial Site 
The head of the trial site will ensure that the trial site file is maintained in accordance 
with applicable ICH guidance and as required by applicable local regulations. The trial 
site will take measures to prevent accidental or premature destruction of these documents. 
 
10.1.6.4 
Records Retention at the Trial Site 
The trial site will retain all documents and records related to this trial for the longest of 
the following 3 periods. However, if the sponsor requires a longer storage period, the 
storage period and method will be discussed with the sponsor. 
 A period of at least 2 years after the date on which approval to market the IMP is 
obtained; However, in the case that development is discontinued or a notification to 
inform that the trial results will not be attached to the approval application is 
received, a period of at least 3 years after the decision date of stopping development, 
or the receiving date of the notification informing that the trial results will not be 
attached to the approval application. 
 A period of at least 3 years after date of trial discontinuation/completion; OR 
 The period of FBR sample storage. 
 
The trial site must not dispose of any records relevant to this trial without either (1) 
written permission from the sponsor or (2) provision of an opportunity for the sponsor to 
collect such records. The trial site will be responsible for maintaining adequate and 
accurate electronic or hard copy source documents of all observations and data generated 
during this trial including any data clarification forms received from the sponsor. Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities. 
 


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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 
 


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


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


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


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ADDITIONAL RISK TO THE SUBJECT: 
No further risk is imposed on the subjects. 
 


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11 
References 
1 
Japan Atherosclerosis Society. Guidelines for Prevention of Atherosclerotic 
Cardiovascular Diseases 2017. 2017. 
2 
Japan Atherosclerosis Society. Guidelines for Prevention of Atherosclerotic 
Cardiovascular Diseases 2022. 2022. 
3 
Ministry of Health, Labour and Welfare. An Outline of the Patient Survey in Japan 
2017. [internet] https://www.mhlw.go.jp/toukei/saikin/hw/kanja/17/index.html 
4 
Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al. 
Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events. N 
Engl J Med. 2015;372(16):1500-9. 
5 
Yusuf S, Bosch J, Dagenais G, Zhu J, Xavier D, Liu L, et al. Cholesterol Lowering in 
Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 
2016;374(21):2021-31. 
6 
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. 
Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 
2015;372(25):2387-97. 
7 
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. 
Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl 
J Med. 2017;376(18):1713-22. 
8 
Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab 
and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 
2018;379(22):2097-107. 
9 
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA 
Guideline on the Management of Blood Cholesterol: A Report of the American 
College of Cardiology/American Heart Association Task Force on Clinical Practice 
Guidelines. Circulation. 2019;139(25):e1082-143. 
10 Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 
ESC/EAS Guidelines for the Management of Dyslipidaemias: Lipid Modification to 
Reduce Cardiovascular Risk. Eur Heart J. 2020;41(1):111-88. 
11 Japan Atherosclerosis Society. Statin Intolerance Clinical Guide 2018. 2018. 
12 Ministry of Health, Labour and Welfare. Guidelines on Clinical Evaluation of 
Medicinal Products for Treatment of Dyslipidemia, PSEHB/PED Notification No. 
0706-1. 2021 
13 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 
Drugs. 2018;18(3):157-73. 
14 Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, et al. 
Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-
Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial. JAMA. 
2016;315(15):1580-90. 
15 Tobert JA, Newman CB. Statin Tolerability: In Defence of Placebo-Controlled Trials. 
Eur J Prev Cardiol. 2016;23(8):891-6. 


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16 Ministry of Health, Labour and Welfare. Clinical Trials That Use Pharmacogenomics. 
PFSB/ELD Notification No. 0930007. 2008. 
17 Ministry of Health, Labour and Welfare. Guideline on Genomic Sampling and 
Management of Genomic Data, PSEHB/PED Notification No. 0118-1. 2018. 
 
 
 


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

SAP_001.pdf: 
 
 
STATISTICAL  ANALYSIS  PLAN 
 
 
 
 
 
 
 
 
 
 
NCT Number: NCT05683340 
Protocol No. 346-102-00002 
Version 1.0 Date: 04/22/2024 


 
 
 
 
Otsuka Pharmaceutical Co., Ltd. 
 
 
Investigational New Drug  
Bempedoic Acid (ETC-1002) 
 
Protocol No. 346-102-00002 
English Translation 
 
A Placebo-controlled, Randomized, Multicenter, Double-blind, Parallel-group Trial to 
Confirm the Superiority of ETC-1002 in Patients With Hyper-LDL Cholesterolemia 
 
A Confirmatory Trial of ETC-1002 in Patients With Hyper-LDL Cholesterolemia 
 
Statistical Analysis Plan 
Version: 1.0 
Date: 22 Apr 2024 
Protocol Date (1st Version): 04 Oct 2022   
Protocol Date (2nd Version): 07 Dec 2022 
 
 
 
 
 
 
 
 
 
 
Confidential 
 
 


Protocol 346-102-00002 
 
 
Statistical Analysis Plan  
2 of 43 
Version 1.0 Date: 04/22/2024 
 
Table of Contents 
Table of Contents ........................................................................................... 2 
List of Appendices.......................................................................................... 4 
List of Abbreviations and Definition of Terms ........................................... 5 
1 
Introduction .......................................................................................... 6 
2 
Trial Objectives ..................................................................................... 6 
3 
Trial Design ........................................................................................... 6 
3.1 
Type/Design of Trial ...........................................................................................6 
3.2 
Trial Treatments ..................................................................................................7 
3.3 
Trial Population ...................................................................................................8 
3.4 
Trial Visit Window ..............................................................................................8 
4 
Sample Size ............................................................................................ 9 
5 
Statistical Analysis Datasets .............................................................. 10 
5.1 
Full Analysis Set (FAS) ....................................................................................10 
5.2 
Safety Analysis Set ............................................................................................10 
5.3 
Handling of Missing Data .................................................................................10 
6 
Primary and Secondary Outcome Variables ................................... 10 
6.1 
Primary Outcome Variables ..............................................................................10 
6.2 
Secondary Outcome Variables ..........................................................................10 
7 
Disposition and Demographic Analysis ............................................ 11 
7.1 
Subject Disposition............................................................................................11 
7.2 
Demographic and Baseline Characteristics .......................................................11 
7.3 
Baseline Disease Evaluation .............................................................................12 
7.4 
Treatment Compliance ......................................................................................12 
7.5 
Prior and Concomitant Medications ..................................................................13 
7.6 
Protocol Deviations ...........................................................................................13 
8 
Efficacy Analysis ................................................................................. 13 
8.1 
Primary Efficacy Endpoint ................................................................................13 
8.1.1 
Primary Efficacy Analysis ..............................................................................14 
8.1.2 
Sensitivity Analyses ........................................................................................14 
8.1.3 
Technical Computational Details for Primary Efficacy Analysis ..................15 


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Version 1.0 Date: 04/22/2024 
 
8.2 
Secondary Efficacy Analyses ............................................................................15 
8.3 
Other Efficacy Analyses ....................................................................................16 
8.4 
Exploratory or Other Analyses ..........................................................................17 
8.5 
Subgroup Analyses ............................................................................................17 
9 
Safety Analyses ................................................................................... 18 
9.1 
Extent of Exposure ............................................................................................18 
9.2 
Adverse Events ..................................................................................................18 
9.2.1 
AEs of Special Interest ...................................................................................19 
9.3 
Clinical Laboratory Data ...................................................................................19 
9.4 
Vital Sign Data ..................................................................................................19 
9.5 
Physical Examination Data ...............................................................................19 
9.6 
Electrocardiogram Data .....................................................................................20 
9.7 
Other Safety Data ..............................................................................................20 
9.7.1 
Body Weight ...................................................................................................20 
10 
Pharmacokinetic Analyses ................................................................. 20 
11 
Pharmacodynamic Analyses .............................................................. 21 
12 
Pharmacogenomic Analyses .............................................................. 21 
13 
Interim Analysis .................................................................................. 21 
14 
Changes in the Planned Analyses ...................................................... 21 
15 
References ............................................................................................ 22 
 


Protocol 346-102-00002 
 
 
Statistical Analysis Plan  
4 of 43 
Version 1.0 Date: 04/22/2024 
 
List of Appendices 
Appendix 1 
Criteria for Identifying Vital Signs and Weight of Potential 
Clinical Relevance ........................................................................ 23 
Appendix 2 
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance ........................................................................ 24 
Appendix 3 
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance ........................................................................ 25 
Appendix 4 
Preferred Terms for Statins, Ezetimibe, and Fibrates ................... 26 
Appendix 5 
Classification of AEs of Special Interest ...................................... 28 
Appendix 6 
Statin Intensity .............................................................................. 31 
Appendix 7 
List of Figures and Tables............................................................. 33 
Appendix 8 
List of Subject Data Listings......................................................... 42 


Protocol 346-102-00002 
 
 
Statistical Analysis Plan  
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Version 1.0 Date: 04/22/2024 
 
List of Abbreviations and Definition of Terms 
Abbreviation Definition 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase   
apo B 
Apolipoprotein B  
ASCVD 
Atherosclerotic cardiovascular disease 
AST 
Aspartate aminotransferase   
BMI 
Body mass index  
eGFR 
Estimated glomerular filtration rate 
FAS 
Full analysis set  
HbA1c 
Glycosylated hemoglobin  
HDL-C 
High-density lipoprotein cholesterol   
hsCRP 
High-sensitivity C-reactive protein   
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use   
LDL 
Low-density lipoprotein   
LDL-C 
Low-density lipoprotein cholesterol   
MedDRA 
Medical Dictionary for Regulatory Activities   
MAR 
Missing at random 
MMRM 
Mixed-model repeated measures 
non-HDL-C 
Non-high-density lipoprotein cholesterol   
PAD 
Peripheral Arterial Disease 
PT 
Preferred term 
OC 
Observed cases 
QTc 
Corrected QT interval  
QTcF 
QT interval corrected for heart rate using Fridericia’s formula   
SAS 
Statistical Analysis System 
SOC 
System organ class  
TC 
Total cholesterol   
TEAE 
Treatment-emergent adverse event   
TG 
Triglyceride   
WHODD 
World Health Organization Drug Dictionary 
 
 


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1 
Introduction 
This statistical analysis plan (SAP) documents the detailed methods for the statistical 
analysis planned in Trial 346-102-00002. 
2 
Trial Objectives 
Primary: 
• To confirm the superiority of ETC-1002 after 12 weeks of administration at 180 
mg/day to placebo in patients with hyper-low-density lipoprotein (hyper-LDL) 
cholesterolemia who have inadequate control of low-density lipoprotein 
cholesterol (LDL-C).  
Secondary: 
• To assess the effects of ETC-1002 on non-high-density lipoprotein cholesterol 
(non-HDL-C), total cholesterol (TC), apolipoprotein B (apo B), high-sensitivity 
C-reactive protein (hsCRP), and glycosylated hemoglobin (HbA1c). To assess the 
proportion of subjects achieving the lipid management goals of LDL-C by 
treatment with ETC-1002.  
• To assess the safety of ETC-1002 when administered at 180 mg/day for 12 weeks.  
 
