Clinical trial NCT02839902
Conditions: Hyperlipidemia
Sponsor: Takeda
Start date: 2016-12-27; Completion date: 2017-08-30
Enrollment: 53 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to explore the effects of 8-week treatment with omega-3-acid ethyl esters on the lipid and lipoprotein profile in the blood in hyperlipidemic patients receiving a HMG-CoA reductase inhibitor by use of HPLC in comparison with the control group of patients not treated with omega-3-acid ethyl esters.

Detailed description:
This study was designed to explore the effects of omega-3-acid ethyl esters on the lipid and lipoprotein profile in the blood in hyperlipidemic patients receiving a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor in comparison with the control group of patients not treated with omega-3-acid ethyl esters in an unblinded manner by use of high performance liquid chromatography (HPLC) using highly-sensitive gel filtration columns, which is a technique for analyzing lipoprotein.

Study participants who gave consent and were assessed as eligible in the eligibility assessment will be stratified by the factors of "fasting triacylglycerol (TG; \<300 mg/dL or 300 mg/dL≤) and age (\<65 years or 65 years≤) at the start of the screening period" and allocated to either the group treated with omega-3-acid ethyl esters or the group not treated with omega-3-acid ethyl esters (1:1 ratio).

Arms: arm 1: A dose of 2 g of omega-3-acid ethyl esters (TAK-085) capsule is orally administered immediately after meal twice a daily (totally 4g per a day) for 8 weeks, plus a stable HMG-CoA reductase inhibitor regimen (started ≥4 weeks prior to informed consent) at a consistent dose. arm 2: Stable HMG-CoA reductase inhibitor regimen at a consistent dose only.
Interventions: intervention 1: TAK-085 intervention 2: Not treated with omega-3-acid ethyl esters
Intervention descriptions: intervention 1: Omega-3-acid ethyl esters (TAK-085) capsule intervention 2: Not treated with omega-3-acid ethyl esters

Protocol documents:
Prot_000.pdf: 
 
 
Title: Lipoprotein-Modifying Effects of Omega-3 Fatty Acids Ethyl Esters Analyzed by 
High Performance Liquid Chromatography in Patients with Hypertriglyceridemia 
(LOTUS) 
 
NCT Number: NCT02839902 
Protocol Approve Date: 07-Jul-2016 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 


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PROTOCOL 
 
 
 
 
Lipoprotein-Modifying Effects of Omega-3 Fatty Acids Ethyl Esters Analyzed by 
High Performance Liquid Chromatography in Patients with Hypertriglyceridemia 
(LOTUS) 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
12-10 Nihonbashi 2-chome, Chuo-ku, Tokyo 
Protocol number 
TAK-085-4002 
Version number/Revision number 
Version 1 
Study drug 
Omega-3-acid ethyl esters 
Creation date 
July 7, 2016 
 
 
 
 
 


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CONFIDENTIAL PROPERTY 
This document is a confidential communication of Takeda. Acceptance of this document constitutes 
agreement by the potential recipient that no information contained herein will be published or 
disclosed without written authorization from Takeda except to the extent necessary to obtain 
informed consent from those study subjects to whom the drug may be administered. Furthermore, 
the information is only intended for review and compliance by the recipient, his or her staff, and 
applicable institutional review committee and regulatory agencies to enable conduction of the study. 


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1.0 
STUDY ADMINISTRATIVE INFORMATION AND CLINICAL STUDY 
PRINCIPLES 
1.1 
Clinical study principles 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
Ethical Guideline for Clinical Research (the Ministry of Education, Culture, Sports, Science and 
Technology and the Ministry of Health, Labour and Welfare, December 22, 2014). 
• 
Good Clinical Practice: Consolidated Guideline (ICH: International Conference on 
Harmonization of Technical Requirement for Registration on Pharmaceuticals for Human Use. 
E6) 
• 
All applicable laws and regulations, including, without limitation, data privacy laws and conflict 
of interest guidelines. 
 
1.2 
Clinical study implementation system 
This study will be conducted in accordance with the requirements of this clinical study protocol 
designed and prepared by the sponsor and also in accordance with the following: 
Sponsor 
Takeda Pharmaceutical Company Limited 
Japan Pharma Business Unit 
Strategic Medical Research Planning Group, Medical Affairs Department 
 
The sponsor shall be responsible for matters related to planning/preparation, 
implementation/operation, and results/reporting in this clinical study. Methods of supervision of the 
contractor entrusted with the services related to this clinical study will be described in the procedure 
to be prepared separately. 
Expenses* required for the operation of this clinical study will be paid by the sponsor. 
* :  Based on the “Consignment Service Contract,” expenses incurred for the services of Office of 
Clinical Study, monitoring, registration/allocation center, statistical processing, and audit shall 


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be paid to the contractor entrusted with services related to this clinical study. Expenses agreed by 
the study site shall be paid to the site based on the “Research Expense Standard.” 
 
 
Chair of the Clinical Study Steering Committee: 
Member of the Clinical Study Steering Committee: 
 
The chair and member of the Clinical Study Steering Committee shall supervise implementation and 
reporting of the clinical study, secure medical guidance of a high degree of professionalism and a 
high-level scientific quality, and revise the study protocol appropriately. 
 
Terms in this protocol are defined as follows: 
Study site: 
A corporation, governmental agency and sole proprietor conducting the study, excluding cases 
where only a part of the services related to storage of samples/information, statistical processing 
and other studies is entrusted. 
Collaborative study site: 
A study site that conducts collaborative study in accordance with the protocol, including a study 
site that obtains new samples/information from study subjects and provides other study sites. 
Investigators, etc: 
Principal investigators and other parties involved in conduction of the study (including operations 
at institutions involved in collection/distribution of samples/information). Those involved only in 
providing existing samples/information outside the study sites and those engaged in part of the 
entrusted operations related to the study are excluded. 
Principal Investigator: 
PPD
PPD


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An investigator who is engaged in implementation of the study and integrates the operations 
involved in this study at an affiliated study site. 
Chief executive of the study site: 
A representative of a corporation, head of a governmental agency, or a sole proprietor 
Study subject: 
A subject (including a dead subject) who meets any of the following:  
1. 
Subjects being studied (including those who have been asked to be studied)  
2. 
Subjects from whom existing samples/information to be used in the study have been 
obtained. 
 


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Table of Contents 
1.0 
STUDY ADMINISTRATIVE INFORMATION AND CLINICAL STUDY 
PRINCIPLES ........................................................................................................... 3 
1.1 
Clinical study principles .................................................................................... 3 
1.2 
Clinical study implementation system ............................................................... 3 
2.0 
STUDY SUMMARY ............................................................................................ 11 
3.0 
ABBREVIATION ................................................................................................. 16 
4.0 
INTRODUCTION ................................................................................................. 17 
4.1 
Background ...................................................................................................... 17 
4.2 
Rationale for the proposed study ..................................................................... 17 
5.0 
STUDY OBJECTIVES AND ENDPOINTS ........................................................ 18 
5.1 
Objectives ........................................................................................................ 18 
5.2 
Definition of endpoints .................................................................................... 18 
5.2.1 Primary endpoints ...................................................................................... 18 
5.2.2 Secondary endpoints .................................................................................. 18 
5.2.3 Safety endpoints ........................................................................................ 18 
6.0 
CLINICAL STUDY DESIGN............................................................................... 19 
6.1 
Clinical study design ....................................................................................... 19 
6.2 
Rationale for the clinical study design ............................................................ 21 
6.3 
Premature termination of entire clinical study or premature termination 
of clinical study at a study site ........................................................................ 22 
6.3.1 Premature termination criteria of entire clinical study .............................. 22 
6.3.2 Criteria for premature termination of study sites....................................... 22 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or clinical study at a study site .................................. 22 
6.4 
Procedures for protocol revision ..................................................................... 23 
7.0 
SELECTION AND WITHDRAWAL CRITERIA OF STUDY SUBJECTS ....... 24 
7.1 
Inclusion criteria .............................................................................................. 24 
7.2 
Exclusion criteria ............................................................................................. 25 
7.3 
Prohibited concomitant drugs and permitted concomitant drugs .................... 27 
7.3.1 Prohibited concomitant drugs .................................................................... 27 


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7.3.2 Permitted concomitant drugs ..................................................................... 27 
7.4 
Study subject management .............................................................................. 27 
7.5 
Criteria for discontinuation or withdrawal of a study subject ......................... 28 
7.6 
Procedures for discontinuation of individual study subjects ........................... 29 
8.0 
STUDY TREATMENT ......................................................................................... 31 
8.1 
Study drug ....................................................................................................... 31 
8.1.1 Dose and administration method ............................................................... 31 
8.1.2 Concomitant drugs ..................................................................................... 31 
8.1.3 Overdose of the study drug ........................................................................ 31 
8.2 
Allocation of the study drug and administration procedure ............................ 32 
8.3 
Preparation and storage of allocation list ........................................................ 32 
9.0 
CLINICAL STUDY PROTOCOL ........................................................................ 33 
9.1 
Clinical study procedures ................................................................................ 33 
9.1.1 Informed consent ....................................................................................... 33 
9.1.2 Demographic data, medical history, and previous treatment drugs .......... 33 
9.1.3 Physical examination ................................................................................. 33 
9.1.4 Body weight, height, and BMI .................................................................. 33 
9.1.5 Vital signs .................................................................................................. 34 
9.1.6 Concomitant drugs ..................................................................................... 34 
9.1.7 Concurrent disease ..................................................................................... 34 
9.1.8 Food and drink consumption before the visit ............................................ 34 
9.1.9 Laboratory tests and the specific 20-lipoprotein fraction assay ................ 35 
9.1.10 Record of study subjects who are withdrawn before randomization......... 35 
9.1.11 Record of randomization ........................................................................... 35 
9.1.12 Contraception ............................................................................................ 35 
9.1.13 Pregnancy .................................................................................................. 36 
9.2 
Compliance with study treatment of study subjects ........................................ 37 
9.3 
Implementation time point of the tests and observation .................................. 37 
9.3.1 Screening period (Visit 1).......................................................................... 37 
9.3.2 Treatment period (Visit 2) ......................................................................... 38 
9.3.3 Treatment period (Visit 3) ......................................................................... 38 


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9.3.4 Completion (Visit 4) or discontinuation .................................................... 39 
10.0 
ADVERSE EVENTS ............................................................................................ 40 
10.1 
Definitions ....................................................................................................... 40 
10.1.1 Adverse events ........................................................................................... 40 
10.1.2 Considerations for adverse events ............................................................. 40 
10.1.3 Serious adverse event ................................................................................ 42 
10.1.4 Severity of adverse events ......................................................................... 43 
10.1.5 Causality of adverse events ....................................................................... 43 
10.1.6 Relationship to study procedures ............................................................... 44 
10.1.7 Date of onset .............................................................................................. 44 
10.1.8 Date of resolution ...................................................................................... 44 
10.1.9 Actions taken for the study drug................................................................ 44 
10.1.10Outcome .................................................................................................... 45 
10.2 
Procedures ....................................................................................................... 46 
10.2.1 Collection and reporting of adverse events ............................................... 46 
10.2.2 Collection and reporting of serious adverse events ................................... 46 
10.2.3 Reporting of additional information concerning adverse events ............... 47 
10.3 
Follow-up of serious adverse events ............................................................... 47 
10.3.1 Reporting of serious adverse events to Ethical Review Board, etc., 
and regulatory authorities .......................................................................... 47 
11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY ........................................ 49 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS ............................... 50 
12.1 
Case report form .............................................................................................. 50 
12.2 
Timing of data entry into the EDC system ...................................................... 51 
12.3 
Storage of records ............................................................................................ 51 
13.0 
STATISTICAL ANALYSIS METHODS ............................................................. 52 
13.1 
Statistical and analytical plans ......................................................................... 52 
13.1.1 Analysis set ................................................................................................ 52 
13.1.2 Analysis of demographic and other baseline characteristics ..................... 52 
13.1.3 Efficacy analysis ........................................................................................ 52 
13.1.4 Safety analysis ........................................................................................... 53 


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13.2 
Criteria for interim analysis and premature discontinuation ........................... 54 
13.3 
Determination of the number of planned study subject ................................... 54 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 55 
14.1 
Monitoring of the study site ............................................................................ 55 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the study protocol .......................................... 55 
14.3 
Quality assurance audits and regulatory agency inspections........................... 55 
15.0 
ETHICAL CONDUCT OF CLINICAL STUDY .................................................. 57 
15.1 
Approval of the Ethical Review Board, etc. .................................................... 57 
15.2 
Conflict of interest ........................................................................................... 58 
15.3 
Informed consent form and information sheet, and the agreement of the 
study subjects ................................................................................................... 58 
15.4 
Personal information of the study subjects ...................................................... 59 
15.5 
Consultation windows for the study subjects or persons related to the 
study concerned ............................................................................................... 60 
15.6 
Financial burden or reward to the study subjects ............................................ 60 
15.7 
Benefits and inconveniences to the study subjects .......................................... 60 
15.7.1 Benefits to study subjects .......................................................................... 60 
15.7.2 Inconveniences to study subjects ............................................................... 60 
15.8 
Attribution of study results and access rights .................................................. 60 
15.8.1 Attribution of study results ........................................................................ 60 
15.8.2 Data access rights ...................................................................................... 60 
15.9 
Reporting of results, publication, disclosure, and clinical study 
registration policy ............................................................................................ 61 
15.9.1 Reporting of results, publication and disclosure ....................................... 61 
15.9.2 Clinical study registration .......................................................................... 61 
15.9.3 Clinical trial results disclosure .................................................................. 61 
15.10 Insurance and compensation for injury ........................................................... 61 
16.0 
REFERENCES ...................................................................................................... 63 


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LIST OF IN-TEXT TABLES 
Table 9.a 
Laboratory tests ......................................................................................... 35 
Table 10.a 
Takeda Medically Significant AE List ...................................................... 43 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Outline of the clinical study design ........................................................... 20 
LIST OF APPENDICES 
Appendix A 
Schedule for Study Procedures .................................................................. 64 


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2.0 
STUDY SUMMARY 
Sponsor: 
Takeda Pharmaceutical Company Limited 
Study drug: 
Omega-3-acid ethyl esters 
Study title: Exploratory study of the effects of omega-3-acid ethyl esters on the lipid and lipoprotein 
profile in the blood 
Protocol number: TAK-085-4002 
Clinical study design: 
To explore the effects of omega-3-acid ethyl esters on the lipid and lipoprotein profile in the blood in 
hyperlipidemic patients receiving a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase 
inhibitor in comparison with the control group of patients not treated with omega-3-acid ethyl esters 
in an unblinded manner by use of high performance liquid chromatography (HPLC) using 
highly-sensitive gel filtration columns, which is a technique for analyzing lipoprotein. 
Study subjects who gave consent and were assessed as eligible in the eligibility assessment will be 
stratified by the factors of “fasting triacylglycerol (TG; < 300 mg/dL or ≥ 300 mg/dL) and age (< 65 
years or ≥ 65 years) at the start of the screening period” and allocated to either the group treated with 
omega-3-acid ethyl esters or the group not treated with omega-3-acid ethyl esters (1:1 ratio). 
Objectives: 
To explore the effects of 8-week treatment with omega-3-acid ethyl esters on the lipid and 
lipoprotein profile in the blood in hyperlipidemic patients receiving a HMG-CoA reductase inhibitor 
by use of HPLC in comparison with the control group of patients not treated with omega-3-acid 
ethyl esters. 
Subjects: Hyperlipidemic patients receiving a HMG-CoA reductase inhibitor 
Planned number of study subjects: 
50 patients evaluable for the primary endpoint 
(25 patients in the group treated with omega-3-acid 
ethyl esters, 25 patients in the group not treated with 
omega-3-acid ethyl esters) 
Number of study sites: 
Around 5 sites  
 
Dose and method of administration: 
Omega-3-acid ethyl esters 2 g is orally administered 
immediately after meal twice daily. 
Route of administration: 
Oral 
Duration of treatment: 
8 weeks 
Duration of evaluation: 
Screening period: 4 weeks 


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Treatment period: 8 weeks 
Total: 12 weeks 
Main criteria for inclusion: 
1. 
Patients diagnosed as hyperlipidemia. 
2. 
Patients constantly receiving a HMG-CoA reductase inhibitor at a stable dose for at least 4 
weeks at the start of observation period. 
3. 
Patients with fasting TG of 150≤ to <400 mg/dL measured at the start of observation period at 
Visit 1 (Week -4). 
4. 
Patients who, in the opinion of the principal investigator or the investigator, are capable of 
understanding the content of the clinical study and complying with the study protocol 
requirements. 
5. 
Patients who can provide written informed consent prior to the conduction of the clinical study 
procedures. 
6. 
Patients aged ≥20 years at the time of informed consent. 
Main criteria for exclusion: 
1. 
Patients who had clinically significant hemorrhagic disorders (e.g., hemophilia, capillary 
fragility, gastrointestinal ulcer, urinary tract hemorrhage, hemoptysis, and vitreous hemorrhage) 
within 24 weeks prior to the start of observation period, or those who concurrently have the 
above disorders. 
2. 
Patients who had thyroid disorders (hyperthyroidism or hypothyroidism) within 24 weeks prior 
to the start of observation period, those who concurrently have the above disorders, or those 
who are orally receiving a therapeutic drug for thyroid disorder. 
3. 
Patients in whom the type of HMG-CoA reductase inhibitors was changed within 12 weeks 
prior to the start of observation period. 
4. 
Patients who received an eicosapentaenoic acid (EPA) preparation or an EPA/docosahexaenoic 
acid (DHA) preparation (including supplements) within 12 weeks prior to the start of 
observation period. 
5. 
Patients who started antidyslipidemic agents within 4 weeks prior to the start of observation 
period. 
6. 
Patients with severe hepatic impairment (e.g., Child-Pugh classification C) 
7. 
Patients who were previously diagnosed as lipoprotein lipase deficiency or apoprotein C-II 
deficiency. 


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8. 
Patients who are concurrently having Cushing's syndrome, uremia, systemic lupus 
erythematosus (SLE), or serum dysproteinemia. 
9. 
Diabetic patients who are currently receiving thiazolidine or insulin. 
10. Patients who are concurrently having hypertension of grade IIINote 1). 
Note 1: Patients with systolic blood pressure of ≥180 mm Hg or diastolic blood pressure of 
≥110 mm Hg regardless of treatment with antihypertensive drugs. 
11. Patients who are habitual drinkers drinking an average of over 100 mL per day (expressed in 
terms of quantity of alcohol), or patients with or with a history of drug abuse or addiction. 
12. Pregnant, lactating or postmenopausal women. 
13. Patients with a history of hypersensitivity or allergy for omega-3-acid ethyl esters. 
14. Patients participating in other clinical studies 
15. Patients assessed ineligible in the study by the principal investigator or the investigator  
STATISTICAL ANALYSIS METHODS: 
(1) Analysis set 
Two analysis sets, “Full Analysis Set (FAS)” and “Safety Analysis Set (SAS)” are used in this study. 
Define FAS as the population of enrolled study subjects who satisfy the following criterion: 
- Study subjects who were randomized and given at least one dose of the study drug. 
Define SAS as the population of enrolled study subjects who satisfy the following criterion: 
- Study subjects who were given at least one dose of the study drug during this clinical study. 
 
(2) Efficacy analysis 
[Primary endpoints] 
Change in mean particle sizes of small dense LDL (sdLDL)-C and LDL-C in the specific 
20-lipoprotein fraction assay 
[Analytical method] 
1) 
At each evaluation time point during the treatment period, summary statistics (number of 
subjects, mean, standard deviation [SD], minimum value, maximum value, quartiles) and a 
two-sided 95% confidence interval for the mean will be calculated in each treatment group, and 
a diagram illustrating the change in the mean ± SD will be prepared. 
2) 
At each evaluation time point during the treatment period, percentage of change from baseline 
will be calculated and analyzed in the same manner as in the above 1). 


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3) 
At each evaluation time point during the treatment period, study subjects will be stratified by 
fasting TG and ages at the start of study drug administration, and summary statistics (number of 
subjects, mean, SD, minimum value, maximum value, quartiles) and a two-sided 95% 
confidence interval for the mean will be calculated and analyzed in each treatment group. 
4) 
At each evaluation time point during the treatment period, percentage of change from baseline 
will be calculated and analyzed in the same manner as in the above 3). 
[Secondary endpoints] 
1) Change in major lipid constituents in the specific 20-lipoprotein fraction assay 
2) Change in fatty acids and sdLDL-C in total lipids 
3) Change in concentration and particle number of lipids, apoprotein and lipoprotein in the 
blood 
[Analytical method] 
1) 
At each evaluation time point during the treatment period, summary statistics (number of 
subjects, mean, SD, minimum value, maximum value, quartiles) and a two-sided 95% 
confidence interval for the mean will be calculated in each treatment group, and a diagram 
illustrating the change in the mean ± SD will be prepared. 
2) 
At each evaluation time point during the treatment period, percentage of change from baseline 
will be calculated and analyzed in the same manner as in the above 1). 
3) 
At each evaluation time point during the treatment period, study subjects will be stratified by 
fasting TG and ages at the start of study drug administration, and summary statistics (number of 
subjects, mean, SD, minimum value, maximum value, quartiles) and a two-sided 95% 
confidence interval for the mean will be calculated and analyzed in each treatment group. 
(3) Analysis of safety endpoints 
[Adverse events] 
The following analyses will be performed for each treatment group. Adverse events will be coded 
using Medical Dictionary for Regulatory Activities (MedDRA) and summarized by System Organ 
Class (SOC) and Preferred Term (PT). 
 
Tabulation of frequency of all adverse events 
 
Tabulation of frequency of adverse events with a causal relationship to the study drug 
 
Tabulation of frequency of all adverse events by severity 
 
Tabulation of frequency of adverse events with a causal relationship to the study drug by 
severity 
 
Tabulation of frequency of adverse events leading to study drug discontinuation 


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 
Tabulation of frequency of serious adverse events 
 
Tabulation of frequency of all adverse events by time of onset 
Rationale for the number of planned study subjects: 
The number of planned study subjects is based on the feasibility to explore the effects of 
omega-3-acid ethyl esters on the lipid and lipoprotein profile in the blood. The number of planned 
study subjects is same in the group treated with omega-3-acid ethyl esters and the group not treated 
with omega-3-acid ethyl esters, which is not based on a statistical consideration.  


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3.0 
ABBREVIATION 
AE 
adverse event 
BMI 
body mass index 
CKD 
chronic kidney disease 
COI 
conflict of interest 
CRO 
contract research organization 
DHA 
docosahexaenoic acid 
EDC 
electronic data capture 
EPA 
eicosapentaenoic acid 
FAS 
full analysis set 
FMD 
flow mediated dilation  
GCP 
Good Clinical Practice 
HDL-C 
high density lipoprotein-cholesterol 
ICH 
International Conference on Harmonisation 
JAPIC 
Japan Pharmaceutical Information Center 
LDL-C 
low density lipoprotein-cholesterol 
MedDRA 
Medical Dictionary for Regulatory Activities 
PT 
Preferred Term 
SAS 
safety analysis set  
sdLDL 
small dense low density lipoprotein 
SLE 
systemic lupus erythematosus 
SOC 
System Organ Class 
TG 
triacylglycerol 


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4.0 
INTRODUCTION 
4.1 
Background 
In recent years, metabolic syndrome has been socially concerned, posing multiple risks including 
for coronary artery disease in association with visceral obesity-induced insulin resistance. 
Dyslipidemia, characteristically observed, represents a series of abnormal findings including 
increased TG, decreased HDL-C, sdLDL and remnant cholesterol in the blood. When one becomes 
highly resistant to insulin, TG increases and LDL quality alters, i.e., sdLDL with particles with small 
diameters increases. SdLDL is easily engulfed by macrophages and thus may accelerate formation of 
atherosclerotic plaque. Among other LDL, sdLDL is a small particle with the mean diameter of 
≤25.5 nm. An overseas report showed 3-fold higher incidence of myocardial infarction in the patient 
population predominantly having sdLDL.1) There is another report that sdLDL was found in ≥70% 
of Japanese patients with myocardial infarction2), suggesting importance of measurement of particle 
sizes of LDL as a part of risk assessment for coronary artery disease. 
Given the above situation, especially after LDL-C was successfully lowered with a HMG-CoA 
reductase inhibitor, it may be important to lower sdLDL in order for further reduction of coronary 
artery disease risk. Recently, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that are 
omega-3 fatty acids have been highlighted as drugs having such activity. EPA and DHA have 
TG-lowering and antiatherosclerosis activities but the mechanism has not been completely 
elucidated. Omega-3-acid ethyl esters (an EPA/DHA preparation, Lotriga®) released in 2013 lower 
TG levels in a dose-dependent manner3) and are expected to have the potential to lower RLP, enlarge 
the LDL particle size, improve FMD, and lower IL-6 levels for example.4) 
The outcomes previously obtained in clinical studies for omega-3-acid ethyl esters indicated that 
efficacy of the product is comparable to of an EPA-E preparation in hyperlipidemic patients for 
which an EPA preparation is indicated. However, change and course of LDL-C after administration 
of omega-3-acid ethyl esters are remain to be elucidated.5) 
In this clinical study, Lotriga® (an EPA/DHA preparation) will be administered to hyperlipidemic 
patients receiving a HMG-CoA reductase inhibitor, and the specific 20-lipoprotein fraction including 
sdLDL will be assayed with HPLC using gel filtration columns, an established assay for precise 
analysis6), for exploration of “quality of lipids,” i.e., numbers of particles of lipids and lipoprotein in 
the blood and their change. 
4.2 
Rationale for the proposed study 
This clinical study was planned to explore the effects of omega-3-acid ethyl esters on the lipid and 
lipoprotein (including sdLDL) profile in the blood in hyperlipidemic patients receiving a HMG-CoA 
reductase inhibitor for elucidation of “quality of lipids.” 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
To explore the effects of 8-week treatment with omega-3-acid ethyl esters on the lipid and 
lipoprotein profile in the blood in hyperlipidemic patients receiving a HMG-CoA reductase inhibitor 
by use of HPLC in comparison with the control group of patients not treated with omega-3-acid 
ethyl esters. 
5.2 
Definition of endpoints 
5.2.1 Primary endpoints 
Change in mean particle sizes of sdLDL-C and LDL-C in the specific 20-lipoprotein 
fraction assay 
5.2.2 Secondary endpoints 
1) 
Change in major lipid constituents in the specific 20-lipoprotein fraction assay 
2) 
Change in fatty acids and sdLDL-C in total lipids 
3) 
Change in concentration and particle number of lipids, apoprotein and lipoprotein in the 
blood 
5.2.3 Safety endpoints 
Adverse events 
 


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6.0 
CLINICAL STUDY DESIGN 
6.1 
Clinical study design 
<Clinical study design> 
This is an multicenter, randomized, open-label study to explore the effects of omega-3-acid ethyl 
esters on the lipid and lipoprotein profile in the blood in hyperlipidemic patients receiving a 
HMG-CoA reductase inhibitor in comparison with the control group of patients not treated with 
omega-3-acid ethyl esters in an unblinded manner by use of HPLC using highly-sensitive gel 
filtration columns, which is a technique for analyzing lipoprotein. 
Considering the factors potentially biasing the lipid and lipoprotein profile in the blood between the 
treatment groups, study subjects who gave consent and were assessed as eligible in the eligibility 
assessment will be stratified for allocation by the factors of “fasting TG (< 300 mg/dL or ≥ 300 
mg/dL) and age (< 65 years or ≥ 65 years) at the start of the screening period” (1:1 ratio). 
 
<Treatment> 
[1] Study drug 
Omega-3-acid ethyl esters 
[2] Dosage regimen 
The group treated with omega-3-acid ethyl esters: Hyperlipidemic patients receiving a HMG-CoA 
reductase inhibitor* will orally receive omega-3-acid ethyl esters 2 g 
immediately after meal twice daily. 
The group not treated with omega-3-acid ethyl esters: Hyperlipidemic patients receiving a 
HMG-CoA reductase inhibitor* will continue to receive the HMG-CoA 
reductase inhibitor at the same dose regimen as at the time of informed 
consent. 
*: Irrespective of the treatment groups, patients will receive a HMG-CoA reductase inhibitor at a 
consistent dose regimen that should have been stable for ≥4 weeks prior to informed consent. 
Change of the HMG-CoA reductase inhibitor and its dose regimen is not allowed throughout the 
screening period and the treatment period. 
[3] Duration of treatment 
8 weeks 
 


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<Planned number of study subjects> 
50 patients evaluable for the primary endpoint 
(25 patients in the group treated with omega-3-acid ethyl esters, 25 patients in the group not treated 
with omega-3-acid ethyl esters) 
 
<Number of study sites> 
Around 5 sites  
 
<Duration of treatment and number of visits for a study subject> 
[1] Duration of treatment 
The duration of the treatment period is 8 weeks. Visit 1 is to obtain informed consent (Day -29 to 
Day -1 before the start of study drug administration), Visit 2 is to administer the study drug for 
the first time (Day -15 to Day -1 before the start of study drug administration), Visit 3 takes place 
in the 4th week after the start of study drug administration (Week 4), and Visit 4 is to administer 
the study drug for the last time (Week 8). 
[2] Number of visits 
Screening period: 1 visit 
Treatment period: 3 visits 
 
Figure 6 (a) shows an outline of the clinical study design. Refer to Appendix A for schedule of 
examinations, observations, and evaluations. 
Figure 6.a 
Outline of the clinical study design 
<Outline of the clinical study> 
Duration of treatment: 8 weeks 
Number of visits: 4 visits 


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(a) by HPLC 
6.2 
Rationale for the clinical study design 
<Rationale> 
This clinical study was designed as an open-label study with the control group of patients who 
will not be treated with omega-3-acid ethyl esters, because the objective is to explore the effects 
of 8-week, twice-daily, oral treatment with omega-3-acid ethyl esters 2 g on the lipid and 
lipoprotein profile in the blood in hyperlipidemic patients receiving a HMG-CoA reductase 
inhibitor. Subjects are to be stratified for allocation (1:1 ratio) by the factors of “fasting TG (< 
300 mg/dL or ≥ 300 mg/dL) and age (< 65 years or ≥ 65 years) at the start of the screening period” 
that may potentially bias the lipid and lipoprotein profile in the blood, so that the potential bias 
between the treatment groups is minimized. 
<Rationale for the dose regimen> 
In accordance with the approved dosage and administration of omega-3-acid ethyl esters, 
omega-3-acid ethyl esters 2 g is to be orally administered immediately after meal twice daily as 
the dose regimen in this study. In the Phase 3 confirmatory study in patients with 
hypertriglyceridemia, superiority of the product 4 g group to the EPA-E group as well as 
non-inferiority of the product 2 g group to the EPA-E group were confirmed for percentage of 
change in TG from baseline at the completion of administration of omega-3-acid ethyl esters 2 or 
4 g or the control EPA preparation 1.8 g/day. Patients receiving omega-3-acid ethyl esters in 
actual clinical practice are likely to have increased TG, therefore the dose of 4 g daily was 
selected as having more marked TG-lowering effect, so that the effects of omega-3-acid ethyl 
esters on the lipid profiles may be investigated in detail. 
<Rationale for the study period> 
In the Phase 3 confirmatory study in patients with hypertriglyceridemia, decrease of TG was 
observed in an early stage (Week 4) after the start of administration with omega-3-acid ethyl 
Visit
1
Week
-4
許容範囲
-29～-1
オメガ-3脂肪酸エチル
非投与群
オメガ-3脂肪酸エチル
投与群
リポ蛋白精密測定(a)
リポ蛋白精密測定(a)
リポ蛋白精密測定(a)
-15～-1
14～41
42～70
HMG-CoA還元酵素阻害薬
HMG-CoA還元酵素阻害薬
同意取得
適格性確認、無作為化
被験薬投与開始
2
3
4
0
4
8
オメガ-3脂肪酸エチル4g（分2）
Eligibility screening, 
randomization, start of 
study drug administration 
Informed 
consent 
Window 
Omega-3-acid ethyl esters 4 g (2 g twice daily) 
HMG-CoA reductase inhibitor 
HMG-CoA reductase inhibitor 
Precise lipoprotein assay(a) Precise lipoprotein assay(a) Precise lipoprotein assay(a) 
The group treated with 
omega-3-acid ethyl 
esters 
The group not treated 
with omega-3-acid 
ethyl esters 
-29 to -1 
-15 to -1 
14 to 41 
42 to 70 


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esters 4 g/day, and the product 2 and 4 g/day showed comparable or more marked TG-lowering 
effect as compared to the control EPA-E preparation 1.8 g/day. For LDL-C, another lipid 
parameter than TG, decrease was observed since Week 4 after the start of administration with the 
product 4 g/day. Therefore, the 8-week treatment duration including additional 4-week treatment 
is set to investigate the effects of omega-3-acid ethyl esters on the lipid profiles in detail in this 
study. As a result of the Phase 3 confirmatory study, no tendency for LDL-C to increase 
constantly was observed in association with treatment with the product, while it is still unknown 
what induced transient LDL-C increase after treatment with the product. 
<Rationale for the number of planned study subjects> 
See Section 13.3. 
6.3 
Premature termination of entire clinical study or premature termination of 
clinical study at a study site 
6.3.1 Premature termination criteria of entire clinical study 
The sponsor should immediately discontinue the study when at least one of the following criteria is 
applicable: 
 
When new information or other evaluation on the safety or efficacy of the study drug becomes 
available that shows a change in the known risk/benefit profile of the concerned compound, and 
risks/benefits are no longer tolerable for study subject participation in the study. 
 