3 
Trial Design 
3.1 
Type/Design of Trial 
This is a placebo-controlled, randomized, multicenter, double-blind, parallel-group trial 
to assess the efficacy and safety of ETC-1002 administered at 180 mg/day for 12 weeks 
in patients with hyper-LDL cholesterolemia who are being treated with hyper-LDL 
cholesterolemia drugs but have inadequate control and cannot achieve the lipid 
management goals. The trial population will include patients with inadequate response to 
statins who cannot achieve the lipid management goals despite being treated with statins, 
and patients with statin intolerance who have experienced safety problems that were 
successfully resolved after stopping or reducing the dose of statins, and cannot achieve 
the lipid management goals. 
A schematic of the trial design is presented in Figure 3.1-1.  
This trial consists of a screening period, placebo run-in period, treatment period, and 
follow-up period. Subjects determined to be eligible in the screening period will proceed 
to the placebo run-in period and continue treatment without changing the type or dosage 
regimen of hypercholesterolemia drugs that have been taken prior to informed consent, 


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and will receive placebo tablets under single-blind conditions. Subjects with less than 
80% compliance with the single-blind placebo tablets during the 4-week placebo run-in 
period will be withdrawn during the placebo run-in period. Subjects who have no safety 
problems or muscle-related adverse events (AEs) during the 4-week placebo run-in 
period and who do not fall under the exclusion criteria as judged by the investigator or 
subinvestigator will be assigned either to the ETC-1002 180-mg/day group or placebo 
group and proceed to the treatment period. Statin response (inadequate response to 
statins/statin intolerance) is set as a randomization stratification factor to ensure equal 
allocation of subjects with inadequate response to statins and those with statin intolerance 
to each treatment group. 
 
 
Figure 3.1-1 
Trial Design Schematic 
 
3.2 
Trial Treatments 
During the treatment period, subjects will receive either ETC-1002 180 mg or a placebo 
for 12 weeks in addition to continued hypercholesterolemia drugs that have been taken 
prior to informed consent. Medications to be taken in the placebo run-in period and 
treatment period are detailed below. 
 
Description 
Placebo Run-in Period 
Treatment Period  
 
Investigational 
medicinal products 
Medications 
Placebo tablets 
ETC-1002 180-mg 
tablets/placebo tablets 
Dosage 
regimen/ 
Mode of 
administration 
 
One tablet once daily/oral  
Screening Period
(1 week)
Follow-up Period
(4 weeks)
Modifiable
Visit
Placebo
Randomized
Lipid-lowering drugs: Type and dose/regimen fixed
Placebo Run-in Period
(single blind) (4 weeks)
Treatment Period
(double blind) (12 weeks)
ETC-1002  180 mg (N = 42)
Placebo (N = 42)
R
Week−5
Week−4
Week−1
Day 1 (Start day of the treatment period)
Week 2
Week 4
Week 12
Week 16
(End of trial: 28 days after the 
final IMP administration)
Week 8
Day1
P
Start of IMP dosing
(Start of trial)
End of treatment
P
R


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Lipid-lowering drugs 
Medications 
Lipid-lowering drugs used before informed consent 
(Statins and/or nonstatins) 
Dosage 
regimen 
Continue treatment without changing the type or dosage 
regimen 
Treatment duration 
4 weeks  
12 weeks  
 
3.3 
Trial Population 
This trial will be conducted in Japanese patients with hyper-LDL cholesterolemia aged 18 
to 85 years, inclusive, at the time of informed consent and who have inadequate response 
to statins/statin intolerance and cannot achieve the lipid management goals specified in 
the Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic 
Cardiovascular Diseases 2017. Subjects considered eligible by the investigator or 
subinvestigator during the screening period will proceed to the placebo run-in period. 
Among subjects with no safety problems or muscle-related AEs in the placebo run-in 
period, those confirmed by the investigator or subinvestigator not to fall under the 
exclusion criteria will be randomized. The target number of randomized subjects is 84 in 
total (42 in the 180-mg/day group and 42 in the placebo group). In addition to patients 
with inadequate response to statins, patients with statin intolerance will be enrolled at 
≥20% of the total in this trial. Statin response (inadequate response to statins/statin 
intolerance) is set as a randomization stratification factor so that subjects with statin 
intolerance will be equally allocated to each treatment group. 
 
3.4 
Trial Visit Window 
For efficacy and safety endpoints (except AEs), acceptable windows of timepoints for 
analysis will be set, with analysis based on analysis timepoints irrespective of timepoints 
recorded in the case report form. Timepoints for analysis will be specified solely based 
on fasting data for non-HDL-C, TC, HDL-C, TG, and LDL-C (calculated using the 
Friedewald formula) among fasting lipid parameters in efficacy endpoints.  The handling 
of fasting data is described in Section 5.3. 
Acceptable windows of timepoints for analysis are shown in Table 3.4-1. For fasting lipid 
parameters (LDL-C [measured using the direct method], non-HDL-C, TC, HDL-C, TG, 
and LDL-C [calculated using the Friedewald formula]) in efficacy endpoints, baseline is 
defined as the mean of the values for Day 1 and Week −1. If only one value is obtained, 
that value will be used as baseline. For efficacy endpoints other than fasting lipid 
parameters and safety endpoints, baseline is defined as the last data point obtained prior 
to the initial investigational medicinal product (IMP) administration in the treatment 
period. The start day of IMP administration is defined as Day 1. If multiple data points 


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are available for a certain acceptable window, the last data point will be used for analysis. 
In the setting of timepoints for analysis during the treatment period (Week 2 to Week 12), 
data obtained from 3 days after the last IMP administration will be excluded. The last 
data obtained between the initial IMP administration and 2 days after the last IMP 
administration in the treatment period will be defined as Last Visit. 
Table 3.4-1 
Acceptable windows of timepoints for analysis 
Week 
Acceptable Window 
Baseline 
Fasting lipid parameters: Mean of the values for 
Day 1 and Week −1 (If only one value is obtained, 
that value will be used as baseline.) 
Other parameters: Last data obtained prior to initial 
IMP administration in the treatment period 
Week 2 
Day 2 to 21 
Week 4 
Day 22 to 42 
Week 8 
Day 43 to 70 
Week 12 
Day 71 to 92 
Last Visit 
Last data obtained between the initial IMP 
administration and 2 days after the last IMP 
administration in the treatment period 
Week 16 (Follow up) 
Timepoint recorded in case report form 
 
4 
Sample Size  
In the phase 2 trial conducted in Japan, the difference in the percent change from baseline 
in LDL-C at Week 12 between the ETC-1002 180-mg group and the placebo group was 
−19%, and the standard deviation of the percent change from baseline in each group 
ranged from 9% to 17%. Since the between-group difference was comparable to the 
results estimated from phase 3 trials conducted outside Japan, the between-group 
difference in this trial is assumed to be −19%. Also considering the standard deviation 
(14% to 25%) in the phase 3 trials conducted outside Japan, in which similar populations 
of subjects to this trial were enrolled, the standard deviation in this trial is conservatively 
assumed to be 25%. Under these assumptions, a total of 76 subjects (38 subjects/group) 
will be required to ensure a power of 90%. Assuming a withdrawal rate of 10%, the total 
number of subjects in this trial will be set at 84. 
 


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5 
Statistical Analysis Datasets 
5.1 
Full Analysis Set (FAS) 
The full analysis set (FAS) will include subjects who receive at least one dose of the IMP 
during the treatment period, and who have LDL-C measurements at baseline and at one 
or more time points after IMP administration during the treatment period.  
5.2 
Safety Analysis Set  
The safety analysis set will include subjects who receive at least one dose of the IMP 
during the treatment period. 
5.3 
Handling of Missing Data 
In the primary analysis of the primary endpoint, a mixed-effects model repeated measures 
(MMRM) analysis assuming missing at random (MAR) will be performed using the 
observed case (OC) data set without imputation of missing data. Details of sensitive 
analyses for the handling of missing data are described in Section 8.1.2.  
Analyses for non-HDL-C, TC, apo B, hsCRP, and HbA1c as secondary endpoints will be 
performed using the OC data set without imputation of missing data. In the analysis of 
the proportion of subjects achieving the lipid management goals of LDL-C (direct 
measurement), subjects with missing LDL-C data will be handled as having not achieved 
the lipid management goals. 
Fasting lipid parameters will be handled as shown in the table below with regard to 
fasting condition. 
Fasting Lipid Parameters 
Handling of Data 
LDL-C (direct measurement) 
Parameter to be used in analysis, irrespective of 
fasting condition  
non-HDL-C, TC, HDL-C, TG,  
LDL-C (Friedewald formula) 
Parameters to be used in analysis only when 
obtained under a fasting condition 
 
6 
Primary and Secondary Outcome Variables 
6.1 
Primary Outcome Variables 
Percent change in LDL-C from baseline at Week 12 
6.2 
Secondary Outcome Variables 
• Percent change in non-HDL-C, TC, apo B, hsCRP, and HbA1c from baseline at 
Week 12 


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• Proportion of subjects whose LDL-C value achieves 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]) at Week 12 
7 
Disposition and Demographic Analysis 
7.1 
Subject Disposition 
For consenting subjects, the number of subjects who provide informed consent, the 
number of screening failures, as well as the number and percentage (using the number of 
subjects who provide informed consent as the denominator) of IMP-treated subjects and 
discontinued subjects in the placebo run-in period will be summarized. For subjects who 
proceed to the placebo run-in period, the number and percentage (using the number of 
subjects who proceed to the placebo run-in period as the denominator) of discontinued 
subjects and the reasons for discontinuation in the placebo run-in period will be 
summarized. 
For randomized subjects, the number of randomized subjects and the number and 
percentage (using the number of randomized subjects as the denominator) of those who 
receive the IMP, those who complete the trial, and those who withdraw from the trial and 
the reasons for withdrawal in the treatment period will be summarized by treatment group 
(ETC-1002 group and placebo group, the same hereinafter) and overall. 
For randomized subjects, the number and percentage (using the number of randomized 
subjects as the denominator) of subjects included in each analysis set will be summarized 
by treatment group and overall. 
The same analysis will also be performed by the randomization stratification factor (statin 
response). 
7.2 
Demographic and Baseline Characteristics 
For the FAS and safety analysis set, descriptive statistics (number of subjects, mean, 
standard deviation, median, minimum, and maximum, the same hereinafter) of age, 
height, body weight, and body mass index (BMI), and estimated glomerular filtration rate 
(eGFR), and frequency distributions of categorized age (<65 years, ≥65 years and <75 
years, ≥75 years), categorized BMI (<25 kg/m2, ≥25 kg/m2 and <30 kg/m2, ≥30 kg/m2), 
categorized eGFR (<60 mL/min/1.73 m2, ≥60 mL/min/1.73 m2 and <90 mL/min/1.73 m2, 
≥90 mL/min/1.73 m2), sex, race, ethnicity, country, presence/absence of past medical 
history, and presence/absence of complications will be summarized by treatment group 
and overall. For body weight, values at screening will be used.  


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The same analysis will also be performed by the randomization stratification factor (statin 
response). 
7.3 
Baseline Disease Evaluation 
For the FAS and safety analysis set, descriptive statistics of baseline LDL-C level and 
frequency distributions of LDL-C level category at baseline (<100 mg/dL, ≥100 mg/dL 
and <120 mg/dL, ≥120 mg/dL and <140 mg/dL, ≥140 mg/dL), presence/absence of 
hypercholesterolemia, presence/absence of familial hypercholesterolemia, risk 
assessment (history of coronary artery disease or familial hypercholesterolemia, high risk, 
or intermediate risk), presence/absence of diabetes mellitus, statin response (inadequate 
response to statins/statin intolerance), and presence/absence of atherosclerotic 
cardiovascular disease (ASCVD) history will be summarized by treatment group and 
overall. In addition, frequency distributions of subjects with diabetes who have 
complications of peripheral arterial disease (PAD) or microangiopathy, or who smoke, 
will be summarized by treatment group and overall. 
The same analysis, excluding statin response, will also be performed by the 
randomization stratification factor (statin response). 
For subjects with statin intolerance in the FAS and safety analysis set, frequency 
distributions of presence/absence of statin intolerance-associated symptoms (muscle 
impairment, hepatic impairment, renal impairment, cognitive impairment, or other) and 
presence/absence of causal medication for statin intolerance (atorvastatin calcium 
trihydrate, fluvastatin sodium, pitavastatin calcium, pravastatin sodium, rosuvastatin 
calcium, or simvastatin) will be summarized by treatment group and overall. 
7.4 
Treatment Compliance 
For the FAS, frequency distributions of IMP compliance rate (<70%, ≥70% to <80%, 
≥80% to <90%, or ≥90%) in the treatment period will be summarized by treatment group 
and overall. The IMP compliance rate will be calculated using the following formula. 
IMP compliance rate (%) = 
Actual number of days of taking IMP 
× 100 
Date of final IMP administration − Date of initial IMP 
administration + 1 
The same analysis will also be performed by the randomization stratification factor (statin 
response). 
For the FAS, the number and percentage of subjects who do not change the type and 
dosage regimen of hypercholesterolemia drugs, which are mandatory concomitant 
medications in this trial, throughout the treatment period will be summarized by 
treatment group and overall. 


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The same analysis will also be performed by the randomization stratification factor (statin 
response). 
7.5 
Prior and Concomitant Medications 
For the FAS, frequency distributions of medications used prior to or during the treatment 
period, including hypercholesterolemia drugs, by drug class and preferred term in the 
World Health Organization Drug Dictionary (WHODD) version Global B3 September 
2022 will be summarized by treatment group and overall. 
For the FAS and safety analysis set, frequency distributions of the presence/absence of 
statin use or ezetimibe use will be summarized by treatment group and overall. The 
preferred terms for statins and ezetimibe are shown in Appendix 4. 
The same analysis will also be performed by the randomization stratification factor (statin 
response). 
7.6 
Protocol Deviations 
For randomized subjects, frequency distributions of the presence/absence of the 
following deviations recorded in the CRF will be summarized by treatment group and 
overall. 
• Dosing 
• Inclusion/exclusion criteria 
• Met withdrawal criteria but was not withdrawn 
• Procedural deviations (affecting primary outcome variables) 
• Prohibited concomitant medications 
The same analysis will also be performed by the randomization stratification factor (statin 
response).  
8 
Efficacy Analysis 
Efficacy analysis will be performed for the FAS. 
8.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the percent change in LDL-C from baseline at Week 12 
obtained by direct measurement. The LDL-C values obtained by direct measurement will 
be used in the analyses irrespective of fasting condition. 


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8.1.1 
Primary Efficacy Analysis 
A MMRM analysis assuming MAR will be performed using the OC data set. The 
comparison between groups will be performed based on the least-squares mean 
difference between the ETC-1002 group and placebo group at Week 12. The two-sided 
significance level will be set at 0.05. The MMRM model will include the treatment 
group, randomization stratification factor, visit, and treatment group-by-visit interaction 
as factors, with baseline and baseline-by-visit interaction as covariates using an 
unstructured error covariance matrix. The Kenward-Roger method will be used to 
calculate the degree of freedom. If the MMRM procedure fails to converge in variance 
component estimation, the following error covariance structures will be used in sequence 
of 1) heterogeneous toeplitz, 2) heterogeneous autoregressive of order 1, and 3) 
heterogeneous compound symmetry, and the first structure to yield convergence will be 
used. If a structure other than unstructured is selected, a sandwich estimator of standard 
error will be used. 
In the MMRM analysis described above, the least-squares mean for each treatment group 
and the least-squares mean difference between the ETC-1002 group and placebo group, 
together with the two-sided 95% confidence intervals, will be calculated for each 
timepoint from baseline to Week 12. 
Timecourse of the least-squares mean ± standard error for the percent change from 
baseline in LDL-C at each visit from baseline to Week 12 will be plotted for each 
treatment group. 
The same analysis as above will also be performed by the randomization stratification 
factor. The randomization stratification factor is not included in the model. 
8.1.2 
Sensitivity Analyses 
Placebo multiple imputation assuming missing not at random (MNAR) will be performed 
as a sensitivity analysis for handling missing data in LDL-C (direct measurement) as the 
primary efficacy endpoint. 
The analysis by multiple imputation will be performed in the following procedures. The 
number of imputations will be set at 100. 
1) Missing data will be imputed using the Fully Conditional Specification method. The 
imputation model for LDL-C (direct measurement) at each timepoint includes the 
randomization stratification factor and LDL-C values (direct measurement) obtained 
prior to the respective timepoints. Imputation will be performed using an imputation 


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model based on the placebo group, assuming MNAR for missing data of the ETC-1002 
group. For missing data in the placebo group, MAR will be assumed. 
2) The multiply imputed dataset will be analyzed using the same MMRM as the primary 
efficacy endpoint. 
3) The analysis results of the multiply imputed dataset will be combined using the 
MIANALYZE procedure in SAS, and the estimated difference between the ETC-1002 
group and placebo group at Week 12, its 95% confidence interval, and p value will be 
calculated. 
8.1.3 
Technical Computational Details for Primary Efficacy Analysis 
The MMRM analysis, which is the primary analysis, will be performed using the 
following SAS code. 
proc mixed; 
  class treatment strata visit subjid; 
  model pchange = treatment visit baseline treatment*visit baseline*visit strata / 
ddfm=kr; 
  repeated visit /type=un subject=subjid; 
  lsmeans treament*visit / diff cl; 
run; 
8.2 
Secondary Efficacy Analyses 
• Percent change from baseline 
For non-HDL-C and TC, the same MMRM analysis as the primary efficacy endpoint will 
be performed. The baseline value for each assessment parameter will be used as 
covariates. 
For apo B, hsCRP, and HbA1c, analysis of covariance using OC data will be performed. 
The least-squares mean for each treatment group and the least-squares mean difference 
between the ETC-1002 group and placebo group, together with the two-sided 95% 
confidence intervals, will be calculated. The model includes the treatment group and 
statin response (inadequate response to statins/statin intolerance), which is the 
randomization stratification factor, as factors and the baseline value for each assessment 
parameter as covariates. 
The timecourse of the least-squares mean ± standard error at each visit from baseline to 
Week 12 will be plotted for each treatment group. Least-squares mean will be calculated 