When there is serious deviation from Ethical Guidelines or ICH-GCP for medical and health 
study involving human subjects. 
6.3.2 Criteria for premature termination of study sites 
Termination of involvement of a study site in the study may be requested prematurely at the 
discretion of the sponsor if the entity (e.g., principal investigator) is found to have significant 
violation of the ethical guidelines, protocol, or contractual agreement for medical and health study 
involving human subjects or becomes unable to ensure proper conduct of the study, or otherwise as 
specified in the contractual agreement. 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or clinical study at a study site 
In the event that the sponsor or a study site committee such as an Ethical Review Board decides to 
prematurely suspend or terminate the entire clinical study or clinical study at a study site, a 
study-specific procedure shall be provided by the sponsor. The procedure shall be followed by 
applicable study sites during the course of clinical study suspension or premature termination. 


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6.4 
Procedures for protocol revision 
If the protocol needs to be revised, the sponsor shall consider and decide whether to revise the 
protocol. 
The principal investigator of each study site shall be informed of the details of each protocol revision. 
Principal investigators shall confirm the content of the revision of the protocol and submit a letter of 
agreement to the sponsor as evidence of agreement with the protocol revision. 
Upon notification, the principal investigator at each study site shall submit the revised contents to 
committees such as the Ethical Review Board, as necessary according to institutional regulations for 
review, and obtain approval from the director of the entity. 


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7.0 
SELECTION AND WITHDRAWAL CRITERIA OF STUDY SUBJECTS 
The principal investigator or investigator shall check for all the inclusion/exclusion criteria including 
the test results prior to randomization. 
7.1 
Inclusion criteria 
Eligibility of study subjects shall be determined in accordance with the following criteria. 
1. 
Patients diagnosed as hyperlipidemia. 
2. 
Patients receiving a HMG-CoA reductase inhibitor continuously at a stable dose regimen 
for at least 4 weeks at the start of observation period at Visit 1 (Day -29 to Day -1 before 
the start of study drug administration) 
3. 
Patients with fasting TG of ≥150 to <400 mg/dL at the start of observation period at Visit 
1 (Day -29 to Day -1 before the start of study drug administration) 
4. 
Patients who, in the opinion of the principal investigator or the investigator, are capable of 
understanding the content of the clinical study and complying with the study protocol 
requirements. 
5. 
Patients who can provide written informed consent prior to the conduction of the clinical 
study procedures. 
6. 
Patients aged ≥20 years at the time of informed consent 
[Rationale for the inclusion criteria] 
1. 
These patients were subjected in the clinical study because omega-3-acid ethyl esters is 
indicated for “hyperlipidemia.” 
2. 
This was set so that the lipid and lipoprotein profile in the blood may be investigated in 
detail when omega-3-acid ethyl esters is added to a HMG-CoA reductase inhibitor. 
Change in the dose regimen of the HMG-CoA reductase inhibitor is not allowed during the 
study, so that efficacy may be assessed accurately. 
3. 
The lower limit was set according to the diagnostic criteria for hypertriglyceridemia in 
“Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic 
Cardiovascular Diseases 2012.” The upper limit was set as using a reference in the clinical 
settings when adding omega-3-acid ethyl esters to a HMG-CoA reductase inhibitor. 
4. 5. These were set as fundamental items for the study. 
6. 
Patients should be ≥20 years of age, so that they may make up their mind to participate in 
the study at their own discretion. 


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7.2 
Exclusion criteria 
Study subjects meeting any of the criteria below shall not be included in this study. 
1. Patients who had clinically significant hemorrhagic disorders (e.g., hemophilia, capillary 
fragility, gastrointestinal ulcer, urinary tract hemorrhage, hemoptysis, and vitreous 
hemorrhage) within 24 weeks prior to the start of observation period(Day -29 to Day -1 
before the start of study drug administration), or those who concurrently have the above 
disorders 
2. Patients who had thyroid disorders (hyperthyroidism or hypothyroidism) within 24 weeks 
prior to the start of observation period (Day -29 to Day -1 before the start of study drug 
administration), those who concurrently have the above disorders, or those who are orally 
receiving a therapeutic drug for thyroid disorder. 
3. Patients in whom the type of HMG-CoA reductase inhibitors was changed within 12 weeks 
prior to the start of observation period (Day -29 to Day -1 before the start of study drug 
administration) 
4. Patients who have received an EPA preparation or an EPA/DHA preparation (including 
supplements) within 12 weeks prior to the start of observation period (Day -29 to Day -1 
before the start of study drug administration) 
5. Patients who have started antidyslipidemic agents within 4 weeks prior to the start of 
observation period (Day -29 to Day -1 before the start of study drug administration) 
6. Patients with severe hepatic impairment (e.g., Child-Pugh classification C) 
7. Patients who were previously diagnosed as lipoprotein lipase deficiency or apoprotein C-II 
deficiency. 
8. Patients who are concurrently having Cushing's syndrome, uremia, systemic lupus 
erythematosus (SLE), or serum dysproteinemia. 
9. Diabetic patients who are currently receiving thiazolidine or insulin. 
10. Patients who are concurrently having hypertension of grade IIINote 1). 
Note 1: Patients with systolic blood pressure of ≥180 mm Hg or diastolic blood pressure of 
≥110 mm Hg regardless of treatment with antihypertensive drugs. 
11. Patients who are habitual drinkers drinking an average of over 100 mL per day (expressed 
in terms of quantity of alcohol), or patients with or with a history of drug abuse or 
addiction. 
12. Pregnant, lactating or postmenopausal women. 


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13. Patients with a history of hypersensitivity or allergy for omega-3-acid ethyl esters. 
14. Patients participating in other clinical studies 
15. Patients assessed ineligible in the study by the principal investigator or the investigator 
Note 2: Alcohol conversion table (reference) 
Alcohol 
Type 
Alcohol content 
Amount corresponding to 100 mL alcohol 
Brewage 
Sake 
15% 
670 mL (approx. 3 cups) 
Beer 
5% 
2,000 mL (approx. 3 large bottles) 
Sparkling liquor 
5% 
2,000 mL 
Wine 
12% 
830 mL 
Chinese rice wine 
18% 
560 mL 
Distilled liquor 
Ko-rui Shochu 
35% 
290 mL 
Otsu-rui Shochu 
25% 
400 mL 
Whiskey 
40% 
250 mL (approx. 3 doubles) 
Brandy 
40% 
250 mL (approx. 3 doubles) 
Vodka 
40% 
250 mL (approx. 3 doubles) 
Mixed liquor 
Plum wine 
13% 
770 mL 
Synthetic sake 
16% 
630 mL 
[Rationale for the exclusion criteria] 
1.13. The product is contraindicated for these patients. 
2. Lipids and lipoproteins in the blood may be affected by thyroid disorders and the 
therapeutic drugs. 
3.4.5. Efficacy may not be assessed accurately in these patients. 
6.10. These were set to ensure safety of the study subjects. 
7. Patients who genetically produce less lipoprotein and apoprotein should be excluded. 
8. Patients with underline diseases commonly seen with secondary hypertriglyceridemia 
should be excluded. 
9. Production of hepatic lipid parameters including TG may not be assessed accurately in these 
patients. 
11. These were set to ensure safety of the study subjects and accurate efficacy assessment. 
12. For the product, safety has not been established for the use during pregnancy, and the 
product should preferably not be administered to lactating women. In addition, production 
of lipid parameters including TG may be affected by estrogen, a female hormone. 
14.15. These were set as fundamental items for the study. 


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7.3 
Prohibited concomitant drugs and permitted concomitant drugs 
7.3.1 Prohibited concomitant drugs 
[Prohibited concomitant drugs] 
The concomitant use of the following drugs* will be prohibited during the clinical study [Visit 1 
(Day -29 to Day -1 before the start of study drug administration) to Visit 4 (Week 8)]. 
(*: including concomitant drugs that were administered at the start of observation period and 
prohibited in the package insert of the HMG-CoA reductase inhibitor) 
1. EPA preparations or EPA/DHA preparations (including supplements) 
2. Antidyslipidemic agents (except for HMG-CoA reductase inhibitors administered at the start 
of observation period) 
Anion exchange resin, fibrates, nicotinic acid derivatives, probucol, phytosterols and 
others (elastase ES, dextran sulfate sodium, polyenephosphatidylcholine, pantethine, 
ezetimibe) 
3. Pancreatic hormones 
Insulin preparation 
4. Androgens 
Testosterone, methyltestosterone 
5. Follicle hormone and luteinizing hormone 
Estrogen and progestogen 
6. Systemic steroids 
7. Thyroid hormone 
<Rationale> 
1 to 7 Efficacy of the study drug may not be assessed accurately with these concomitant drugs. 
7.3.2 Permitted concomitant drugs 
Concomitant use of “HMG-CoA reductase inhibitors,” “antidiabetic drugs (except for insulin)” 
or “antihypertensive drugs” is allowed during the study period. However, for “HMG-CoA 
reductase inhibitors” and “antidiabetic drugs (except for insulin),” dose modification, addition of 
new treatment drugs, or change of treatment drugs shall not be allowed unless the principal 
investigator or investigator considers it necessary due to adverse events, etc. 
7.4 
Study subject management 
The principal investigator or investigator shall instruct study subjects regarding the following: 


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(1) Guidance for study subjects for improving lifestyle should not be changed or modified during 
the clinical study. Study subjects shall be instructed to avoid excessive exercise to the extent 
possible during the study period. 
(2) Study subjects shall be instructed not to consume alcohol after 9:00 pm 2 days before the 
hospital visit and not to consume food after 9:00 pm the day before the hospital visit until the 
test to be performed in the fasting state. Although water can be taken as desired on the day of 
blood collection, study subjects shall be instructed to visit the hospital in a fasting state in order 
that fasting morning samples can be collected. 
(3) Study subjects shall be instructed to avoid eating/drinking to excess, extreme change in dietary 
content (eating a high-fat meal, etc.) or excessive exercise, and spend time on a routine basis 
the day before the hospital visit. 
(4) Study subjects shall be instructed to visit the hospital according to the schedule and take the test 
as prescribed during the study period. 
(5) Study subjects shall be instructed to comply with the instructions or restrictions (taking the 
study drug, prohibited drugs for concomitant use, those allowed for concomitant use, etc.) 
during the study period. 
(6) Upon concomitant use of anticoagulants (warfarin potassium, etc.) or antiplatelet drugs (aspirin, 
etc.) listed under Precautions for Coadministration in the package insert of the study drug, study 
subjects shall be instructed to promptly report in the event of an adverse drug reaction, such as 
bleeding. 
(7) Study subjects must notify the principal investigator or investigator in advance if they receive 
treatment from other physicians. If treated by other physicians, the study subjects shall be 
instructed to promptly report the details of the treatment. 
7.5 
Criteria for discontinuation or withdrawal of a study subject 
The principal investigator or investigator shall record the main reason for discontinuation of protocol 
treatment on the case report form (CRF) according to the classification described below. Refer to 
Section 9.1.11 for study subjects who withdraw from the study before randomization. 
1. Adverse events 
When the study subject had an adverse event that requires withdrawal of the study subject from 
the study because continued participation in the study would impose an unacceptable risk to the 
study subject’s health, or when the study subject is unwilling to continue study participation 
because of the adverse event. 


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2. Major protocol deviation 
When it is discovered after randomization that a study subject does not meet the eligibility 
criteria or is not adhering to the protocol, and continued participation in the study would impose 
an unacceptable risk to the study subject’s health. 
3. Lost to follow-up 
When the study subject failed to make visits and could not be contacted despite the attempts to 
contact the study subject. 
4. Voluntary termination 
When the study subject wishes to withdraw from the study. The reason for discontinuation shall 
be obtained to the extent possible. 
5. Study termination 
When the sponsor or a committee such as the Ethical Review Board or regulatory authority has 
decided to terminate the study. Refer to Section 6.3.1 for details. 
6. Pregnancy 
When a female study subject was found to be pregnant. 
Note: The study subject must discontinue the study immediately after she was found to be 
pregnant. Refer to Section 9.1.13 for the procedures. 
7. Lack of efficacy  
When efficacy of the study drug is not evident and continuation of the study may pose an 
unacceptable risk to the study subjects in the opinion of the principal investigator or 
investigator. 
8. Others 
When the principal investigator or investigator determined to terminate the study for other 
reasons. 
The specific reasons should be recorded on the CRF. 
7.6 
Procedures for discontinuation of individual study subjects 
The principal investigator or investigator shall terminate a study subject’s study participation when 
the study subject meets the criteria described in Section 7.5. Individual study subjects may 
discontinue their study participation without giving a reason at any time during the study. Should a 
study subject’s participation be discontinued, the primary reason for termination shall be recorded on 


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the CRF by the principal investigator or investigator. In addition, efforts shall be made to perform all 
tests/observations/evaluations scheduled at the time of discontinuation. 


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8.0 
STUDY TREATMENT 
8.1 
Study drug 
Generic name: Omega-3-acid ethyl esters 
Chemical name: Ethyl icosapentate; 
ethyl(5Z,8Z,11Z,14Z,17Z)−icosa−5,8,11,14,17−pentaenoate 
Docosahexaenoic acid ethyl ester; 
ethyl(4Z,7Z,10Z,13Z,16Z,19Z)−docosa−4,7,10,13,16,19−hexaenoate 
8.1.1 Dose and administration method 
For subjects who were allocated to the omega-3 group, omega-3-acid ethyl esters 2 g is to be orally 
administered immediately after meal twice daily for 8 weeks. The principal investigator or 
investigator chose patients needed treatment with omega-3-acid ethyl esters 4 g/day as a result of 
assessment. In principle, the dosage prescribed to the study subject should not be changed until the 
end of the study. Since the study subject should visit the study site in the fasting state, the 
post-breakfast dose, if any, should be administered immediately after the first meal in the day after 
completion of the prescribed test. 
Medication should be started the day after completion of all the tests at Week 0. 
8.1.2 Concomitant drugs 
The “HMG-CoA reductase inhibitors” or “antidiabetic drugs (except for insulin)” taken at the start 
of observation period should continue without dose modification during the study period. Addition 
or change of these drugs are not allowed. 
8.1.3 Overdose of the study drug 
Overdose is defined as intentional or accidental administration of the study drug at a higher dose 
than that specified in the protocol, either by a health professional or by the study subject. 
To consistently collect important safety information about overdose, the principal investigator or 
investigator(s) shall record all cases of overdose on the “Overdose” page of the CRF, irrespective of 
the presence or absence of accompanying adverse event. Adverse events associated with overdose 
shall be recorded on the “Adverse events” page of the CRF, in accordance with the procedures 
described in Section 10.0, “Adverse Events.” 


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In addition, serious adverse events associated with overdose shall be recorded in accordance with the 
procedures described in Section 10.2.2, “Collection and reporting of serious adverse events.” 
In the event of overdose, the principal investigator or investigator shall treat the subject as required 
based on symptoms. 
8.2 
Allocation of the study drug and administration procedure 
The principal investigator or investigator shall access the Case Registration Web System to allocate 
the study subjects. The principal investigator or the designee shall notify the information required for 
allocation in addition to the study subject identification (ID) code. Then, subjects will allocate to 
omega-3 group or control group through the Case Registration Web System. The principal 
investigator or investigator shall prescribe the study drug and/or HMG-CoA reductase inhibitor 
according to the notification, and record the prescribed dose for each study subject in the CRF. 
8.3 
Preparation and storage of allocation list 
The allocation responsible person (designated by the sponsor) shall create an allocation procedure. 
Information on the allocation shall be kept in a safe place and shall not be available to anyone other 
than authorized persons, to secure independency from the clinical study. 
Using fasting TG values and ages as stratified factors, stratified allocation shall be performed at the 
Registration Center at the start of treatment period. For allocation, the Registration Center shall use 
the Allocation Procedure for Stratified Allocation prepared by the allocation responsible person. 
 