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based on MMRM analysis for non-HDL-C and TC, and based on analysis of covariance 
for apo B, hsCRP, and HbA1c. 
The same analysis as above will also be performed by the randomization stratification 
factor. The randomization stratification factor is not included in the model for MMRM 
analysis and analysis of covariance. 
• Lipid management goals based on risk assessment 
The proportion of subjects whose LDL-C value (direct measurement) achieves the lipid 
management goals (<100 mg/dL [history of coronary artery disease or heterozygous 
familial hypercholesterolemia], <120 mg/dL [high risk], or <140 mg/dL [intermediate 
risk]) at Week 12 will be analyzed using the Cochran-Mantel-Haenszel test stratified by 
statin response (inadequate response to statins/statin intolerance). The difference between 
the ETC-1002 group and the placebo group will be calculated, along with the two-sided 
95% confidence intervals (based on Cochran-Mantel-Haenszel). The proportion in each 
treatment group and the two-sided 95% interval (based on the Clopper-Pearson method) 
will also be calculated. Subjects with missing LDL-C data at Week 12 will be handled as 
having not achieved the lipid management goals. The same analysis will be performed for 
other timepoints (Week 2, Week 4, and Week 8).  
For the proportion of subjects having achieved the lipid management goals, the 
proportion in each treatment group and the two-sided 95% interval (based on the 
Clopper-Pearson method) will be calculated by the randomization stratification factor 
(statin response). Fisher's exact test will be performed for the comparison between the 
ETC-1002 group and the placebo group, and the difference in proportions and its exact 
two-sided 95% interval (based on score statistics) will be calculated. 
The same analysis as above will be performed using OC data. 
8.3 
Other Efficacy Analyses 
For HDL-C, TG, and LDL-C (Friedewald formula), the same MMRM analysis as the 
primary efficacy endpoint will be performed. The baseline value for each assessment 
parameter will be used as covariates. 
The timecourse of the least-squares mean ± standard error at each visit from baseline to 
Week 12 will be plotted for each treatment group. 
The same analysis as above will also be performed by the randomization stratification 
factor. The randomization stratification factor is not included in the model for MMRM 
analysis. 


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8.4 
Exploratory or Other Analyses 
For efficacy endpoints (LDL-C [direct method], non-HDL-C, TC, apo B, hsCRP, HbA1c, 
HDL-C, TG, and LDL-C [Friedewald formula]), descriptive statistics for the actual value, 
change from baseline, and percent change from baseline at each time point (baseline, 
Week 2, Week 4, Week 8, Week 12, and Week 16 [follow up]) will be calculated by 
treatment group. In addition, summarization at Last Visit will be performed. 
For percent change from baseline at Week 12 in efficacy endpoints (LDL-C [direct 
method], non-HDL-C, TC, apo B, hsCRP, HbA1c, HDL-C, TG, and LDL-C [Friedewald 
formula]), robust regression analysis will be performed using OC data. The model 
includes treatment group and statin response (inadequate response to statins/statin 
intolerance), which is the randomization stratification factor, as factors and the baseline 
value for each assessment parameter as covariates. 
The same analysis as above will also be performed by the randomization stratification 
factor. The randomization stratification factor is not included in the model for robust 
regression analysis. 
8.5 
Subgroup Analyses 
Subgroup analyses will be performed by the following items for the percent change in 
LDL-C (direct method) from baseline at Week 12, the primary endpoint. Using the same 
MMRM as for the primary analysis, the least-squares mean for each treatment group and 
the least-squares mean difference between the ETC-1002 group and placebo group, 
together with the two-sided 95% confidence intervals, will be calculated for each 
subgroup. In the analysis for the statin response subgroup, the randomization 
stratification factor (statin response) will not be included in the model. Statin intensity 
categories and preferred terms for ezetimibe and fibrates are shown in Appendix 6 and 
Appendix 4, respectively. 
• Statin response (Inadequate response to statins, Statin intolerance) 
• Sex (Male, Female) 
• Familial hypercholesterolemia (Yes, No) 
• Diabetes mellitus (Yes, No) 
• Age (<65 years, ≥65 years and <75 years, ≥75 years) 
• Statin use (Yes, No) 
• BMI (<25 kg/m2, ≥25 kg/m2 and <30 kg/m2, ≥30 kg/m2) 
• eGFR (<60 mL/min/1.73 m2, ≥60 mL/min/1.73 m2 and <90 mL/min/1.73 m2, ≥90 
mL/min/1.73 m2) 


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• LDL-C at baseline (<100 mg/dL, ≥100 mg/dL and <120 mg/dL, ≥120 mg/dL and 
<140 mg/dL, ≥140 mg/dL) 
• History of ASCVD (Yes, No) 
• Statin intensity (Low-intensity statins, High-intensity statins, No statins) 
• Ezetimibe use (Yes, No) 
• Fibrate use (Yes, No) 
 
9 
Safety Analyses 
Tabulation by treatment group 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. The 
same tabulation will also be performed by the randomization stratification factor (statin 
response). 
9.1 
Extent of Exposure 
Descriptive statistics will be calculated for the duration of IMP treatment in the treatment 
period (Date of final IMP administration in the treatment period − Date of initial IMP 
administration in the treatment period + 1) and for the total number of days of IMP 
administration in the treatment period (The total number of days of taking IMP in the 
treatment period).  
9.2 
Adverse Events 
All AEs will be coded by system organ class (SOC) and preferred term (PT) using the 
Medical Dictionary for Regulatory Activities (MedDRA) version 26.1. The incidence of 
the following events will be calculated by SOC, PT, and overall. If a subject experiences 
the same event more than once, the more severe event will be used. 
• Treatment-emergent adverse events (TEAEs) in the treatment period 
• 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. 
Summary tables (only for events occurring at ≥5% of subjects in any group) will also be 
prepared for TEAEs and for TEAEs potentially causally related to the IMP.  
The incidence of TEAEs not judged to be adverse reactions to the COVID-19 vaccine 
will be calculated by SOC, PT, and overall. 


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9.2.1 
AEs of Special Interest 
The incidence of AEs of special interest will be calculated by SOC and PT. AEs of 
special interest potentially causally related to the IMP will be summarized in the same 
manner. The classification of AEs of special interest is shown in Appendix 5.  
9.3 
Clinical Laboratory Data 
Among the urinalysis parameters in laboratory tests, parameters except for pH and 
specific gravity will be included in the qualitative urinalysis. 
For parameters other than qualitative urinalysis, descriptive statistics of the actual value 
and change from baseline will be calculated at each visit (baseline, Week 4, Week 8, 
Week 12, Last Visit, and Week 16 [follow up]). For qualitative urinalysis parameters, 
shift tables at each visit from baseline will be prepared. For parameters other than 
qualitative urinalysis, measured values will be categorized using the reference ranges of 
“below the lower limit of reference range”, “within the reference range” and “above the 
upper limit of reference range”, and shift tables at each visit from baseline will be 
prepared. 
The number and percentage of subjects meeting the criteria for identifying laboratory 
values of potential clinical relevance (Appendix 2: Criteria for Identifying Laboratory 
Values of Potential Clinical Relevance) after IMP administration during the treatment 
period will be calculated. All data obtained after IMP administration during the treatment 
period, including those at unscheduled visits, will be analyzed. 
9.4 
Vital Sign 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 visit (baseline, Week 
2, Week 4, Week 8, Week 12, Last Visit, and Week 16 [follow up]). 
The number and percentage of subjects meeting the criteria for identifying vital signs of 
potential clinical relevance (Appendix 1: Criteria for Identifying Vital Signs and Weight 
of Potential Clinical Relevance) after IMP administration during the treatment period will 
be calculated. All data obtained after IMP administration during the treatment period, 
including those at unscheduled visits, will be analyzed. 
9.5 
Physical Examination Data 
Physical findings recorded in the CRF will be presented in a listing of subjects. 


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9.6 
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 visit (baseline, Week 4, Week 12, and Last Visit). 
The number and percentage of subjects with a QTcF of >450 msec, >480 msec, or 
>500 msec at any postdose visit during the treatment period 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 during the treatment period visit will 
be calculated. All data obtained after IMP administration during the treatment period, 
including those at unscheduled visits, will be analyzed. The number and percentage of 
subjects meeting these criteria at each postdose visit will also be calculated. 
For assessment of normality/abnormality, shift tables at each visit from baseline will be 
prepared. 
The number and percentage of subjects meeting the criteria for identifying ECG 
measurements of potential clinical relevance (Appendix 3: Criteria for Identifying ECG 
Measurements of Potential Clinical Relevance) after IMP administration during the 
treatment period will be calculated. All data obtained after IMP administration during the 
treatment period, including those at unscheduled visits, will be analyzed. 
9.7 
Other Safety Data 
9.7.1 
Body Weight 
Descriptive statistics of the actual value and change from baseline will be calculated at 
each visit (baseline, Week 4, Week 8, Week 12, and Last Visit). 
The number and percentage of subjects meeting the criteria for identifying body weight 
of potential clinical relevance (Appendix 1: Criteria for Identifying Vital Signs and 
Weight of Potential Clinical Relevance) after IMP administration during the treatment 
period will be calculated. All data obtained after IMP administration during the treatment 
period, including those at unscheduled visits, will be analyzed. 
 