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9.0 
CLINICAL STUDY PROTOCOL 
9.1 
Clinical study procedures 
The principal investigator or investigator shall collect data in accordance with the procedure below. 
In principle, all the tests, observations, and evaluations of study subjects shall be performed by the 
same principal investigator or investigator with the exception of the specific 20-lipoprotein fraction. 
The study schedule is provided in Appendix A. 
9.1.1 Informed consent 
The procedures for obtaining informed consent are described in Section 15.3. 
Consent shall be obtained from the study subject before initiation of study procedures. 
Study subject ID code is given to each study subject from whom informed consent was acquired and 
who was randomized. The study subject ID code shall be used throughout the study period and shall 
not be changed. 
9.1.2 Demographic data, medical history, and previous treatment drugs 
Demographic data shall be collected regarding date of birth, gender, time (year/month) of onset (or 
diagnosis) of hyperlipidemia, frequency of consumption of fish (almost every day, once/2 days, 1 to 
2 times/week, almost never), HMG-CoA reductase inhibitor administered before start of observation 
period, and smoking and drinking history. 
Medical history data shall be collected regarding clinically problematic diseases or symptoms that 
disappeared or were terminated within 1 year from initiation of screening period and that related to 
target conditions. When the symptoms or disease continues, it shall be considered as a concurrent 
disease (Refer to Section 9.1.7). 
Previous treatment drug data shall be collected regarding all drugs used within 12 weeks before the 
initiation of screening period and that are related to criteria for eligibility and assessment of efficacy. 
9.1.3 Physical examination 
All subsequent physical examinations after the start of study drug administration shall be assessed 
for clinically significant changes from the baseline examination. 
9.1.4 Body weight, height, and BMI 
Body weight and height shall be measured. The sponsor shall calculate the BMI using the following 
formula. 
Body Mass Index: BMI=body weight (kg)/[height(m)]2 
Height shall be measured to the nearest whole number in centimeters. Body weight shall be 
measured to one decimal place in kilograms. The result of BMI shall be shown to one decimal place. 
Example: 


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Height = 176 cm, body weight = 79.2 kg, BMI = 79.2/1.762 = 25.6 kg/m2 
9.1.5 Vital signs 
For vital signs, blood pressure in sitting position (after resting for at least 5 minutes) and a pulse rate 
(bpm) shall be measured. 
When timing for the vital signs measurement overlaps with blood collection, priority shall be given 
to blood collection, and the vital signs shall be measured within 30 minutes before or after the blood 
collection. 
9.1.6 Concomitant drugs 
Concomitant drugs are all drugs to be given in addition to the study drug. Drugs prescribed by 
doctors or the over-the-counter medicines purchased by the study subjects shall be included. At 
every hospital visit of the study subject, the name, dose and dose regimen, route of administration 
and treatment duration should be investigated for the drugs (including vitamin compound, 
over-the-counter medication, and Chinese medicine) used other than the study drug from the start of 
the screening period to the completion of the clinical study. HMG-CoA reductase inhibitor 
administered before start of observation period is not treated as concomitant drug. 
9.1.7 Concurrent disease 
A concurrent disease shall be defined as a disease or symptom present at the start of the screening 
period or observed from the start of the screening period until before the start of study drug 
administration. Clinically problematic laboratory test data, ECG findings, and abnormal physical 
examination findings observed at the start of the screening period shall be considered as a concurrent 
disease at the discretion of the principal investigator or investigator. The content of concurrent 
disease (diagnosis) shall be investigated. 
9.1.8 Food and drink consumption before the visit 
The principal investigator or investigator shall confirm with the study subject about food and drink 
consumed before the visit at every visit. 
• 
Alcohol should not be consumed from 9:00 pm 2 days before the visit, and food should not be 
consumed from 9:00 pm the day before the visit until the fasting test. 
• 
Excessive eating/drinking and extreme change in dietary content should be avoided on the day 
before the fasting test. 


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9.1.9 Laboratory tests and the specific 20-lipoprotein fraction assay 
According to the observation schedule (Appendix A), samples are to be collected in each study site 
for the following laboratory tests and the specific 20-lipoprotein fraction assay. The fasting test is to 
be performed under ≥10-h fasting. 
The principal investigator or investigator shall evaluate and keep the reported laboratory test results. 
Results of the specific 20-lipoprotein fraction assay shall be assessed by the chair and member of the 
Clinical Study Steering Committee. 
 
Table 9.a Laboratory tests 
Hematology(a) 
Serum chemistry(a) 
Platelet count 
Total cholesterol, TG, HDL-C, LDH, AST, 
ALT, ALP, γ-GTP, CK(CPK) 
Specific 20-lipoprotein fraction(b), lipid content of each lipoprotein fraction (b), mean 
particle size of LDL(b), mean particle size of HDL (b) 
Apoprotein, remnant lipoprotein 
  
Apolipoprotein A1(a), A2(a), B(a), B-48(a), B-100(c), C-II(a), C-III(a), C-II/III(a), E(a), RemL-C(a) 
Others 
Fatty acid fraction in total lipids(a) 
Lipoprotein lipase(c), high-sensitive CRP(a) 
24-fatty acid fraction, T/T, EPA/AA 
(a) To be measured in 
(b) To be assayed for the sub-class6) specified for each fraction number using HPLC 
 in 
Fraction No. 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Particle 
diameter 
>90 
75 
64 
53.6 
44.5 
36.8 
31.3 
28.6 
25.5 
23 
20.7 
18.6 
16.7 
15 
13.5 
12.1 
10.9 
9.8 
8.8 
7.6 
Sub-Class 
Chylomicrons 
large VLDL 
medium 
VLDL 
small 
VLDL 
large 
LDL 
medium 
LDL 
small 
LDL 
very small LDL 
very 
large 
HDL 
large 
HDL 
medium 
HDL 
small 
HDL 
very small HDL 
 
(c) 
To be measured in 
The principal investigator shall keep laboratory test reference values including the historical data 
with the exception of the specific 20-fraction assay using
9.1.10 Contraception 
Female subjects of childbearing potential (e.g., nonsterilized or premenopausal female subjects) 
must use adequate contraception from signing on the informed consent throughout the study period. 
At the time of acquisition of informed consent from an applicable study subject, signature on the 
informed consent should be acquired only after explanation is made about what is the adequate 
PPD
PPD
PPD
CCI
CCI


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contraception and that the subject must avoid to be pregnant during the study period by use of the 
informed consent form until the subject thoroughly understands them. 
9.1.11 Pregnancy 
When a study subject was found to be pregnant during the study period, the fact that the female 
study subject participated in the study when she became pregnant with the details of the study drug 
should be transferred to her obstetrician upon agreement with her. 
Pregnancy during the study period and until the day of the last study drug administration should be 
reported to the sponsor with the format separately specified. 
9.1.12 Record of study subjects who are withdrawn before randomization 
A CRF shall be created for all study subjects who have signed the consent form and withdrawn 
before randomization. 
The following items are to be described on the CRF. 
• 
Date of consent obtainment 
• 
Date of birth 
• 
Gender 
• 
Eligibility 
• 
Adverse events (with details, if any) 
• 
Reason for discontinuation 
The primary reason for withdrawal before randomization shall be recorded on the CRF according to 
the following classification: 
• 
Adverse events 
• 
Not satisfying at least one of the inclusion criteria or meeting any of the exclusion criteria 
• 
Major protocol deviation 
• 
Lost to follow-up 
• 
Voluntary discontinuation (specify the reason) 
• 
Study termination 
• 
Pregnancy 
• 
Others (specify the reason) 
Study subject ID codes assigned to study subjects withdrawn from the study before randomization 
shall not be reused. 


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9.1.13 Record of randomization 
Study subjects to be randomized shall meet all of the inclusion criteria and shall not meet any of the 
exclusion criteria according to8.2 Section 8.2. The principal investigator or investigator shall specify 
the primary reason why the study subject cannot be randomized. 
9.2 
Compliance with study treatment of study subjects 
The principal investigator or investigator shall confirm compliance with the study treatment with 
study subject at every visit. Throughout the study period, overall treatment compliance shall be 
checked in the interview and categorized into the 2 categories of “≥50% or <50% of the prescribed 
dose.” If poor compliance with study treatment (e.g., <50% of the prescribed dose) has been found 
through the interview and does not improve, the study subject may be withdrawn from the study if 
appropriate for the circumstances. 
9.3 
Implementation time point of the tests and observation 
The schedule for all tests, observations, and evaluations is shown in Appendix A. The principal 
investigator or investigator shall perform the tests, observations, and evaluations at the time points 
shown below. 
9.3.1 Screening period (Visit 1) 
At Visit 1 (Day -29 to Day -1 before the start of study drug administration), the study shall be 
explained using the informed consent form to the study subjects who meet the inclusion criteria 
(except for 3) in Section 7.1 and do not meet any of the exclusion criteria in Section 7.2, and consent 
shall be obtained in accordance with Section 15.3. 
Tests, observations, and evaluations to be performed at Visit 1 (Day -29 to Day -1 before the start of 
study drug administration) are shown below. 
• 
Informed consent 
• 
Demographic data, medical history, previous treatment drug(s) 
• 
Physical examination 
• 
Height, body weight and BMI 
• 
Vital signs 
• 
Concomitant drugs 
• 
Concurrent disease 
• 
Laboratory tests (fasting) 
Items to be checked: Food and drink consumption before visit 
o 
Confirm that alcohol was not consumed from 9:00 pm 2 days before the visit and food 
was not consumed from 9:00 pm the day before the visit 


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o 
Confirm that excessive eating/drinking and extreme change in dietary content were not 
made on the day before the visit. 
9.3.2 Treatment period (Visit 2) 
In consideration of the results of tests and observation at Visit 1 (Day -29 to Day -1 before the 
start of study drug administration), the principal investigator and the investigator shall perform 
the following tests, observations, and evaluations for each study subject. 
Items to be checked: Food and drink consumption before visit 
o 
Confirm that alcohol was not consumed from 9:00 pm 2 days before the visit and food 
was not consumed from 9:00 pm the day before the visit 
o 
Confirm that excessive eating/drinking and extreme change in dietary content were not 
made on the day before the visit. 
 
• 
Physical examination 
• 
Vital signs 
• 
Concomitant drugs 
• 
Concurrent disease 
• 
Laboratory tests 
 
The principal investigator or the investigator shall give notification to the Registration Center 
(accessing to the Case Registration Web System) regarding study subjects in whom all the tests, 
observation and evaluation at Visit 2 (Day -15 to Day -1 before the start of study drug 
administration) have been completed and study drug administration was considered possible. 
The principal investigator or the investigator shall prescribe the study drug at a dose notified from 
the Registration Center and tell the study subject to take the drug starting from the next day. 
Refer to Section 9.1.11 for preparation of records relating to the study subjects withdrawn before 
randomization. 
9.3.3 Treatment period (Visit 3) 
In consideration of the results of tests and observation at Visit 2 (Day -15 to Day -1 before the 
start of study drug administration), the principal investigator and the investigator shall perform 
the following tests, observations, and evaluations for each study subject. If the study drug 
administration is discontinued, study subjects should, to the extent possible, undergo tests, 
observations, and evaluations required for the last visit within 3 days from the last dose taken. 
 
Items to be checked: Food and drink consumption before visit 


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o 
Confirm that alcohol was not consumed from 9:00 pm 2 days before the visit and food 
was not consumed from 9:00 pm the day before the visit 
o 
Confirm that excessive eating/drinking and extreme change in dietary content were not 
made on the day before the visit. 
 
• 
Physical examination 
• 
Vital signs 
• 
Concomitant drugs 
• 
Laboratory tests 
• 
Treatment compliance 
• 
Evaluation of adverse events 
9.3.4 Completion (Visit 4) or discontinuation 
Visit 4 is the last visit, and the principal investigator or the investigator shall perform the 
following tests, observations, and evaluations for each study subject. If the study drug 
administration is discontinued, study subjects should, to the extent possible, undergo tests within 
3 days from the last dose taken. 
 
Items to be checked: Food and drink consumption before visit 
o 
Confirm that alcohol was not consumed from 9:00 pm 2 days before the visit and food 
was not consumed from 9:00 pm the day before the visit 
o 
Confirm that excessive eating/drinking and extreme change in dietary content were not 
made on the day before the visit. 
 
• 
Physical examination 
• 
Vital signs 
• 
Concomitant drugs 
• 
Laboratory tests 
• 
Treatment compliance 
• 
Evaluation of adverse events 
 
At completion of the clinical study, the status of all study subjects administered the study drug shall 
be recorded on the CRF. 


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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse events 
An adverse event is defined as any untoward medical occurrence in a patient or a study subject 
receiving a pharmaceutical product (including the study drug). It does not necessarily have an 
apparent causal relationship with this pharmaceutical product (including study drug). 
An adverse event can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
laboratory abnormality), symptom, or disease temporally associated with the use of a pharmaceutical 
product (including the study drug), regardless of whether it is considered related to the 
pharmaceutical product (including the study drug) or not. 
10.1.2 Considerations for adverse events 
Generally unfavorable findings are described below: 
• 
Newly diagnosed disease or unexpected aggravation of existing symptom (intermittent event of 
an existing symptom is not considered an adverse event) 
• 
Requiring action or medical practice 
• 
Requiring invasive diagnostic treatment 
• 
Requiring discontinuation or a change in the dose of the study drug or a concomitant medication 
• 
Considered unfavorable by the principal investigator or the investigator 
Diagnosis name and signs/symptoms: 
Adverse events shall be recorded by diagnosis name. Accompanying signs (including abnormal 
laboratory values) and symptoms shall not be recorded as adverse events. If an adverse event could 
not be expressed by a diagnosis name, the signs or symptoms shall be recorded as the adverse event. 
 
Laboratory test values: 
Abnormal laboratory values shall be recorded as adverse events when the principal investigator or 
the investigator judges the results are clinically problematic (in other words, when certain action or 
medical practice is required, or when the principal investigator or the investigator judges the change 
has exceeded the normal physiological variation range of the study subject). Retest and/or continued 
monitoring of an abnormality are not considered medical practice. Also, repeated or additional 


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conduction of non-invasive tests for verification, evaluation, and monitoring of an abnormality are 
not considered medical practice. 
However, when abnormal laboratory values are the accompanying symptoms of a disease diagnosed 
as an adverse event (e.g., increased creatinine due to renal dysfunction, etc.), the adverse event shall 
be handled by its diagnosis name. 
Pre-existing conditions (a disease or symptom that is present at the start of the screening period or 
that is observed from the start of the screening period until before the start of study drug 
administration): 
A disease or symptom that is present at the start of the screening period or that is observed from the 
start of the screening period until before the start of study drug administration are considered a 
concurrent disease and not considered an adverse event. When a concurrent disease is aggravated, 
the aggravation shall be determined as an adverse event and the principal investigator or the 
investigator shall record on the CRF that the adverse event is an aggravation of the concurrent 
disease (e.g., “aggravation of hypertension,” etc.). 
If a study subject has a pre-existing episodic condition (e.g., asthma, epilepsy), each episode shall be 
recorded as an adverse event if the episodes become more frequent, serious, or severe in nature. If a 
study subject has a chronic concurrent condition (e.g., cataracts, rheumatoid arthritis), worsening of 
the condition shall be recorded as adverse event if the degree of the worsening exceeds that which 
would be expected. The principal investigator or the investigator shall ensure that the adverse event 
term to be reported represents the change in the condition from baseline (e.g. “worsening of…”).  
Worsening of adverse events: 
If a study subject experiences a worsening of the adverse event after a change of the study drug, or 
secondary signs and symptoms are caused by the adverse event, the worsening or the secondary 
signs and symptoms shall be recorded as a new adverse event on the CRF. The principal investigator 
or the investigator shall use an adverse event term that explicitly means a change of the condition 
(e.g., “worsening of…”). 
Change of severity of adverse events: 
If the study subject experiences changes in the severity of an adverse event, the event shall be 
recorded once, at its peak severity. 
Previously planned surgery or treatment: 
Preplanned surgeries or treatment that were scheduled before the start of study drug administration 
shall not be considered adverse events. However, when the existing symptom is aggravated to a 
degree requiring emergency surgery or treatment, the condition or the event shall be considered an 


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adverse event. A concurrent disease that resulted from previously planned surgery shall be reported 
as an adverse event. 
Non-urgent surgery or treatment: 
Non-urgent surgery or treatment that does not induce a change in the condition of a study subject 
(cosmetic surgery, etc.) shall not be considered an adverse event; However, it shall be recorded in 
the source documents. Concurrent diseases due to a non-urgent surgery shall be reported as an 
adverse event. 
The Insufficient clinical response (lack of efficacy): 
Insufficient clinical response, efficacy, or pharmacological action shall not be recorded as an adverse 
event. The principal investigator or the investigator shall make the distinction between worsening of 
a pre-existing condition and lack of therapeutic efficacy. 
Overdose: 
Overdose of any medication without manifested symptoms shall not be recorded as an adverse event, 
but the overdose shall be recorded on the “Overdose” page of the CRF. Any manifested symptoms 
shall also be recorded as adverse events on the “Adverse events” of the CRF. 
10.1.3 Serious adverse event 
Of all the unfavorable medical events that develop with administration of a pharmaceutical product 
(including study drug) (irrespective of dose), a serious adverse event is an event that: 
1. results in death, 
2. is life threatening*, 
3. requires inpatient hospitalization or prolongation of existing hospitalization, 
4. results in persistent or significant disability/incapacity, 
5. leads to a congenital anomaly/birth defect, or 
6. other medically significant condition: a medically important event that causes a risk to a 
study subject even if it is not immediately life-threatening and does not result in death or 
hospitalization, or requires an action or treatment to prevent the results described in 1 to 5 
above. In addition, points described in the Takeda Medically Significant Adverse Event List 
(Table 10 (a)) are included in this section. 
* The term “life threatening” refers to an event in which the study subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death if it was 
more severe. 


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Table 10.a 
Takeda Medically Significant AE List 
Acute respiratory failure/acute respiratory 
distress syndrome (ARDS) 
Torsades de pointes/ ventricular 
fibrillation/ventricular tachycardia 
Malignant hypertension 
Convulsive seizure (including convulsion 
and epilepsy) 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/ 
Oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
Hepatic necrosis 
Acute hepatic failure 
Anaphylactic shock 
Acute renal failure  
Pulmonary hypertension 
Pulmonary fibrosis (including interstitial 
pneumonia) 
Neuroleptic malignant syndrome/ malignant 
hyperpyrexia 
Spontaneous abortion/ stillbirth and fetal death 
Confirmed or suspected transmission of infection 
by a medicinal product 
Confirmed or suspected endotoxin shock 
10.1.4 Severity of adverse events 
The severity of adverse events shall be classified and defined as shown below. 
Mild 
The event is transient and easily tolerated 
by the subject. 
Moderat
e 
The event interrupts the subject’s usual 
activities. 
Severe 
The event causes considerable interference 
with the subject’s usual activities. 
10.1.5 Causality of adverse events 
The causal relationship of each adverse event to the study drug shall be classified and defined as 
shown below. 
Related 
An adverse event that follows a temporal sequence (including clinical course after 
discontinuation), or an adverse event in which there is at least a reasonable 
probability that a causal relationship to the study drug cannot be ruled out, although 
other factors such as underlying disease, concurrent diseases, or concomitant 
drugs/treatment are also suspected. 
Not 
related 
An adverse event that does not follow a temporal sequence from administration of 
the study drug. Very likely due to other factors such as underlying disease, 
concurrent diseases, or concomitant drugs/treatment. 


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10.1.6 Relationship to study procedures 
The relationship shall be recorded as “Yes” if the principal investigator or the investigator considers 
that there is reasonable possibility that an adverse event is due to a study procedure. Otherwise, the 
relationship shall be recorded as “No.” 
10.1.7 Date of onset 
The date of onset of adverse event shall be determined according to the following rules: 
Adverse events 
Date of onset 
Signs, symptoms, diseases 
(diagnoses) 
The date on which the first signs/symptoms were noted by the 
study subject and/or the principal investigator or investigator. 
Asymptomatic diseases 
The date on which a diagnosis was confirmed through a test(s). 
The date on which a diagnosis was confirmed, even when the 
test results indicate an old sign(s) of the disease or an 
approximate time of its onset. 
Exacerbation of concurrent 
diseases 
The date on which the first worsening of diseases/symptoms was 
noted by the study subject and/or the principal investigator or 
investigator. 
Onset of a test abnormality 
after the start of study drug 
administration 
The date on which a clinically significant laboratory abnormality 
was detected. 
Worsening of a baseline test 
abnormality after initiation of 
study treatment 
The date on which a clear increase/decrease in a laboratory 
parameter was clinically confirmed based on the time profile of 
the parameter. 
10.1.8 Date of resolution 
The date of resolution of an adverse event is the date on which the study subject recovered 
(including resolution with sequelae). If a study subject died due to the adverse event concerned, it 
shall be the date of death. The adverse event shall be recorded as “ongoing” if the study subject has 
not yet recovered by the end of the study. 
10.1.9 Actions taken for the study drug 
Actions taken for the study drug shall be classified or defined as shown below. 
Drug withdrawn 
The study drug is discontinued because of an adverse event (including 
withdrawal by the study subject at his/her own discretion). 
When the study is discontinued but study drug administration is still continued, 
the classification should be “Dose not changed.” 


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Dose not 
changed 
The dose was not changed after the onset of the adverse event. 
The study drug was discontinued, reduced, or increased because of another 
adverse event. 
The study drug was discontinued or reduced for a reason other than the 
adverse event, e.g., inadvertence of the study subject. 
Unknown 
It has not been possible to determine what action has been taken because the 
study subject is lost to follow-up. 
Not Applicable 
The administration of the study drug had already been completed or 
discontinued before the onset of the adverse event. 
Dose reduced 
The dose of the study drug is reduced because of an adverse event (including dose 
reduction by the study subject at his/her own discretion). 
10.1.10 Outcome 
Outcome of adverse events is classified as follows: 
Category 
Criteria 
Recovered 
- Disappearance or recovery of symptoms and findings 
- Laboratory values returned to normal or baseline 
Improved 
- The intensity is lowered by one or more stages 
- Symptoms or findings mostly disappeared 
- Laboratory values improved, but have not returned to normal or baseline 
- The study subject died from a cause other than the concerned adverse event 
while the condition was resolving (recording of the date of death unnecessary) 
Not 
recovered 
- No change in symptoms, findings, or laboratory data 
- The symptoms, findings, or laboratory data on the final day of observable 
period were aggravated compared with the date of onset 
- Irreversible congenital anomaly 
- The study subject died from another cause before resolution of the concerned 
adverse event (recording of the date of death unnecessary) 
Recovered 
with sequelae 
- Disability that disturbs daily life 
Death 
- Direct relationship between death and the concerned adverse event, etc. 
“Direct relationship” means that the concerned adverse event, etc. was the 
cause of death, or the concerned adverse event, etc. was clearly responsible 
for death. 
- Outcome of an adverse event which was not determined (judged, presumed) a 
direct cause of death observed in the same study subject is not considered as 
death. 
- The date of death shall be recorded. 
Unknown 
- Follow-up specified in the protocol after the date of onset was not possible due 
to change of hospitals or relocation, etc. 


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10.2 
Procedures 
10.2.1 Collection and reporting of adverse events 
10.2.1.1 Adverse event collection period 
Adverse events shall be collected from the start of administration with the study drug until 
completion of the treatment period (or discontinuation). 
10.2.1.2 Reporting of adverse events 
At each study visit, the principal investigator or investigator shall check for the presence of any 
onset of subjective symptoms. A neutral question, such as “How have you been feeling since your 
last visit?” may be asked to collect any adverse events that occurred between the previous and 
present visits. 
The principal investigator or investigator shall follow up all study subjects experiencing an adverse 
event irrespective of the causal relationship with the study drug, until the symptom resolve, or any 
clinically significant abnormal laboratory values have returned to baseline or there is a satisfactory 
explanation for the change (permanent and irreversible adverse events, etc.). All adverse events shall 
be recorded in the CRF. For the adverse event, the name, date of onset, date of resolution, category, 
severity, causal relationship with the study procedures (the procedure possibly having causal 
relationship, if applicable), causal relationship with the study drug (i.e. "Not related" or "Related"), 
action taken for the study drug, outcome, and seriousness shall be recorded. 
Follow-up period of adverse events shall be until recovery of the adverse events, or the time when 
the principal investigator or investigator judges that further follow-up would be unnecessary. 
10.2.2 Collection and reporting of serious adverse events 
When a serious adverse event develops during the period of collecting adverse events, it shall be 
reported according to the following procedures. 
At the time of onset of a serious adverse event or after notification of the onset by the study subject, 
the principal investigator shall report the serious adverse event to the chief executive of the study site 
immediately, and the sponsor or CRO to whom the sponsor has entrusted responsibility shall notify 
the principal investigator of the study site. 
The principal investigator shall then report the serious adverse event to the sponsor (for the contact 
information, refer to the attachment) within 1 working day after notification of the onset. Further, the 
investigator shall submit a formal report within 10 calendar days to the sponsor. 


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Furthermore, it shall be mandatory to include the contents below in the report to be submitted to the 
sponsor within 1 working day, and other items shall be reported as far as possible. 
• 
Brief description of adverse event and the reason for why it was determined as serious 
• 
Study subject ID code 
• 
Name of principal investigator or the investigator 
• 
Name of the study drug 
• 
Determined causal relationship 
10.2.3 Reporting of additional information concerning adverse events 
If the sponsor requests provision of additional information concerning adverse events for reporting 
to regulatory authorities, the principal investigator or the investigator shall confirm the necessary 
additional information and enter in the Electronic Data Capture (EDC) system or submit a report 
within the period specified by the sponsor. 
10.3 
Follow-up of serious adverse events 
When information that was not included in the detailed report was obtained later, principal 
investigator or the investigator shall state it in the copy of the report on serious adverse events, or 
create another document and submit it to the contact address shown on the attached sheet. Relevant 
data collected at the study site (e.g., ECG charts, laboratory test values, discharge summary, 
postmortem results) shall be sent to the sponsor or the committee such as the Ethical Review Board 
upon request. 
The principal investigator or the investigator shall follow-up all serious adverse events, etc., until 
recovery is confirmed, or the final outcome is determined. 
10.3.1 Reporting of serious adverse events to Ethical Review Board, etc., and 
regulatory authorities 
When the chief executive of study site receives a report of a serious adverse event from the principal 
investigator, the chief executive of study site shall consult the Ethical Review Board, etc., and notify 
the study sites that are conducting the clinical study through the sponsor or the CRO consigned by 
the sponsor. 
When the principal investigator reported a serious adverse event for which a causal relationship to 
the study (study drug) cannot be ruled out and is unexpected, the chief executive of the study site 
shall prepare a written report of the unexpected serious adverse event containing the information 
reported by the principal investigator plus the information below, and submit the report to the 


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Minister of Health, Labour and Welfare, and notify other study sites conducting the clinical study. 
(The chief executive of the study site may report it to the Minister of Health, Labour and Welfare via 
the sponsor, and notify it to other clinical study sites via the sponsor.) 
• 
Actions taken for serious adverse events 
(discontinuation of new enrollment, revision of informed consent form, re-consents to other 
study subjects, etc.) 
• 
Date of review, summery of review, result, necessary action, etc., related to Ethical Review 
Board, etc. 
• 
Notification to other collaborative study sites 
The sponsor shall report, in accordance with regulations, unexpected serious adverse drug reactions 
and other serious adverse events that are subject to emergency reporting to regulatory authorities, the 
principal investigators, and the chief executive of study site. 
From the time point of first acknowledging the event or receiving additional information, the 
sponsor or the CRO consigned by the sponsor shall comply with regulatory required time frames for 
reporting, and make emergency reports concerning unexpected serious adverse drug reactions and 
expected serious adverse drug reactions to regulatory authorities. Also, the sponsor shall, in the same 
way, make an emergency report of other critical safety information that may have a major effect on 
the study drug risk-benefit, continuation of study drug administration, or continuation of clinical 
study. The study site shall submit copies of emergency report documents to the Ethical Review 
Board, etc. 


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11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY 
Neither Clinical Study Steering Committee, Independent Data Monitoring Committee nor Clinical 
Endpoint Committee are to be employed in this study. 


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12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS 
Data management operations shall be performed according to the standard operating procedure by 
the data management department of the sponsor independent from the medical affairs department. 
Adverse events, medical history and concurrent disease shall be coded using the MedDRA. Drugs 
shall be coded using the World Health Organization (WHO) Drug Dictionary. 
12.1 
Case report form 
The principal investigator or investigator shall complete a CRF for each study subject who has 
signed the informed consent form. 
The sponsor or the designee shall provide access rights to the EDC system to the study site. Before 
use of the EDC system, the sponsor shall provide training to the principal investigator, investigators, 
and study collaborators. The CRF shall be used to report the information collected during the study 
period to the sponsor. CRF must be completed in Japanese. Data shall be directly entered in 
preparing the CRF. 
A change or correction of the CRF shall be recorded as an audit trail that records the information 
before and after the change or correction, the person who made the change or correction, date of 
change or correction, and its reason. 
The principal investigator shall ensure the accuracy and completeness of the CRF, and provide an 
electronic signature on the relevant page of the CRF. The principal investigator shall bear full 
responsibility for the accuracy and reliability of all data entered on the CRF. 
The following data shall be recorded on the CRF directly (unless recorded in the source document). 
• 
Eligibility, completion status, reason for discontinuation, seriousness of adverse events, 
severity of adverse events and causal relationship between adverse events and the study 
drug or the study procedures, and outcome 
The following data shall not be recorded directly into the CRF. 
• 
Laboratory test values 
• 
Data on the specific 20-lipoprotein fraction assay 
When the principal investigator or the investigator makes a change or correction in the data entered 
on the CRF after fixation of clinical data base, a record (Data Clarification Form; DCF) of change or 
correction on the CRF provided by the sponsor shall be used. The principal investigator shall 
confirm that the record of change or correction on the CRF is accurate and complete, and sign or 
write name/affix a seal, and date it. 


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The sponsor or the designee shall confirm that the CRFs are completed appropriately according to 
the procedures set by study. The sponsor or the designee shall have access to the medical records of 
the study subjects and in-house records to ensure the accuracy of the CRF as necessary. The 
completed CRF is the property of the sponsor, and the principal investigator or the investigator shall 
not disclose the information to a third party without a written permission from the sponsor. 
12.2 
Timing of data entry into the EDC system 
The sponsor or the designee shall request the principal investigator and investigator to promptly 
enter data into the EDC following enrolment of the study subject, each visit during study treatment, 
completion/discontinuation of the study, and follow-up period. 
12.3 
Storage of records 
The principal investigator or the chief executive of the study site shall store the following materials, 
including those specified in Section 12.1, and study-specific documents to be investigated or audited 
by the regulatory authority and the sponsor or the designee. The documents include the list of study 
subject ID code, medical records, clinical study worksheets (if used), original signed and dated 
informed consent forms, the record (copy) of modification or correction on the CRF, and electric 
copies of EDC including audit trail. The principal investigator and the chief executive of the study 
site shall appropriately retain the material/information related to this study for at least 5 years from 
the date of reporting the end of the study by the principal investigator, or for 3 years from the date of 
reporting final publication of the study result, whichever date is later. However, when the sponsor 
requires a longer storage period, the chief executive of the study site shall discuss the period and 
methods of storage with the sponsor. 