10 
Pharmacokinetic Analyses 
No pharmacokinetic analysis is planned.  
 


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11 
Pharmacodynamic Analyses 
No pharmacodynamic analysis is planned. 
 
12 
Pharmacogenomic Analyses 
No pharmacogenomic analysis is planned. 
 
13 
Interim Analysis 
No interim analysis is planned. 
 
14 Changes in the Planned Analyses 
Not applicable.  
 


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15 
References 
Not applicable. 


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Appendix 1 
Criteria for Identifying Vital Signs and Weight of Potential 
Clinical Relevance 
Variable 
Criterion Valuea 
Change Relative to Baselinea 
Pulse Rate 
>120 bpm 
15 bpm increase 
Pulse Rate 
<50 bpm 
15 bpm decrease 
Systolic Blood Pressure 
>160 mmHg 
20 mmHg increase 
Systolic Blood Pressure 
<90 mmHg 
20 mmHg decrease 
Diastolic Blood Pressure 
>100 mmHg 
15 mmHg increase 
Diastolic Blood Pressure 
<50 mmHg 
15 mmHg decrease 
Weight 
N/A 
≥7% increase 
Weight 
N/A 
≥7% decrease 
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column. 


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Appendix 2 
Criteria for Identifying Laboratory Values of Potential 
Clinical Relevance 
Laboratory Tests 
Criteria 
Chemistry 
 
AST 
3 x upper limit of normal (ULN) 
ALT 
3 x ULN 
Bilirubin, Total 
2 x ULN 
ALP 
3 x ULN 
Urea Nitrogen 
30 mg/dL 
Creatinine 
2.0 mg/dL 
Creatine Kinase (CK) 
4 x ULN 
Uric Acid 
9 mg/dL 
Hematology 
 
Hematocrit 
Males: 37% and 3 percentage points decrease from 
baseline 
Females: 32% and 3 percentage points decrease from 
baseline 
Hemoglobin 
Males: 11.5 g/dL 
Females: 9.5 g/dL 
Leukocyte Count 
2,800 106/L 
Leukocyte Count 
16,000 106/L 
Platelet Count 
7.5 1010/L 
Platelet Count 
70 1010/L 
Urinalysis 
 
Protein 
Increase of 2 units 
Glucose 
Increase of 2 units 
Additional Criteria 
 
Chloride 
90 mEq/L 
Chloride 
118 mEq/L 
Potassium 
2.5 mEq/L 
Potassium 
6.5 mEq/L 
Sodium 
126 mEq/L 
Sodium 
156 mEq/L 
Calcium 
8.2 mg/dL 
Calcium 
12 mg/dL 
Glucose 
Fasting: 126 mg/dL  
Non-fasting: 200 mg/dL 
Glucose 
50 mg/dL 
Total Cholesterol 
240 mg/dL  
LDL Cholesterol 
160 mg/dL 
HDL Cholesterol 
<40 mg/dL 
Triglycerides, Fasting 
150 mg/dL 


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Appendix 3 
Criteria for Identifying ECG Measurements of Potential 
Clinical Relevance 
Variable 
Criterion Valuea 
Change Relative to Baselinea 
Heart Rate 
120 bpm 
Increase of 15 bpm 
Heart Rate 
50 bpm 
Decrease of 15 bpm 
PR 
200 msec 
Increase of 50 msec 
QRS 
120 msec 
Increase of 20 msec 
aIn order to be identified as potentially clinically relevant, an on-treatment value must meet the 
“Criterion Value” and also represent a change from the subject’s baseline value of at least the 
magnitude shown in the “Change Relative to Baseline” column. 


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Appendix 4 
Preferred Terms for Statins, Ezetimibe, and Fibrates  
Drug 
CRF Option for 
Drug Name 
(English) 
Preferred Term 
WHODD 
Drug Name 
Preferred Term 
WHODD 
Drug Code 
WHODD 
Drug Code 
6 Digits 
Statins 
Pravastatin 
sodium 
PRAVASTATIN SODIUM 
00880402001 
008804 
 
Simvastatin 
SIMVASTATIN 
00848101001 
008481 
 
Rosuvastatin 
calcium 
ROSUVASTATIN 
CALCIUM 
01588602001 
015886 
 
Pitavastatin 
calcium 
PITAVASTATIN CALCIUM 
06470002001 
064700 
 
Atorvastatin 
calcium trihydrate 
ATORVASTATIN 
CALCIUM TRIHYDRATE 
01326106001 
013261 
 
Fluvastatin 
sodium 
FLUVASTATIN SODIUM 
01224502001 
012245 
 
Caduet No. 1 
AMLODIPINE BESILATE; 
ATORVASTATIN 
CALCIUM 
12872303001 
128723 
 
Caduet No. 2 
AMLODIPINE BESILATE; 
ATORVASTATIN 
CALCIUM 
12872303001 
128723 
 
Caduet No. 3 
AMLODIPINE BESILATE; 
ATORVASTATIN 
CALCIUM 
12872303001 
128723 
 
Caduet No. 4 
AMLODIPINE BESILATE; 
ATORVASTATIN 
CALCIUM 
12872303001 
128723 
 
Amaluet No. 1 
AMLODIPINE BESILATE; 
ATORVASTATIN 
CALCIUM TRIHYDRATE 
12872304001 
128723 
 
Amaluet No. 2 
AMLODIPINE BESILATE; 
ATORVASTATIN 
CALCIUM TRIHYDRATE 
12872304001 
128723 
 
Amaluet No. 3 
AMLODIPINE BESILATE; 
ATORVASTATIN 
CALCIUM TRIHYDRATE 
12872304001 
128723 
 
Amaluet No. 4 
AMLODIPINE BESILATE; 
ATORVASTATIN 
CALCIUM TRIHYDRATE 
12872304001 
128723 
 
Atozet LD 
ATORVASTATIN 
CALCIUM; EZETIMIBE 
12872002001 
128720 
 
Atozet HD 
ATORVASTATIN 
CALCIUM; EZETIMIBE 
12872002001 
128720 
 
Rosuzet LD 
EZETIMIBE; 
ROSUVASTATIN 
CALCIUM 
10641002001 
106410 
 
Rosuzet HD 
EZETIMIBE; 
ROSUVASTATIN 
CALCIUM 
10641002001 
106410 
 
Other 
LIPID MODIFYING 
AGENTS, COMBINATIONS 
90083401001 
900834 
Ezetimibe 
Ezetimibe 
EZETIMIBE 
01587001001 
015870 
 
Atozet LD 
ATORVASTATIN 
CALCIUM; EZETIMIBE 
12872002001 
128720 


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Drug 
CRF Option for 
Drug Name 
(English) 
Preferred Term 
WHODD 
Drug Name 
Preferred Term 
WHODD 
Drug Code 
WHODD 
Drug Code 
6 Digits 
 
Atozet HD 
ATORVASTATIN 
CALCIUM; EZETIMIBE 
12872002001 
128720 
 
Rosuzet LD 
EZETIMIBE; 
ROSUVASTATIN 
CALCIUM 
10641002001 
106410 
 
Rosuzet HD 
EZETIMIBE; 
ROSUVASTATIN 
CALCIUM 
10641002001 
106410 
 
Other 
LIPID MODIFYING 
AGENTS, COMBINATIONS 
90083401001 
900834 
Fibrates 
Other 
CLOFIBRATE 
00001301001 
000013 
 
Other 
BEZAFIBRATE 
00544101001 
005441 
 
Other 
FENOFIBRATE 
00499301001 
004993 
 
Other 
PEMAFIBRATE 
08922801001 
089228 
 


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Appendix 5 
Classification of AEs of Special Interest  
AE of Special Interest 
PT Code 
PT Term 
Hepatic dysfunction-related 
10001547 
Alanine aminotransferase abnormal 
Hepatic dysfunction-related 
10001551 
Alanine aminotransferase increased 
Hepatic dysfunction-related 
10003477 
Aspartate aminotransferase abnormal 
Hepatic dysfunction-related 
10003481 
Aspartate aminotransferase increased 
Hepatic dysfunction-related 
10058477 
Blood bilirubin abnormal 
Hepatic dysfunction-related 
10005364 
Blood bilirubin increased 
Hepatic dysfunction-related 
10062685 
Hepatic enzyme abnormal 
Hepatic dysfunction-related 
10060795 
Hepatic enzyme increased 
Hepatic dysfunction-related 
10068237 
Hypertransaminasaemia 
Hepatic dysfunction-related 
10024690 
Liver function test abnormal 
Hepatic dysfunction-related 
10077692 
Liver function test increased 
Hepatic dysfunction-related 
10062688 
Transaminases abnormal 
Hepatic dysfunction-related 
10054889 
Transaminases increased 
Hepatic dysfunction-related 
10019670 
Hepatic function abnormal 
Myopathy-related  
10028372 
Muscular weakness 
Myopathy-related  
10028320 
Muscle necrosis 
Myopathy-related  
10028334 
Muscle spasms 
Myopathy-related  
10028411 
Myalgia 
Myopathy-related  
10028653 
Myositis 
Myopathy-related  
10028625 
Myoglobin blood increased 
Myopathy-related  
10059888 
Myoglobin blood present 
Myopathy-related  
10028631 
Myoglobin urine present 
Myopathy-related  
10058735 
Myoglobinaemia 
Myopathy-related  
10028629 
Myoglobinuria 
Myopathy-related  
10028641 
Myopathy 
Myopathy-related  
10028648 
Myopathy toxic 
Myopathy-related  
10074769 
Necrotising myositis 
Myopathy-related  
10033425 
Pain in extremity 
Myopathy-related  
10039020 
Rhabdomyolysis 
Myopathy-related  
10005468 
Blood creatine phosphokinase abnormal 
Myopathy-related  
10005470 
Blood creatine phosphokinase increased 


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AE of Special Interest 
PT Code 
PT Term 
Myopathy-related  
10005477 
Blood creatine phosphokinase MM increased 
Tendon rupture/disorder-related 
10043248 
Tendon rupture 
Tendon rupture/disorder-related 
10028331 
Muscle rupture 
Tendon rupture/disorder-related 
10039227 
Rotator cuff syndrome 
Tendon rupture/disorder-related 
10074599 
Tendon discomfort 
Tendon rupture/disorder-related 
10043239 
Tendon disorder 
Tendon rupture/disorder-related 
10043242 
Tendon injury 
Tendon rupture/disorder-related 
10069650 
Tendon necrosis 
Tendon rupture/disorder-related 
10066371 
Tendon pain 
Tendon rupture/disorder-related 
10043255 
Tendonitis 
Diabetes-related 
10005554 
Blood glucose abnormal 
Diabetes-related 
10005557 
Blood glucose increased 
Diabetes-related 
10012601 
Diabetes mellitus 
Diabetes-related 
10012607 
Diabetes mellitus inadequate control 
Diabetes-related 
10012671 
Diabetic ketoacidosis 
Diabetes-related 
10018429 
Glucose tolerance impaired 
Diabetes-related 
10018478 
Glucose urine present 
Diabetes-related 
10018473 
Glycosuria 
Diabetes-related 
10018484 
Glycosylated haemoglobin increased 
Diabetes-related 
10020635 
Hyperglycaemia 
Diabetes-related 
10056997 
Impaired fasting glucose 
Diabetes-related 
10023379 
Ketoacidosis 
Diabetes-related 
10023388 
Ketonuria 
Diabetes-related 
10023391 
Ketosis 
Diabetes-related 
10067585 
Type 2 diabetes mellitus 
Diabetes-related 
10057597 
Urine ketone body present 
Renal dysfunction-related 
10069339 
Acute kidney injury 
Renal dysfunction-related 
10005481 
Blood creatinine abnormal 
Renal dysfunction-related 
10005483 
Blood creatinine increased 
Renal dysfunction-related 
10005846 
Blood urea abnormal 
Renal dysfunction-related 
10005851 
Blood urea increased 
Renal dysfunction-related 
10050760 
Blood urea nitrogen/creatinine ratio increased 
Renal dysfunction-related 
10068447 
Creatinine renal clearance abnormal 


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AE of Special Interest 
PT Code 
PT Term 
Renal dysfunction-related 
10011372 
Creatinine renal clearance decreased 
Renal dysfunction-related 
10018356 
Glomerular filtration rate abnormal 
Renal dysfunction-related 
10018358 
Glomerular filtration rate decreased 
Renal dysfunction-related 
10030302 
Oliguria 
Renal dysfunction-related 
10072370 
Prerenal failure 
Renal dysfunction-related 
10038435 
Renal failure 
Renal dysfunction-related 
10061480 
Renal function test abnormal 
Renal dysfunction-related 
10062237 
Renal impairment 
Metabolic acidosis 
10027417 
Metabolic acidosis 
Hypoglycemia-related 
10005554 
Blood glucose abnormal 
Hypoglycemia-related 
10005555 
Blood glucose decreased 
Hypoglycemia-related 
10020993 
Hypoglycaemia 
Hypoglycemia-related 
10021000 
Hypoglycaemic coma 
Hypoglycemia-related 
10021002 
Hypoglycaemic encephalopathy 
Hypoglycemia-related 
10048803 
Hypoglycaemic seizure 
Hypoglycemia-related 
10040576 
Shock hypoglycaemic 
Cognitive dysfunction-related 
10057668 
Cognitive disorder 
Cognitive dysfunction-related 
10010305 
Confusional state 
Cognitive dysfunction-related 
10013395 
Disorientation 
Cognitive dysfunction-related 
10027175 
Memory impairment 
Cognitive dysfunction-related 
10048294 
Mental status changes 
Cognitive dysfunction-related 
10001949 
Amnesia 
Elevated uric acid-related 
10005861 
Blood uric acid increased 
Elevated uric acid-related 
10020903 
Hyperuricaemia 
Elevated uric acid-related 
10018627 
Gout 
Decreased hemoglobin-related 
10018884 
Haemoglobin decreased 
Decreased hemoglobin-related 
10018838 
Haematocrit decreased 
Decreased hemoglobin-related 
10002034 
Anaemia 
 


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Appendix 6 
Statin Intensity  
Item 
Category 
CRF Option for 
Drug Name 
(English) 
Preferred Term 
WHODD 
Drug Name 
Preferred 
Term 
WHODD 
Drug Code 
WHODD 
Drug 
Code 
6 digits 
Statin 
Intensity 
Low-
intensity 
Pravastatin 
sodium 
PRAVASTATIN SODIUM 
00880402001 
008804 
 
 
Simvastatin 
SIMVASTATIN 
00848101001 
008481 
 
 
Fluvastatin 
sodium 
FLUVASTATIN SODIUM 
01224502001 
012245 
 
High-
intensity 
Rosuvastatin 
calcium 
ROSUVASTATIN 
CALCIUM 
01588602001 
015886 
 
 
Pitavastatin 
calcium 
PITAVASTATIN 
CALCIUM 
06470002001 
064700 
 
 
Atorvastatin 
calcium trihydrate 
ATORVASTATIN 
CALCIUM TRIHYDRATE 
01326106001 
013261 
 
 
Caduet No.1 
AMLODIPINE BESILATE; 
ATORVASTATIN 
CALCIUM 
12872303001 
128723 
 
 
Caduet No.2 
AMLODIPINE BESILATE; 
ATORVASTATIN 
CALCIUM 
12872303001 
128723 
 
 
Caduet No.3 
AMLODIPINE BESILATE; 
ATORVASTATIN 
CALCIUM 
12872303001 
128723 
 
 
Caduet No.4 
AMLODIPINE BESILATE; 
ATORVASTATIN 
CALCIUM 
12872303001 
128723 
 
 
Amaluet No.1 
AMLODIPINE BESILATE; 
ATORVASTATIN 
CALCIUM TRIHYDRATE 
12872304001 
128723 
 
 
Amaluet No.2 
AMLODIPINE BESILATE; 
ATORVASTATIN 
CALCIUM TRIHYDRATE 
12872304001 
128723 
 
 
Amaluet No.3 
AMLODIPINE BESILATE; 
ATORVASTATIN 
CALCIUM TRIHYDRATE 
12872304001 
128723 
 
 
Amaluet No.4 
AMLODIPINE BESILATE; 
ATORVASTATIN 
CALCIUM TRIHYDRATE 
12872304001 
128723 
 
 
Atozet LD 
ATORVASTATIN 
CALCIUM; EZETIMIBE 
12872002001 
128720 
 
 
Atozet HD 
ATORVASTATIN 
CALCIUM; EZETIMIBE 
12872002001 
128720 
 
 
Other 
LIPID MODIFYING 
AGENTS, 
COMBINATIONS 
90083401001 
900834 
 
 
Other 
LIPID MODIFYING 
AGENTS, 
COMBINATIONS 
90083401001 
900834 
 
 
Rosuzet LD 
EZETIMIBE; 
ROSUVASTATIN 
CALCIUM 
10641002001 
106410 


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Item 
Category 
CRF Option for 
Drug Name 
(English) 
Preferred Term 
WHODD 
Drug Name 
Preferred 
Term 
WHODD 
Drug Code 
WHODD 
Drug 
Code 
6 digits 
 
 
Rosuzet HD 
EZETIMIBE; 
ROSUVASTATIN 
CALCIUM 
10641002001 
106410 
 
 
 


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Appendix 7 
List of Figures and Tables 
CT-1.1-1 Subject Disposition During Placebo Run-in Period (Informed Subjects) 
CT-1.1-2 Subject Disposition During Placebo Run-in Period by Statin Response 
(Informed Subjects) 
CT-1.2-1 Subject Disposition During Treatment Period (Randomized Subjects) 
CT-1.2-2 Subject Disposition During Treatment Period by Statin Response (Randomized 
Subjects) 
CT-1.3-1 Analysis Set (Randomized Subjects) 
CT-1.3-2 Analysis Set by Statin Response (Randomized Subjects) 
CT-2.1-1 Reasons for Discontinuation During Placebo Run-in Period (Screened Subjects) 
CT-2.1-2 Reasons for Discontinuation During Placebo Run-in Period by Statin Response 
(Screened Subjects) 
CT-2.2-1 Reasons for Discontinuation During Treatment Period (Randomized Subjects) 
CT-2.2-2 Reasons for Discontinuation During Treatment Period by Statin Response 
(Randomized Subjects) 
CT-2.3-1 Summary of Major Protocol Deviations by Type of Deviation (Randomized 
Subjects) 
CT-2.3-2 Summary of Major Protocol Deviations by Type of Deviation by Statin 
Response (Randomized Subjects) 
CT-3.1.1-1 Demographic and Baseline Characteristics (Full Analysis Set) 
CT-3.1.1-2 Demographic and Baseline Characteristics by Statin Response (Full Analysis 
Set) 
CT-3.1.2-1 Demographic and Baseline Characteristics (Safety Analysis Set) 
CT-3.1.2-2 Demographic and Baseline Characteristics by Statin Response (Safety 
Analysis Set) 
CT-3.2.1-1 Baseline Disease Characteristics (Full Analysis Set) 
CT-3.2.1-2 Baseline Disease Characteristics by Statin Response (Full Analysis Set) 
CT-3.2.2-1 Baseline Disease Characteristics (Safety Analysis Set) 
CT-3.2.2-2 Baseline Disease Characteristics by Statin Response (Safety Analysis Set) 