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13.0 
STATISTICAL ANALYSIS METHODS 
The person in charge of analysis and the designee [analysis personnel, who belongs to contract 
research organization (CRO) independent from the sponsor] shall perform the statistical analysis. 
The sponsor will not be involved in the statistical analysis. 
13.1 
Statistical and analytical plans 
The analysis personnel shall prepare a statistical analysis plan (SAP) before the acquisition of the 
informed consent of the earliest study subject, and issue the first edition. Detailed definition of 
endpoints and analytical methods should be specified in the SAP to deal with all the purposes of the 
study. 
13.1.1 Analysis set 
Two analysis sets, “FAS” and “SAS” are used in this study. The FAS primarily used for efficacy 
analysis will be defined as “study subjects who have been randomized and received the study drug at 
least once,” and the SAS as “study subjects who have received the study drug at least once during 
the clinical study.” 
13.1.2 Analysis of demographic and other baseline characteristics 
From “SAS” primary study subject background items will be tabulated. 
13.1.3 Efficacy analysis 
From FAS the following shall be analyzed. 
13.1.3.1 Analysis of the primary endpoint 
Change in mean particle sizes of sdLDL-C and LDL-C in the specific 20-lipoprotein fraction assay 
[Analytical method] 
1) 
At each evaluation time point during the treatment period, summary statistics (number of 
subjects, mean, standard deviation [SD], minimum value, maximum value, quartiles) and a 
two-sided 95% confidence interval for the mean will be calculated in each treatment group, 
and a diagram illustrating the change in the mean ± SD will be prepared. 
2) 
At each evaluation time point during the treatment period, percentage of change (Visit 3 or 4 
- Visit 2 in the treatment period) will be calculated in each treatment group and analyzed in 
the same manner as in the above 1). 
3) 
At each evaluation time point during the treatment period, study subjects will be stratified by 
fasting TG and ages at the start of study drug administration, and summary statistics (number 


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of subjects, mean, SD, minimum value, maximum value, quartiles) and a two-sided 95% 
confidence interval for the mean will be calculated and analyzed in each treatment group. 
4) 
At each evaluation time point during the treatment period, percentage of change from baseline 
will be calculated and analyzed in the same manner as in the above 3). 
13.1.3.2 Analysis of secondary endpoints 
1) Change in major lipid constituents in the specific 20-lipoprotein fraction assay 
2) Change in fatty acids and sdLDL-C in total lipids 
3) Change in concentration and particle number of lipids, apoprotein and lipoprotein in the 
blood 
[Analytical method] 
1) 
At each evaluation time point during the treatment period, summary statistics (number of 
subjects, mean, SD, minimum value, maximum value, quartiles) and a two-sided 95% 
confidence interval for the mean will be calculated in each treatment group, and a diagram 
illustrating the change in the mean ± SD will be prepared. 
2) 
At each evaluation time point during the treatment period, percentage of change (Visit 3 or 
4 - Visit 2 in the treatment period) will be calculated in each treatment group and analyzed 
in the same manner as in the above 1). 
3) 
At each evaluation time point during the treatment period, study subjects will be stratified 
by fasting TG and ages at the start of study drug administration, and summary statistics 
(number of subjects, mean, SD, minimum value, maximum value, quartiles) and a 
two-sided 95% confidence interval for the mean will be calculated and analyzed in each 
treatment group. 
13.1.4 Safety analysis 
From SAS the following will be analyzed. 
Adverse events 
The following analyses will be performed for each treatment group. Adverse events will be coded 
using MedDRA and summarized by System Organ Class (SOC) and Preferred Term (PT). 
 
Tabulation of frequency of all adverse events 
 
Tabulation of frequency of adverse events with a causal relationship to the study drug 
 
Tabulation of frequency of all adverse events by severity 


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 
Tabulation of frequency of adverse events with a causal relationship to the study drug by 
severity 
 
Tabulation of frequency of adverse events leading to study drug discontinuation 
 
Tabulation of frequency of serious adverse events 
 
Tabulation of frequency of all adverse events by time of onset 
13.2 
Criteria for interim analysis and premature discontinuation 
No interim analysis is planned. 
13.3 
Determination of the number of planned study subject  
50 patients evaluable for the primary endpoint 
(25 patients in the group treated with omega-3-acid ethyl esters, 25 patients in the group not treated 
with omega-3-acid ethyl esters) 
 
[Rationale for the number of planned study subjects] 
The number of planned study subjects is based on the feasibility to explore the effects of 
omega-3-acid ethyl esters on the lipid and lipoprotein profile in the blood. The number of planned 
study subjects is same in the group treated with omega-3-acid ethyl esters and the group not 
treated with omega-3-acid ethyl esters, which is not based on a statistical consideration.  


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Monitoring of the study site 
The sponsor or the designee shall perform periodic monitoring of the study site during the study to 
confirm that the study is conducted in accordance with all specifications in the study protocol. In the 
monitoring, the data recorded on the CRF will be checked by comparing them with those in the 
source documents. Source documents are the original documents, data and records. The principal 
investigator and the chief executive of the study site shall ensure that the sponsor or the designee and 
the Ethical Review Board, etc., have access to the source documents. 
The sponsor or the designee shall access the records, including the list of study subject ID codes, 
medical records of the study subjects, and signed and dated original consent forms to confirm that 
the study is appropriately conducted in compliance with the study protocol. Also, confirm the 
consistency between CRF and the related source documents. The principal investigator, investigator, 
and other personnel involved in the study shall spare sufficient time to facilitate monitoring 
procedures during visits to the study site. 
Detailed procedures for monitoring shall be described separately in the written procedures. 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the study protocol 
The principal investigator or investigator shall record all deviations from Ethical Guidelines for 
Medical and Health Research Involving Human Subjects, and study protocol. 
If any deviation is found, the principal investigator shall promptly notify the chief executive of the 
study site for the clinical study and the sponsor. As necessary, the principal investigator will discuss 
protocol revisions with the sponsor to reach agreement. For protocol revisions, draft revisions should 
be submitted as early as possible to the chief executive of the study site for approval of the 
committee such as the Ethical Review Board. 
14.3 
Quality assurance audits and regulatory agency inspections 
The sponsor or the designee shall perform audit at the study site as necessary. In such a case, the 
auditor designated by the sponsor shall contact the study site in advance to determine the date of 
audit. The auditor may ask to visit the facilities where laboratory specimens are collected and any 
other facilities used during the clinical study. In addition, this study may be inspected by regulatory 
agencies, including those of foreign governments (e.g., the Food and Drug Administration [FDA], 
the United Kingdom Medicines and Healthcare products Regulatory Agency [MHRA]). If the study 
site is contacted for an inspection by a regulatory body, the sponsor should be notified promptly. The 


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principal investigator and the chief executive of the study site shall ensure that the auditor has access 
to all the study-related source documents. 


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15.0 
ETHICAL CONDUCT OF CLINICAL STUDY 
This clinical study shall be conducted with the highest respect for the individual participants (i.e., 
study subjects) according to the study protocol, the ethical principles that have their origin in the 
Declaration of Helsinki, and “Ethical Guidelines for Medical and Health Research Involving Human 
Subjects.” Each principal investigator will conduct the study according to regulatory requirements 
and in accordance with “Responsibilities of the Principal Investigator” in Appendix B. 
15.1 
Approval of the Ethical Review Board, etc. 
The Ethical Review Board, etc., shall be constituted in accordance with the regulations. 
The sponsor or the designee should obtain the document listing the name and title of each committee 
member. When a committee member directly participates in this clinical study, the document 
describing that he/she is not participating in deliberation or voting for the study will be obtained. 
The sponsor or the designee shall supply relevant documents for submission to study site committee 
such as the Ethical Review Board for the protocol’s review and approval. In addition to the study 
protocol, a copy of the informed consent form and information sheet, written materials related to 
study subject recruitment, advertisement, and other documents required by regulations, when 
necessary, shall be submitted to the central committee or a study site committee such as the Ethical 
Review Board to obtain approval. The sponsor or the designee must obtain written approval of the 
protocol and the informed consent form and information sheet from the study site committee such as 
the Ethical Review Board before commencement of the study. The study site committee such as the 
Ethical Review Board’s approval must refer to the study by exact protocol title, number and version 
date; identify versions of other documents (e.g., informed consent form and information sheet) 
reviewed; and state the approval date. The sponsor shall notify the study site, the principal 
investigator, and investigator after confirming the validity of the regulatory documents of the study 
site. Protocol procedures such as obtainment of consent shall not be started until the study site, the 
principal investigator, and investigator receive notification. 
The study site shall observe all requirements that the Ethical Review Board, etc. prescribe. The 
requirements may include notifications to committees such as the Ethical Review Board, for 
example, revision of the protocol, revision of the informed consent form and information sheet, 
revision of materials related to study subject recruitment, reports on safety in accordance with the 
regulatory requirements, reports on status of implementation of the study at intervals determined by 
a study site committee such as the Ethical Review Board, and submission of the study completion 
report. The sponsor or the designee shall obtain written approval from the Ethical Review Board, etc. 
related to the above mentioned items and all related materials. 


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15.2 
Conflict of interest 
This clinical study shall be conducted with the support of the sponsor. 
Prior to the conduction of this clinical study, the principal investigators involved in this clinical 
study shall ensure appropriate management of any conflicts of interest (COI) in the conduct of the 
study in accordance with the rules of the study site.7)-11) 
The study site shall observe all requirements that the Ethical Review Board, etc. prescribe. This will 
include self-declaration of COI, clinical study protocol, informed consent form and information 
sheet. 
15.3 
Informed consent form and information sheet, and the agreement of the 
study subjects 
The informed consent form shall contain specific requirements of the Declaration of Helsinki, 
Ethical Guidelines for Medical and Health Research Involving Human Subjects and all applicable 
laws and regulations. The informed consent form and information sheet shall specify the use of 
personal information and medical information of study subjects in this clinical study (both in and 
outside Japan: supply to a third party), and disclosure. The informed consent form will explain in 
detail the nature of the clinical study, its objectives, and potential risks and benefits. The informed 
consent form will detail the requirements of the participant and the fact that study subject is free to 
withdraw at any time without giving a reason and without any negative effect on further medical 
care. 
The principal investigator is responsible for the preparation, contents, and approval of the informed 
consent form and information sheet by the committee such as the Ethical Review Board. The 
informed consent form and information sheet must be approved by the committee such as the Ethical 
Review Board prior to use. 
The informed consent form shall be written in language that can be easily understood by the 
potential study subjects. The principal investigator or investigator shall be responsible for providing 
detailed explanation of the informed consent form to the potential study subjects. Information should 
be given in both oral and written form whenever possible and in manner deemed appropriate by the 
committee such as the Ethical Review Board. 
The principal investigator or investigator must (1) give the opportunity to ask questions and (2) 
sufficient time to consider whether to participate in the study to the potential study subjects. If the 
potential study subject decides to participate, the informed consent form must be signed and dated by 
the potential study subject prior to entering into the study. The principal investigator or investigator 
shall instruct the potential study subject or representative to sign using their legal names, not 


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nicknames, using a blue or black ball point ink pen. Also the principal investigator or investigator 
shall sign and date the informed consent form prior to entering into the study. 
Once signed, the original informed consent form shall be retained by the principal investigator or 
investigator. The principal investigator or investigator shall record the date that the potential study 
subject signed the informed consent form in the subject’s medical record. A copy of the signed 
informed consent form shall be given to the study subject. 
The principal investigator or investigator shall follow the same procedure as for obtaining the initial 
consent when newly obtaining re-consent from the concerned study subject when the informed 
consent form and information sheet is revised. The date of obtaining new consent shall be recorded 
in the study subject’s medical record, and a copy of the revised consent form shall be provided to the 
study subject. 
15.4 
Personal information of the study subjects 
The sponsor or the designee shall affirm the principle of the protection of study subjects' 
private/personal information. Throughout this study, study subject ID codes shall be used to link the 
subject's source data to the sponsor's study database and study-related documents. Limited 
information on study subjects such as gender, age, and date of birth may be used within the scope of 
all applicable laws and regulations for identification of study subjects and confirmation of accuracy 
of study subject ID code. 
For verification of the conduct of the study in compliance with this protocol and the Ethical 
Guidelines for Medical and Health Research Involving Human Subjects, the sponsor shall require 
the principal investigator to provide the study sponsor’s designee, representatives of regulatory 
authorities, designated auditors, and committees such as the Ethical Review Board direct access to 
study subjects’ original medical records (source data or documents), including laboratory test results, 
admission and discharge records during a subject’s study participation, and autopsy reports. The 
principal investigator or investigator shall obtain specific authorization of the study subject as part of 
the informed consent process for access to study subject's original medical records by study 
sponsor’s designee and representatives of regulatory authorities (see Section 15.3). 
When providing a copy of source documents to the sponsor, the principal investigator or investigator 
shall delete information that may lead to identification of an individual (name and address of study 
subject, other personal information not recorded on the CRF of the study subject). 


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15.5 
Consultation windows for the study subjects or persons related to the study 
concerned 
The principal investigator shall establish a contact service to respond to inquiries concerning this 
clinical study from study subjects or concerned people. Details of the contacts for inquiries will be 
described in the informed consent form and information sheet. 
15.6 
Financial burden or reward to the study subjects 
Of the expenses for this clinical study, the sponsor shall offer compensation for medical treatment 
not covered by health insurance as study expenses. The study subjects shall pay expenses for 
medical treatment covered by ordinary health insurance. 
In addition, the principal investigator shall pay expenses such as transportation expenses for 
participation in this clinical study to the study subjects at each visit from the research funds. Details 
of the financial burden on the study subjects and rewards shall be described in the informed consent 
form and information sheet. 
15.7 
Benefits and inconveniences to the study subjects 
15.7.1 Benefits to study subjects 
By participating in this clinical study, the study subjects may understand one’s own condition of 
vascular endothelial function in detail. 
15.7.2 Inconveniences to study subjects 
By participating in this clinical study the burden of the study subject may increase as number of 
visits will increase compared to daily medical care. 
15.8 
Attribution of study results and access rights 
15.8.1 Attribution of study results 
The study results and data obtained from this study shall belong to the sponsor. 
15.8.2 Data access rights 
Access rights for all data and information generated from this study will be given to personnel 
approved by the sponsor. In addition, secondary use (meta-analysis, etc.) of the data obtained in this 
clinical study may be possible if used in such a way that the data shall not be linked to personal 
identification information. 


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15.9 
Reporting of results, publication, disclosure, and clinical study registration 
policy 
15.9.1 Reporting of results, publication and disclosure 
The principal investigator shall report a written summary of results of the study to the chief 
executive of the study site and provide the sponsor with all the results and data obtained from the 
study. Only the sponsor may disclose the study information to other principal investigators, 
investigators or regulatory authorities during the study period, except when required by laws and 
regulations. The sponsor shall be responsible for publication of the study protocol and study-related 
results (including the public web site) except for other cases permitted in the study contract. 
During the study period and after the end of study, the sponsor or the designee should promptly 
summarize the results and present it to medical journals and academic conferences, etc. The sponsor 
may publish any data or information obtained from the study (including data and information 
provided by the principal investigator) without obtaining agreement of the principal investigator. 
The principal investigator or the investigator should obtain the prior written approval from the 
sponsor when publishing the information obtained in this study at an academic conference, etc. 
15.9.2 Clinical study registration 
To ensure that information on clinical study is made accessible to the public in a timely manner and 
to comply with applicable laws, regulations, and guidelines, Takeda Pharmaceutical Company 
Limited shall register all clinical study being conducted in patients around the world at public trial 
registration sites, including at least the website(s) of ClinicalTrials.gov (and) Japan Pharmaceutical 
Information Center Clinical Trials Information (JAPIC), before initiation of the clinical study. On 
such websites, the study location (city, country), study subject recruitment status, and contact 
information for Takeda Pharmaceutical Company Limited are open to the public. 
15.9.3 Clinical trial results disclosure 
Takeda Pharmaceutical Company Limited shall post the study results, irrespective of the nature of 
the results, at the public trial registration site(s) of Clinical Trials.gov (and) JAPIC in accordance 
with applicable laws and regulations. 
15.10 Insurance and compensation for injury 
In case of injuries, each study subject in the clinical study must be insured in accordance with the 
regulations applicable to the study site where the subject is participating. The sponsor or the 
designee shall buy an insurance policy to compensate for health injury in study subjects. 


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Healthy injury in a study subject will be compensated as specified in the study contract. 
Compensation-related questions by the principal investigator or investigators should be made to the 
sponsor or the designee. 