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CT-3.3.1 Symptoms and Medications of Statin Intolerance (Full Analysis Set with Statin 
Intolerance) 
CT-3.3.2 Symptoms and Medications of Statin Intolerance (Safety Analysis Set with 
Statin Intolerance) 
CT-4.1.1-1 Prior Medications (Full Analysis Set) 
CT-4.1.1-2 Prior Medications by Statin Response (Full Analysis Set) 
CT-4.1.2-1 Concomitant Medications (Full Analysis Set) 
CT-4.1.2-2 Concomitant Medications by Statin Response (Full Analysis Set) 
CT-4.2-1 Concomitant Hypercholesterolemic Treatment Medications (Full Analysis Set) 
CT-4.2-2 Concomitant Hypercholesterolemic Treatment Medications by Statin Response 
(Full Analysis Set) 
CT-4.3-1 Concomitant Hypercholesterolemic Treatment Medications (Safety Analysis 
Set) 
CT-4.3-2 Concomitant Hypercholesterolemic Treatment Medications by Statin Response 
(Safety Analysis Set) 
CT-5.1 Primary Analysis: Percent Change From Baseline in LDL-C at Week 12 
(MMRM) (Full Analysis Set) 
CT-5.2-1 Primary Analysis: Percent Change From Baseline in LDL-C (MMRM) (Full 
Analysis Set) 
CT-5.2-2 Primary Analysis: Percent Change From Baseline in LDL-C (MMRM) by 
Statin Response (Full Analysis Set) 
CT-5.3 Sensitivity Analysis of MNAR using Placebo Based Imputation in Percent 
Change From Baseline in LDL-C at Week 12 (Full Analysis Set) 
CT-6.1 Secondary Analysis: Percent Change From Baseline in Efficacy Parameters and 
Incidence of Subjects who Achieved the Target Value in LDL-C at Week 12 (Full 
Analysis Set) 
CT-6.2 Other Efficacy Analysis: Percent Change From Baseline in Efficacy Parameters 
at Week 12 (Full Analysis Set) 
CT-6.3-1 Secondary Analysis: Percent Change From Baseline in Efficacy Parameters 
(MMRM) (Full Analysis Set) 


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CT-6.3-2 Secondary Analysis: Percent Change From Baseline in Efficacy Parameters 
(MMRM) by Statin Response (Full Analysis Set) 
CT-6.4-1 Secondary Analysis: Percent Change From Baseline in Efficacy Parameters 
(ANCOVA) (Full Analysis Set) 
CT-6.4-2 Secondary Analysis: Percent Change From Baseline in Efficacy Parameters 
(ANCOVA) by Statin Response (Full Analysis Set) 
CT-6.5-1 Secondary Analysis: Incidence of Subjects who Achieved the Target Value in 
LDL-C (Full Analysis Set) 
CT-6.5-2 Secondary Analysis: Incidence of Subjects who Achieved the Target Value in 
LDL-C by Statin Response (Full Analysis Set) 
CT-6.6-1 Secondary Analysis: Incidence of Subjects who Achieved the Target Value in 
LDL-C (OC) (Full Analysis Set) 
CT-6.6-2 Secondary Analysis: Incidence of Subjects who Achieved the Target Value in 
LDL-C by Statin Response (OC) (Full Analysis Set) 
CT-6.7-1 Other Efficacy Analysis: Percent Change From Baseline in Efficacy Parameters 
(MMRM) (Full Analysis Set) 
CT-6.7-2 Other Efficacy Analysis: Percent Change From Baseline in Efficacy Parameters 
(MMRM) by Statin Response (Full Analysis Set) 
CT-6.8-1 Exploratory Analysis: Descriptive Statistics for Efficacy Parameters Values, 
Change and Percent Change From Baseline (Full Analysis Set) 
CT-6.8-2 Exploratory Analysis: Descriptive Statistics for Efficacy Parameters Values, 
Change and Percent Change From Baseline by Statin Response (Full Analysis Set) 
CT-6.9-1 Exploratory Analysis: Robust Regression for Efficacy Parameters (Full 
Analysis Set) 
CT-6.9-2 Exploratory Analysis: Robust Regression for Efficacy Parameters by Statin 
Response (Full Analysis Set) 
CT-6.10-1 Subgroup Analysis: Percent Change From Baseline in LDL-C at Week 12 
(MMRM) by Statin Response (Full Analysis Set) 
CT-6.10-2 Subgroup Analysis: Percent Change From Baseline in LDL-C at Week 12 
(MMRM) by Sex (Full Analysis Set) 
CT-6.10-3 Subgroup Analysis: Percent Change From Baseline in LDL-C at Week 12 
(MMRM) by Familial Hypercholesterolemia (Full Analysis Set) 


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CT-6.10-4 Subgroup Analysis: Percent Change From Baseline in LDL-C at Week 12 
(MMRM) by Diabetes Mellitus (Full Analysis Set) 
CT-6.10-5 Subgroup Analysis: Percent Change From Baseline in LDL-C at Week 12 
(MMRM) by Age (Full Analysis Set) 
CT-6.10-6 Subgroup Analysis: Percent Change From Baseline in LDL-C at Week 12 
(MMRM) by Statin Therapy  (Full Analysis Set) 
CT-6.10-7 Subgroup Analysis: Percent Change From Baseline in LDL-C at Week 12 
(MMRM) by BMI (Full Analysis Set) 
CT-6.10-8 Subgroup Analysis: Percent Change From Baseline in LDL-C at Week 12 
(MMRM) by eGFR (Full Analysis Set) 
CT-6.10-9 Subgroup Analysis: Percent Change From Baseline in LDL-C at Week 12 
(MMRM) by Baseline LDL-C (Full Analysis Set) 
CT-6.10-10 Subgroup Analysis: Percent Change From Baseline in LDL-C at Week 12 
(MMRM) by ASCVD (Full Analysis Set) 
CT-6.10-11 Subgroup Analysis: Percent Change From Baseline in LDL-C at Week 12 
(MMRM) by Baseline Statin Intensity (Full Analysis Set) 
CT-6.10-12 Subgroup Analysis: Percent Change From Baseline in LDL-C at Week 12 
(MMRM) by Ezetimibe Therapy (Full Analysis Set) 
CT-6.10-13 Subgroup Analysis: Percent Change From Baseline in LDL-C at Week 12 
(MMRM) by Fibrate Therapy (Full Analysis Set) 
CT-7.1-1 Extent of Exposure to Investigational Medicinal Product (Safety Analysis Set) 
CT-7.1-2 Extent of Exposure to Investigational Medicinal Product by Statin Response 
(Safety Analysis Set) 
CT-7.2-1 Treatment Compliance (Full Analysis Set) 
CT-7.2-2 Treatment Compliance by Statin Response (Full Analysis Set) 
CT-7.3-1 Hypercholesterolemic Treatment Compliance (Full Analysis Set) 
CT-7.3-2 Hypercholesterolemic Treatment Compliance by Statin Response (Full 
Analysis Set) 
CT-8.1-1 Overall Summary of Adverse Events (Safety Analysis Set) 
CT-8.1-2 Overall Summary of Adverse Events by Statin Response (Safety Analysis Set) 


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CT-8.2-1 Incidence of TEAEs by MedDRA System Organ Class and Preferred Term 
(Safety Analysis Set) 
CT-8.2-2 Incidence of TEAEs by MedDRA System Organ Class and Preferred Term by 
Statin Response (Safety Analysis Set) 
CT-8.2-3 Incidence of TEAEs of at Least 5% in Any Group by MedDRA System Organ 
Class and Preferred Term (Safety Analysis Set) 
CT-8.2-4 Incidence of TEAEs of at Least 5% in Any Group by MedDRA System Organ 
Class and Preferred Term by Statin Response (Safety Analysis Set) 
CT-8.3-1 Incidence of IMP-related TEAEs by MedDRA System Organ Class and 
Preferred Term (Safety Analysis Set) 
CT-8.3-2 Incidence of IMP-related TEAEs by MedDRA System Organ Class and 
Preferred Term by Statin Response (Safety Analysis Set) 
CT-8.3-3 Incidence of IMP-related TEAEs of at Least 5% in Any Group by MedDRA 
System Organ Class and Preferred Term (Safety Analysis Set) 
CT-8.3-4 Incidence of IMP-related TEAEs of at Least 5% in Any Group by MedDRA 
System Organ Class and Preferred Term by Statin Response (Safety Analysis Set) 
CT-8.4-1 Incidence of TEAEs by Severity by MedDRA System Organ Class and 
Preferred Term (Safety Analysis Set) 
CT-8.4-2 Incidence of TEAEs by Severity by MedDRA System Organ Class and 
Preferred Term by Statin Response (Safety Analysis Set) 
CT-8.5-1 Incidence of IMP-related TEAEs by Severity by MedDRA System Organ Class 
and Preferred Term (Safety Analysis Set) 
CT-8.5-2 Incidence of IMP-related TEAEs by Severity by MedDRA System Organ Class 
and Preferred Term by Statin Response (Safety Analysis Set) 
CT-8.6-1 Incidence of TEAEs With an Outcome of Death by MedDRA System Organ 
Class and Preferred Term (Safety Analysis Set) 
CT-8.6-2 Incidence of TEAEs With an Outcome of Death by MedDRA System Organ 
Class and Preferred Term by Statin Response (Safety Analysis Set) 
CT-8.7-1 Incidence of IMP-related TEAEs With an Outcome of Death by MedDRA 
System Organ Class and Preferred Term (Safety Analysis Set) 
CT-8.7-2 Incidence of IMP-related TEAEs With an Outcome of Death by MedDRA 
System Organ Class and Preferred Term by Statin Response (Safety Analysis Set) 


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CT-8.8-1 Incidence of Serious TEAEs by MedDRA System Organ Class and Preferred 
Term (Safety Analysis Set) 
CT-8.8-2 Incidence of Serious TEAEs by MedDRA System Organ Class and Preferred 
Term by Statin Response (Safety Analysis Set) 
CT-8.9-1 Incidence of IMP-related Serious TEAEs by MedDRA System Organ Class and 
Preferred Term (Safety Analysis Set) 
CT-8.9-2 Incidence of IMP-related Serious TEAEs by MedDRA System Organ Class and 
Preferred Term by Statin Response (Safety Analysis Set) 
CT-8.10-1 Incidence of TEAEs Leading to Discontinuation of Investigational Medicinal 
Product Administration by MedDRA System Organ Class and Preferred Term (Safety 
Analysis Set) 
CT-8.10-2 Incidence of TEAEs Leading to Discontinuation of Investigational Medicinal 
Product Administration by MedDRA System Organ Class and Preferred Term by Statin 
Response (Safety Analysis Set) 
CT-8.11-1 Incidence of IMP-related TEAEs Leading to Discontinuation of 
Investigational Medicinal Product Administration by MedDRA System Organ Class and 
Preferred Term (Safety Analysis Set) 
CT-8.11-2 Incidence of IMP-related TEAEs Leading to Discontinuation of 
Investigational Medicinal Product Administration by MedDRA System Organ Class and 
Preferred Term by Statin Response (Safety Analysis Set) 
CT-8.12-1 Incidence of AESIs by MedDRA System Organ Class and Preferred Term 
(Safety Analysis Set) 
CT-8.12-2 Incidence of AESIs by MedDRA System Organ Class and Preferred Term by 
Statin Response (Safety Analysis Set) 
CT-8.13-1 Incidence of IMP-related AESIs by MedDRA System Organ Class and 
Preferred Term (Safety Analysis Set) 
CT-8.13-2 Incidence of IMP-related AESIs by MedDRA System Organ Class and 
Preferred Term by Statin Response (Safety Analysis Set) 
CT-8.14-1 Incidence of TEAEs of Non-Side Effect From COVID-19 Vaccine by 
MedDRA System Organ Class and Preferred Term (Safety Analysis Set) 


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CT-8.14-2 Incidence of TEAEs of Non-Side Effect From COVID-19 Vaccine by 
MedDRA System Organ Class and Preferred Term by Statin Response (Safety Analysis 
Set) 
CT-9.1 Listing of Deaths (Safety Analysis Set) 
CT-9.2 Listing of Serious Adverse Events Other Than Death (Safety Analysis Set) 
CT-9.3 Listing of Discontinuations Due to Adverse Events (Safety Analysis Set) 
CT-10.1.1-1 Descriptive Statistics for Clinical Laboratory Test Results - Serum 
Chemistry (Safety Analysis Set) 
CT-10.1.1-2 Descriptive Statistics for Clinical Laboratory Test Results by Statin 
Response - Serum Chemistry (Safety Analysis Set) 
CT-10.1.2-1 Descriptive Statistics for Clinical Laboratory Test Results - Hematology 
(Safety Analysis Set) 
CT-10.1.2-2 Descriptive Statistics for Clinical Laboratory Test Results by Statin 
Response - Hematology (Safety Analysis Set) 
CT-10.1.3-1 Descriptive Statistics for Clinical Laboratory Test Results - Urinalysis 
(Safety Analysis Set) 
CT-10.1.3-2 Descriptive Statistics for Clinical Laboratory Test Results by Statin 
Response - Urinalysis (Safety Analysis Set) 
CT-10.2.1-1 Shift Tables of Clinical Laboratory Test Results - Serum Chemistry (Safety 
Analysis Set) 
CT-10.2.1-2 Shift Tables of Clinical Laboratory Test Results by Statin Response - Serum 
Chemistry (Safety Analysis Set) 
CT-10.2.2-1 Shift Tables of Clinical Laboratory Test Results - Hematology (Safety 
Analysis Set) 
CT-10.2.2-2 Shift Tables of Clinical Laboratory Test Results by Statin Response - 
Hematology (Safety Analysis Set) 
CT-10.2.3-1 Shift Tables of Clinical Laboratory Test Results - Urinalysis (Safety 
Analysis Set) 
CT-10.2.3-2 Shift Tables of Clinical Laboratory Test Results by Statin Response - 
Urinalysis (Safety Analysis Set) 


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CT-10.2.4-1 Shift Tables of Clinical Laboratory Test Results - Qualitative Urinalysis 
(Safety Analysis Set) 
CT-10.2.4-2 Shift Tables of Clinical Laboratory Test Results by Statin Response - 
Qualitative Urinalysis (Safety Analysis Set) 
CT-10.3-1 Incidence of Potentially Clinically Significant Abnormalities in Laboratory 
Tests (Safety Analysis Set) 
CT-10.3-2 Incidence of Potentially Clinically Significant Abnormalities in Laboratory 
Tests by Statin Response (Safety Analysis Set) 
CT-10.4 Listing of Abnormal Laboratory Findings (Safety Analysis Set) 
CT-11.1-1 Descriptive Statistics for Vital Signs (Safety Analysis Set) 
CT-11.1-2 Descriptive Statistics for Vital Signs by Statin Response (Safety Analysis Set) 
CT-11.2-1 Incidence of Potentially Clinically Significant Abnormalities in Vital Signs 
(Safety Analysis Set) 
CT-11.2-2 Incidence of Potentially Clinically Significant Abnormalities in Vital Signs by 
Statin Response (Safety Analysis Set) 
CT-11.3-1 Descriptive Statistics for Body Weight (Safety Analysis Set) 
CT-11.3-2 Descriptive Statistics for Body Weight by Statin Response (Safety Analysis 
Set) 
CT-11.4-1 Incidence of Potentially Clinically Significant Abnormalities in Body Weight 
(Safety Analysis Set) 
CT-11.4-2 Incidence of Potentially Clinically Significant Abnormalities in Body Weight 
by Statin Response (Safety Analysis Set) 
CT-12.1-1 Descriptive Statistics for ECG Parameters (Safety Analysis Set) 
CT-12.1-2 Descriptive Statistics for ECG Parameters by Statin Response (Safety 
Analysis Set) 
CT-12.2-1 Categorical Analysis of ECG - QTcF (Safety Analysis Set) 
CT-12.2-2 Categorical Analysis of ECG by Statin Response - QTcF  (Safety Analysis 
Set) 
CT-12.3-1 Shift Table of ECG Findings (Normal/Abnormal Assessments) (Safety 
Analysis Set) 


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CT-12.3-2 Shift Table of ECG Findings (Normal/Abnormal Assessments) by Statin 
Response (Safety Analysis Set) 
CT-12.4-1 Incidence of Potentially Clinically Significant Abnormalities in ECG 
Parameters (Safety Analysis Set) 
CT-12.4-2 Incidence of Potentially Clinically Significant Abnormalities in ECG 
Parameters by Statin Response (Safety Analysis Set) 
CF-1-1 Percent Change From Baseline by Visit in Efficacy Parameters (LSMean+-SE) 
(Full Analysis Set) 
CF-1-2 Percent Change From Baseline by Visit in Efficacy Parameters (LSMean+-SE) 
by Statin Response (Full Analysis Set) 
 
 


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Appendix 8 
List of Subject Data Listings 
DREAS-1 Discontinued Subjects and Reason for Discontinuation (Screened Subjects) 
SUBEX-1 Subjects Excluded From Analysis Set (Randomized Subjects) 
DEMOG-1 Demographic Characteristics (Screened Subjects) 
SMED-1 Investigational Medicinal Product Compliance (Screened Subjects) 
SMED-2.1 Prior Hypercholesterolemic Treatment (Screened Subjects) 
SMED-2.2 Hypercholesterolemic Treatment Compliance (Screened Subjects) 
EFF-1.1 Listing of Primary Efficacy Endpoint - LDL-C (Randomized Subjects) 
EFF-1.2 Listing of Efficacy Endpoints Other Than LDL-C (Randomized Subjects) 
AE-1 Adverse Events (Informed Subjects) 
LAB-1.1 Laboratory Values (Hematology) (Screened Subjects) 
LAB-1.2 Laboratory Values (Blood Chemistry) (Screened Subjects) 
LAB-1.3 Laboratory Values (Urinalysis) (Screened Subjects) 
LAB-2 Laboratory Values (Fasting Lipid) (Screened Subjects) 
PDATA-1 Study Completion Status and Reason for Discontinuation (Screened Subjects) 
PDATA-2 Inclusion Criteria and Exclusion Criteria Not Met  
PDATA-3.1 Medical History (Hypercholesterolemia) (Informed Subjects) 
PDATA-3.2 Medical History (Screened Subjects) 
PDATA-4 Physical Examination (Screened Subjects) 
PDATA-5.1 Prior and Concomitant Medication (Screened Subjects) 
PDATA-5.2 Prior and Concomitant Therapy (Screened Subjects) 
PDATA-6 Vital Signs and Body Weight (Screened Subjects) 
PDATA-7 12-Lead ECG Parameters and Findings (Screened Subjects) 
PDATA-8 Pregnancy Test (Screened Subjects) 
PDATA-9 TSH and Virus Test (Screened Subjects) 
PDATA-10 Blood Draw Time for Biomarker and DNA storage (Screened Subjects) 
PDATA-11 Screen Failures  
PDATA-12 Post-treatment Follow-up (Randomized Subjects) 


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PDATA-13 Randomization (Randomized Subjects) 
PDEV-1 Protocol Deviations (Screened Subjects)