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16.0 
REFERENCES 
1. 
Austin MA. Low density lipoprotein subclass patterns and risk of myocardial infarction. 
N Engl J Med. 1995; 333: 1301-1307. 
2. 
Koba S, et al. Small dense low density lipoprotein in Japanese men with coronary artery 
disease. 
J Am Coll Cardiol. 2009; 53(23): 2186-2196. 
3. 
Tatsuno I, Saito Y, et al. Efficacy and safety of TAK-085 compared with eicosapentaenoic 
acid in Japanese subjects with hypertriglyceridemia undergoing lifestyle modification: the 
omega-3 fatty acids randomized double-blind(ORD)study. 
J Clin Lipidol. 2013; 7(3):199-207. 
4. 
Tousoulis D, Plastiras A, et al. Omega-3 PUFAs improved endothelial function and arterial 
stiffness with a parallel antiinflammatory effect in adults with metabolic syndrome.  
Atherosclerosis. 2014; 232(1):10-16. 
5. 
Lotriga® Granular Capsules, Package Insert (Version 5 revised in December 2013) 
6. 
Okazaki M and Yamashita S. Recent advances in analytical methods on lipoprotein 
subclasses: caluculation of particle numbers from lipid levels by gel permeation HPLC using 
"Sphericial Particle Model".  
J. Oleo sci. 2016; 65(4) :265-282. 
7. 
Report of the Working Group on Conflict of Interest (Ministry of Education, Culture, Sports, 
Science and Technology dated November 1, 2002) 
8. 
Guidelines for determining the conflict of interest polity for clinical research (Review group 
for ethical aspects of clinical study and conflict of interest, March 2006) 
9. 
Guidelines on the Management of COI in Health and Labor Sciences Research (No. 0331001, 
science, issued on March 31, 2008, and approved by the Chief of the Health Sciences 
Division) 
10. Guidelines for management of COI in medical research (COI Committee of Japan 
Association of Medical Sciences, February 2011) 
11. Common guidelines for conflict of interest (COI) in clinical research (Japanese Society of 
Internal Medicine, Japan Society of Hematology, Japanese Circulation Society, Japan 
Endocrine Society, Japan Diabetes Society, Japan Geriatrics Society, Japanese Respiratory 
Society, Japanese Society of Hematology, Japanese Society of Allergology, Japanese 
Association for Infectious Diseases, Aug 2011) 


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Appendix A 
Schedule for Study Procedures 
Screening 
period 
Treatment period 
Discontinua- 
tion(e) 
Visit timing 
Week 
-4 
0 
4 
8 
Day 
-1(d) 
28 
56 
Window (day) 
-29 to -1 
-15 to -1 
14 to 41 
42 to 70 
Within 3 
days after the 
last dose 
Visit No. 
1 
2 
3 
4 
Informed consent 
X 
Inclusion/exclusion 
criteria 
X 
Demographic data, 
medical history, previous 
treatment drug(s) 
X 
Physical examination 
X 
X 
X 
X 
X 
Height 
X 
Body weight 
X 
BMI 
X 
Vital signs 
X 
X 
X 
X 
X 
Concomitant drugs(a) 
X 
X 
X 
X 
X 
Concurrent disease 
X 
X 
Laboratory tests 
Hematology/ Serum 
chemistry 
X(c) 
X 
X 
X 
X 
Specific lipoprotein 
fraction assay(b) 
X(c) 
X 
X 
X 
X 
Lipoprotein assay(b) 
X(c) 
X 
X 
X 
X 
Mean particle diameter 
of LDL/HDL(b) 
X(c) 
X 
X 
X 
X 
Fatty acid fraction in 
total lipids 
X(c) 
X 
X 
X 
X 
Others 
X(c) 
X 
X 
X 
X 
Study drug prescription 
X 
X 
Treatment compliance 
X 
X 
X 
Food and drink 
consumption before the 
visit 
X 
X 
X 
X 
Evaluation of adverse 
events 
←X→ 
←X→ 
←X 
←X 
 
(a) All concomitant drugs will be recorded. 
(b) By HPLC 
(c) To be performed before the Visit 2 tests 
(d) Medication will be started the day after the completion of all the tests of Week 0. The start date of medication will 
be referred to as Day 1. 
(e) To be performed to the extent possible 
 


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Appendix B Responsibilities of the Principal Investigator 
1. 
To appropriately conduct the clinical study in compliance with this study protocol and the 
“Ethical Guidelines for Medical and Health Research Involving Human Subjects” and with the 
highest respect for human rights, safety, and welfare of study subjects. 
2. 
To prepare a list of any other investigators and/or study collaborators when certain important 
study-related activities are divided by investigators and/or study collaborators, and submit the 
list to the sponsor as required. 
3. 
To prepare the informed consent form and information sheet and revise it as necessary. 
4. 
To check the contents of the study contract. 
5. 
To provide sufficient information on the protocol, drug and duties of each personnel to 
investigators and study collaborators, and give guidance and supervision. 
6. 
To select study subjects who satisfy the inclusion criteria, give explanation using written 
information, and obtain consent in writing. 
7. 
To be responsible for all medical judgments related to the clinical study. 
8. 
Corresponding to request from the chief executive of the study site, to report the latest progress 
status at least once a year to the chief executive of the study site. 
9. 
To confirm and comprehended the most update status regarding the COI of the investigators 
participating in the clinical study according to the procedure at an affiliated study site. 
10. To ensure, together with the chief executive of the study site, that sufficient medical care is 
provided to study subjects for all study-related clinically problematic adverse events throughout 
the period of subjects’ study participation and thereafter. 
11. When a study subject is treated at another medical institution or department, to inform the 
acting physician at the medical institution or department in writing of the study subject’s study 
participation and study completion/discontinuation after obtaining the study subject’s consent, 
and prepare a record. 
12. When emergency reporting of serious adverse events, etc., is required, to immediately report it 
in writing to the chief executive of the study site and the sponsor. 
13. To prepare correct and complete CRFs, and submit them to the sponsor with an electronic 
signature. 
14. To verify any entries on the CRFs prepared by the investigator or transcribed by the study 
collaborator from source data, electronically sign and submit them to the sponsor. 
15. To discuss a revision of the protocol, etc., when proposed by the sponsor. 
16. To report the study completion in writing to the chief executive of the study site. 

SAP_001.pdf: 
 
 
Title: Lipoprotein-Modifying Effects of Omega-3 Fatty Acids Ethyl Esters Analyzed by 
High Performance Liquid Chromatography in Patients with Hypertriglyceridemia 
(LOTUS) 
 
NCT Number: NCT02839902 
Statistical analysis plan Approve Date: 31-Oct-2017 
 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 


 
 
 
Lipoprotein-Modifying Effects of Omega-3 Fatty Acids Ethyl Esters 
Analyzed by High Performance Liquid Chromatography in Patients 
with Hypertriglyceridemia (LOTUS) 
(Protocol number:TAK-085-4002) 
 
 
Statistical Analysis Plan 
(Ver.2.0:31OCT2017) 
 
 
Sponsor: Takeda Pharmaceutical Company Limited 
 
 
 
 
Authorizer:  
Takeda Pharmaceutical Company Limited 
 
Biostatistics Manager: 
 
PPD
PPD
PPD
PPD


Contents 
1 
DEFINITIONS of TERMS ............................................................................................ 1 
2 
TIME WINDOW ............................................................................................................ 1 
3 
ANALYSIS SET ............................................................................................................. 1 
4 
CONSIDERATIONS for ANALYSIS ............................................................................ 1 
5 
OTHER DATA HANDLING .......................................................................................... 2 
6 
SUBJECTS, DEMOGRAPHIC and OTHER BASELINE CHARACTERISTICS ..... 3 
6.1 
Subject Disposition ................................................................................................. 3 
6.2 
Demographics and Other Baseline Characteristics ............................................. 5 
6.3 
Compliance .............................................................................................................. 7 
7 
EFFICACY EVALUATIONS ......................................................................................... 8 
7.1 
Primary Endpoint and the Analytical Methods ................................................... 8 
7.2 
Secondary Endpoints and the Analytical Methods .............................................. 9 
7.3 
Other Analyses ....................................................................................................... 9 
8 
SAFETY EVALUATION ................................................................................................ 9 
8.1 
Frequency of Adverse Event Occurrence .............................................................. 9 
8.2 
Vital Signs and Laboratory Test .......................................................................... 12 
9 
LISTING ....................................................................................................................... 13 
10 
CONSIDERATIONS on STATISTICAL ANALYSIS .............................................. 13 
10.1 Adjustments for Covariates ................................................................................. 13 
10.2 Handling of Dropouts or Missing Data ............................................................... 13 
10.3 Criteria for Interim Analysis and Early Discontinuation ................................. 13 
10.4 Multicenter Studies .............................................................................................. 13 
10.5 Multiple Comparisons/Multiplicity ..................................................................... 13 
10.6 Subgroup Analysis ................................................................................................ 13 
11 
REVISION HISTORY .............................................................................................. 15 
Appendix 1 Details of Analysis Variables .......................................................................... 17 
 


 
1 
 
1 
DEFINITIONS of TERMS 
・ Summary Statistics: Number of subjects, mean, standard deviation, maximum values, 
minimum values, and quartiles. 
・ Treatment Group:Treated with Omega-3 FAE, Not treated with Omega-3 FAE 
 
2 
TIME WINDOW 
For each assessment, observation and evaluation item, evaluable data is selected according to 
the following table. When there are multiple data exist within a time window, the one with the 
closest date to the reference date is adopted, and if the differences from the reference date are 
the same for multiple data, the later one is adopted. 
 
＜Vital Sign, Laboratory Tests, Lipoprotein Fraction＞ 
Time Point 
Reference Date 
Time Allowance 
Number of Study Days 
Week 0 
-1 
-15～-1 
Week 4 
28 
14～41 
Week 8 
56 
42～70 
 
*Treated with Omega-3 FAE: The day before study drug administration is indicated as “Day -1” 
and “Day 1” for the administration day. 
Not Treated with Omega-3 FAE: The day of visit at Week 0 is indicated as “Day -1” and “Day 
1” for the next day after the visit. 
 
3 
ANALYSIS SET 
・ Full Analysis Set 
The subjects who were randomized and given at least one dose of the study drug. 
・ Safety Analysis Set 
The subjects who are given at least one dose of the study drug. 
 
4 
CONSIDERATIONS for ANALYSIS 
・ Significance level, Confidence coefficient  
Significance level of 5%(2-sided) will be used for analysis. 
Confidence coefficient of 95% (2-sided) will be used for all confidence intervals. 
・ Display digit 
 [Mean, Confidence coefficient, Quartiles] 
Round to the one digits lower than significant digits of the data. 


 
2 
 
 [Standard Deviation] 
Round to the 2 digits lower than significant digits of the data. 
 [Minimum and Maximum Values] 
Display the data at the significant digits.  
 [Proportion, Percentage] 
Round to the one decimal place. 
[P-value] 
 Round down to four decimal places. If p-value is less than 0.0001, display “p<0.0001” 
 
5 
OTHER DATA HANDLING 
[Data Handling for Study Drug] 
・ Duration of Treatment(Treated with Omega-3 FAE) 
Duration of Treatment = Date of the Last Dose – Date of the First Dose + 1 
 
[Data Handling for Duration of Hyperlipidemia] 
・ Duration of hyperlipidemia (year) 
Duration of hyperlipidemia (year) = (Date of first dose (year/month) – Onset/Diagnosis 
Date of hyperlipidemia (year/month)) / 12 (rounded off to two decimal places) 
If only the month of the onset of hyperlipidemia is unknown, the month of the onset of 
hyperlipidemia is regarded as “January”. 
 
[Data Handling for Below (or Above) the limit of Quantification] 
・ Efficacy Data 
(Laboratory Test (except Total Cholesterol, TG, HDL-C) and Lipoprotein Fraction) 
Below (or equal to) the limit of Quantification: Lower Limit of Quantification to be 
replaced. 
Above (or equal to) the limit of Quantification: Upper Limit of Quantification to be 
replaced. 
・ Safety Data 
(Vital Sign and Laboratory Test (Total Cholesterol, TG, HDL-C)) 
Below (or equal to) the limit of Quantification: 0 to be replaced. 
Above (or equal to) the limit of Quantification: Upper Limit of Quantification to be 
replaced. 
 
[Data Handling for Adverse Event] 


 
3 
 
・ An adverse event is defined as any untoward medical occurrence in a patient or a subject 
receiving a pharmaceutical product (including the study drug). It does not necessarily have 
an apparent causal relationship with this pharmaceutical product (including study drug). 
A treatment-emergent AE (TEAE) is defined as an AE which occurs after taking the first 
dose of trial medication. 
The first dose date of “Not treated with Omega-3 FAE” is defined as the next day of the 
visit in Week 0. 
・ Time to first Onset 
Time to first Onset=AE Start date - The first dose date + 1 
・ Related AE 
AE is classified into Related/Not Related only for Treated with Omega-3 FAE group 
・ Non-Serious TEAEs 
Non-Serious TEAE is defined as Non-Serious TEAEs of at least 5% in any treatment group 
by SOC and PT. 
 
[Laboratory Test] 
・ (EPA+DHA)/AA Ratio 
(Eicosapentaenoic Acid + Docosahexaenoic Acid)/ Arachidonic Acid  
・ DHA/AA Ratio 
Docosahexaenoic Acid / Arachidonic Acid  
・ non-HDL 
Total Cholesterol - HDL-C 
 
6 
SUBJECTS, DEMOGRAPHIC and OTHER BASELINE CHARACTERISTICS 
6.1 
Subject Disposition 
6.1.1 Study Information 
Analysis Set: All subjects who were obtained informed consent 
Analysis Variables: The earliest date of informed consent 
The latest date of the last date of administration 
MedDRA Version 
SAS Version 
Analysis Methods: For the above analysis items, the following analysis will be 
performed. 
(1) Show the above items. 
The latest date of the last date of administration will be presented only for 
treated with Omega-3 FAE. 


 
4 
 
6.1.2 Eligibility of Subjects 
Analysis Set: All subjects who were obtained informed consent 
Analysis Variables: Randomization into the treatment period of the study 
[Yes, No (and the reason)] 
Analysis Methods: For the above analysis items, the following analysis will be 
performed. 
(1) Summary of frequency distribution 
 
6.1.3 Disposition of Subjects 
6.1.3.1 Status at the End of Study 
Analysis Set: Randomized subjects 
Analysis Variables: Status at the end of study 
[Complete, Incomplete (and the reason)] 
Analysis Methods: For the above analysis items, the following analysis will be 
performed for each treatment group and all subjects in the analysis set. 
(1) Summary of frequency distribution 
 
6.1.4 Protocol Deviations and Analysis Datasets 
6.1.4.1 Protocol Deviations  
Analysis Set: Randomized subjects 
Analysis Variables: Protocol Deviations 
[Major GCP Violations, Deviations of Protocol Entry Criteria, 
Deviations of Discontinuation Criteria, Deviations Related to 
Treatment Procedure or Dose, Deviations Concerning Excluded 
Medication or Therapy, Deviations to Avoid Emergency Risk, Other 
Deviations] 
Analysis Methods: For the above analysis items, the following analysis will be 
performed for each treatment group and all subjects in the analysis 
set. 
(1) Frequency distribution 
Summarize the number of subjects who have deviated from the 
protocol, classify the deviations into above category, and show the 
breakdown of deviations. Subjects applicable for multiple 
categories will be counted once in each category. 
 


 
5 
 
6.1.4.2 Datasets Analyzed 
Analysis Set: Randomized subjects 
Analysis Variables: Full Analysis Set [Inclusion, Exclusion] 
Safety Analysis Set [Inclusion, Exclusion] 
Analysis Methods: For the above analysis items, the following analysis will be 
performed for each treatment group and all subjects in the 
analysis set.  
(1) Summary of frequency distribution  
 
6.2 
Demographics and Other Baseline Characteristics 
6.2.1 Distribution of Demographics Items 
Analysis Set; Safety Analysis Set, Full Analysis Set 
Analysis Variables:  
Age(Week -4)(years)  [Min<= - <65, 65<=Max] 
Age (Week 0) (years) [Min<= - <65, 65<=Max] 
Gender [Male, Female] 
Height (Week -4) (cm) [Min<= - <150, 150<= - <160,  
160<= - <170, 170<= - <=Max] 
Weight (Week -4) (kg) 
[Min<= - <50.0, 50.0<= - <60.0, 
60.0<= - <70.0, 70.0<= - <80.0, 
80.0<= - <=Max] 
BMI(Week -4)(kg/m2)[Min<= - <18.5, 18.5<= - <25.0 
25.0<= - <=Max]  
Duration of Hyperlipidemia (years) [Min<5, 5<=Max] 
Frequency of Fish Intake [Almost Every Day, About Every Two Days, 
About Once or Twice Per Week, Rarely] 
Smoking Classification [Never Smoked, Current Smoker, Ex-Smoker] 
Drink Alcohol Almost Every Day?  [Yes, No] 
Fasting Triglycerides(Week -4)(mg/dL) 
[Min<= - <300, 300<= - <=Max] 
Fasting Triglycerides (Week 0)(mg/dL) 
[Min<= - <300, 300<= - <=Max] 
Cholesterol Concentration in sd LDL Fraction (Week 0) 
Triglycerides Concentration in sd LDL Fraction (Week 0) 
Free Cholesterol Concentration in sd LDL Fraction (Week 0) 


 
6 
 
Phospholipid Concentration in sd LDL Fraction (Week 0) 
Particle Size (nm) of LDL (Cholesterol Monitor) (Week 0) 
Particle Size (nm) of LDL (Triglycerides Monitor) (Week 0) 
Particle Size (nm) of LDL (Free Cholesterol Monitor) (Week 0) 
Particle Size (nm) of LDL (Phospholipid Monitor) (Week 0) 
 
Analysis Methods: For the above analysis items, the following analysis will be 
performed for each treatment group and all subjects in the 
analysis set. 
(1) Summary of frequency distribution for discrete variables 
and summary statistics for continuous variables. 
 
6.2.2 Medical History and Concurrent Medical Conditions 
Analysis Set: Safety Analysis Set 
Analysis Variables: Medical history, Concurrent medical conditions 
Analysis Methods: For the above analysis items, the following analysis will be 
performed for each treatment group. Analysis variables will 
be coded using the MedDRA dictionary and be summarized 
into SOC and PT. SOCs will be sorted in alphabetical order, 
then PTs will be sorted in frequency order. 
(1) Medical history: Summary of frequency distribution by 
SOC/PT 
(2) Concurrent medical conditions: Summary of frequency 
distribution by SOC/PT 
     The method of accounting for the frequency is as follows. 
     [Number of subjects with AE] 
For each summary, subjects with one or more events within a level of 
SOC term is counted only once in that level. Similarly, subjects with 
one or more events within a level of PT term is counted only once in 
that level. 
 
6.2.3 Medication History and Concomitant Medications 
Analysis Set: Safety Analysis Set 
Analysis Variables:  
HMG-CoA Reductase Inhibitor 
Medication history 


 
7 
 
Concomitant medications 
Analysis Methods: For the above analysis items, the following analysis will be 
performed for each treatment group. Analysis variables will be 
coded using the WHO (World Health Organization) Drug. 
Coded medications will be sorted in frequency order. 
Medications used more than once within a subject will be 
counted only once for the subject. 
(1) Summary of frequency distribution of HMG-CoA 
Reductase Inhibitor 
(2) Summary of frequency distribution of medication history 
(3) Summary of frequency distribution of concomitant 
medications that started and stopped prior to baseline  
(4) Concomitant medications that were ongoing at baseline 
and those that started after baseline 
 
6.3 
Compliance  
6.3.1 Study Medication Compliance 
Analysis Set: Safety Analysis Set 
Analysis Variables: Study medication compliance (%) 
 [(Min<= - <50.0, 50.0<= - <=Max]  
Time Point: Week 4, Week 8 
Analysis Methods: For the above analysis items, the following analysis will be 
performed for treated with Omega FAE group by time point.  
(1) Summary of frequency distribution 
 
6.3.2 Diet Compliance before Visit 
Analysis Set: Safety Analysis Set 
Analysis Variables: Any Alcohol from 9:00 PM on 2 days before or 9:00 PM on 
previous day to Fasting Test? [Yes, No] 
Overeat or Overdrink or Extreme Diet Change on the day 
before fasting test? [Yes, No] 
Time Point: Week 4, Week 8 
Analysis Methods: For the above analysis items, the following analysis will be 
performed for each treatment group and all subjects in the 
analysis set by time point. 
(1) Summary of frequency distribution 


 
8 
 
 
6.3.3 Study Medication Exposure 
Analysis Set: Safety Analysis Set 
Analysis Variables: Duration of exposure (days), 
  [1<= - <29, 29<= - <57, 57<= - <=Max] 
Analysis Methods: For the above analysis items, the following analysis will be 
performed for each treatment group and all subjects in the 
analysis set. 
(1) Summary of frequency distribution for categorical variables 
and summary statistics for continuous variables 
 
7 
EFFICACY EVALUATIONS 
7.1 
Primary Endpoint and the Analytical Methods 
Analysis Set: Full Analysis Set 
Analysis Variables: Change of sd LDL-C by Lipoprotein fraction and particle size 
of LDL  
Time Point：Week 0, Week 4, Week 8 
Stratified Variable: Fasting Triglycerides (Week -4)  
 [Min<= - <300, 300<= - <Max] 
Age (Week -4) [Min<= - <65, 65<= - <Max]  
Analysis Methods: 
(1) Summary statistics of observed value and 95% confidence interval 
for the mean will be calculated by treatment groups and time point. 
In addition, Mean (+/-SD) plots will be made by treatment group and 
time point. Mean differences and the 95% confidence interval 
(two-sided) will also be provided.  
(2) The same analyses described in (1) will be performed on percent 
change from baseline. 
(3) Subgroup analysis of observed value and percent change from 
baseline will be conducted by stratified variables described above. 
Summary statistics, 95% confidence interval for the mean, mean 
differences and the 95% confidence interval (two-sided) will be 
provided. 
(4) The same analyses described in (3) will be performed on percent 
change from baseline. 


 
9 
 
(5) ANCOVA (analysis of covariance), with Fasting Triglycerides at 
week -4(Min<= - <300, 300<= - <=Max), and Age at week 
-4(Min<= - <65, 65<= Max) as covariate, Treatment group as 
independent variable, will be applied to the data of percent change at 
Week 0 to Week 8. (alpha=0.05 through an ANCOVA strategy) 
 
7.2 
Secondary Endpoints and the Analytical Methods 
Analysis Set: Full Analysis Set 
Analysis Variables:  
(1) Change of lipid component by Lipoprotein Fraction in Major Lipid  
(2) Change of fatty acid in all lipid and sd LDL-C 
(3) Change of serum lipid, lipid concentration of apolipoprotein and 
lipoprotein and particle number of lipoprotein  
* See appendix 1 for detail of items. 
Time Point: Week 0, Week 4, Week 8 
Stratified Variable: Fasting Triglycerides (Week -4) 
 [Min<= - <300, 300<= - <Max] 
Age (Week -4) [Min<= - <65, 65<= - <Max]  
Analysis Methods: The same analyses described in 7.1 will be performed on the 
Items described above. 
For the Analysis variable 2), exploratory analysis will be 
performed about relationship between percent change from 
baseline of sd LDL at Week 8 and percent change from 
baseline of fatty acid in all lipid at Week 8. 
 
7.3 
Other Analyses 
Analysis Set: Full Analysis Set  
Analysis Variables:Lipoprotein Lipase, HS-CRP  
Time Point: Week 0, Week 4, Week 8 
Analysis Methods: The same analyses described in 7.1(1), (2) will be performed on 
the Items described above. 
 
8 
SAFETY EVALUATION 
8.1 
Frequency of Adverse Event Occurrence 
8.1.1 Brief Summary of Adverse Events 
Analysis Set: Safety Analysis Set 


 
10 
 
Analysis Variables: Adverse Event(Treatment-Emergent Adverse Events),  
Non-Serious TEAEs 
Category Classification:  
Causal relationship with treatment drug [Related, Not related] 
Severity [Mild, Moderate, Severe] 
Time to onset [1<= - <29, 29<= - <57, 57<= - <=Max]   
For the above analysis items, the following analyses of frequency distribution will 
be performed. 
1) All TEAEs 
2) Drug-related TEAEs 
3) All TEAEs by severity 
4) Drug-related TEAEs by severity. 
5) TEAEs leading to discontinuation 
6) Serious TEAEs 
7) Drug-related serious TEAEs 
8) Serious TEAEs leading to discontinuation 
9) TEAEs leading to death 
10) TEAEs by time to onset 
Incidence rates will be calculated as following on each analysis. 
       [Number of Subjects] 
      ・Frequency by Severity 
Subjects with one or more adverse events within a level of MedDRA term 
is counted only once in that level using the most severe incident. The 
denominator when calculating the incidence of adverse events is the 
number of subjects of safety analysis set. 
      ・Frequency by Time to Onset 
        Subjects with one or more adverse events within a level of MedDRA term 
is counted in each period. The denominator when calculating the 
incidence of adverse events is the subject that “Drug continued after the 
period” or “TEAE was occurred after the period”. The numerator is the 
subject that “TEAE occurred in the period”.  
    ・Analyses Other Than the Above 
Subjects with one or more adverse events within a level of MedDRA term 
is counted only once for that MedDRA term. The denominator when 
calculating the incidence of adverse events is the number of subjects of 
safety analysis set. 


 
11 
 
 
8.1.2 Display of TEAE 
Analysis Set: Safety Analysis Set 
Analysis Variables: TEAE 
Category Classification: 
Relationship with treatment drug [Related, Not Related] 
Severity [Mild, Moderate, Severe] 
Time to onset [1<= - <29, 29<= - <57, 57<= - <=Max]   
Analysis Methods: For the above analysis items, the following analysis will be 
performed for each treatment group. Analysis variables will be coded using the 
MedDRA dictionary and be summarized into SOC and PT. SOCs will be sorted in 
alphabetical order, then PTs will be sorted in frequency order. 
1) All TEAEs by SOC and PT 
2) Drug-related TEAEs by SOC and PT 
3) All TEAEs by severity by SOC and PT 
4) Drug-related TEAEs by severity by SOC and PT 
5) TEAEs leading to discontinuation by SOC and PT 
6) Serious TEAEs by SOC and PT 
7) Non-serious TEAEs of at least 5% in any group by SOC and PT 
8) Drug-related serious TEAEs by SOC and PT 
9) Serious TEAEs leading to discontinuation by SOC and PT 
10) TEAEs leading to death 
11) TEAEs by time to onset, SOC and PT. 
 
  Incidence rates will be calculated as following on each analysis. 
   [Number of Subjects] 
      ・Frequency (by SOC/PT) 
Within each summary, subjects with one or more adverse events within a 
level of SOC term is counted only once in that level. Similarly, subjects 
with one or more adverse events within a level of PT term is counted only 
once in that level. The denominator when calculating the incidence of 
adverse events is the number of subjects of safety analysis set. 
     ・Frequency by Severity (by SOC/PT) 
Subjects with one or more adverse events within a level of SOC/PT term 
is counted only once in that level using the most severe incident. The 
denominator when calculating the incidence of adverse events is the 


 
12 
 
number of subjects of safety analysis set. 
      ・Frequency by Time to Onset 
        Subjects with one or more adverse events within a level of MedDRA term 
is counted in each period. The denominator when calculating the 
incidence of adverse events is the subject that “Drug continued after the 
period” or “TEAE was occurred after the period”. The numerator is the 
subject that “TEAE occurred in the period”.  
 
8.2 
Vital Signs and Laboratory Test  
8.2.1 Vital Signs 
Analysis Set: Safety Analysis Set 
Analysis Variables: Sitting blood pressure (Systolic, Diastolic), Sitting Pulse (bpm) 
Time Point: Week 0, Week 4, Week 8 
Analysis Methods: For the above analysis items, the following analysis will be 
performed 
(1) Summary statistics for observed value will be calculated by Time point. 
Line plot of individual data will also be provided. 
(2) The same analyses described in (1) will be performed on change (Week4 /8 
–Week 0) from baseline. 
 
8.2.2 Laboratory Test 
Analysis Set: Safety Analysis Set 
Analysis Variables: Hematology (Platelets) 
Serum Chemistry(Total Cholesterol, TG, HDL-C, non-HDL , 
LDH, AST, ALT, ALP, γ-GTP, CK(CPK)) 
Category Classification: Classification by reference value 
[Lower, Normal, High] 
Time Point: Week 0, Week 4, Week 8 
Analysis Methods: For the above analysis items, the following analysis will be 
performed 
(1) Summary statistics for observed value will be calculated by time point. 
Line plot of individual data will also be provided. 
(2) The same analyses described in (1) will be performed on change (Week4 /8 
–Week 0) from baseline. 
(3) Shift table will be reported by time point with classification above. 
 


 
13 
 
9 
LISTING 
Following lists will be create for randomized subjects 
・Demographics 
・Medical history 
・Concurrent medical conditions 
・Medication history 
・Concomitant medications 
・Compliance of drug exposure 
・Discontinued subjects 
・Vital Signs 
・Laboratory Test (Lipoprotein fraction) 
・Laboratory Test (Hematology, Serum chemistry) 
・Laboratory Test (Apoprotein, Remnant lipoprotein) 
・Laboratory Test (Fatty acid analysis of total serum lipids) 
・Adverse Events 
 
10 CONSIDERATIONS on STATISTICAL ANALYSIS 
10.1 Adjustments for Covariates 
ANCOVA will be performed on primary and secondary endpoints with Fasting triglycerides at 
week -4(Min<= - <300, 300<= - <=Max), and Age at week -4(Min<= - <65, 65<= Max) as 
covariate. Details are described in 7.1(5) and 7.2. 
 
10.2 Handling of Dropouts or Missing Data 
Imputation will not be performed. 
 
10.3 Criteria for Interim Analysis and Early Discontinuation 
Interim analysis will not be performed. 
 
10.4 Multicenter Studies 
Analyses for consideration of centers will not be performed. 
 
10.5 Multiple Comparisons/Multiplicity 
It does not adjust multiplicity. 
 
10.6 Subgroup Analysis 
    Subgroup analysis will be performed in 7.1 and 7.2. 


 
14 
 
 
 
 


 
15 
 
11 REVISION HISTORY 
 
Ver. 
Date 
Author 
Revised Content 
Reason for 
Revision 
1 
30NOV2016 
First Edition 
 
2 
31OCT2017 
5.OTHER DATA HANDLING 
[Data Handling for Adverse 
Event] 
“Non-Serious TEAEs” and 
“Laboratory Test” 
Additional items 
 
 
 
6.1.3.1.Status at the End of Study 
Analysis Variables: 
(Before)  
Status at the End of Study 
Drug  
(After)  
Status at the End of Study 
Analysis Methods: 
(Before)  
For the above analysis items, the 
following analysis will be 
performed only for Treated with 
Omega-3 FAE 
(After) 
 For the above analysis items, the 
following analysis will be 
performed for each treatment 
group and all subjects in the 
analysis set. 
Correction of errors 
PPD
PPD


 
16 
 
Ver. 
Date 
Author 
Revised Content 
Reason for 
Revision 
 
 
 
8.1.1.Brief Summary of Adverse 
Events 
Analysis Variables: 
(Before)  
Adverse Events 
(Treatment-Emergent Adverse 
Events) 
(After)  
Adverse Events 
(Treatment-Emergent Adverse 
Events),  
Non-Serious TEAEs 
Additional items 
 
 
 
8.1.2.Display of TEAE 
Non-serious TEAEs of at least 5% 
in any group by SOC and PT 
Additional items 
 
 
 
8.2.1.Vital Signs  
(3) Shift table, by using 
classification based on criteria, 
will be made at each time point 
(Week 4 or Week 8) from Week 0  
Deleted the 
section in terms of 
meaning of Vital 
Signs in this Study 
 
 
 
8.2.2.Laboratory Test 
Analysis Variables: 
(Before)  
Serum Chemistry (LDH, AST, 
ALT, ALP, γ-GTP, CK(CPK)) 
(After) 
Serum Chemistry(Total 
Cholesterol, TG, HDL-C, 
non-HDL , LDH, AST, ALT, ALP, 
γ-GTP, CK((CPK) )  
Correction of errors 
 
 
 
Category Classification: 
Classification by reference value 
[Lower, Normal, High] 
Additional items 


 
17 
 
Appendix 1 Details of Analysis Variables 
Primary Efficacy Endpoint and Secondary Efficacy Endpoint in Protocol are described below in 
detail. 
1.  Efficacy Analysis 
1.1  Primary Endpoint 
1) Change of sd LDL-C by Lipoprotein fraction and particle size of LDL  
 (1) sd LDL-C by Lipoprotein Fraction 
Cholesterol Concentration in sd LDL Fraction 
Triglycerides Concentration in sd LDL Fraction  
Free Cholesterol Concentration in sd LDL Fraction 
Phospholipid Concentration in sd LDL Fraction 
TG/Cholesterol ratio in sd LDL Fraction 
(2) Particle Size of LDL 
Particle Size of LDL (Cholesterol Monitor) 
Particle Size of LDL (Triglycerides Monitor) 
Particle Size of LDL (Free Cholesterol Monitor) 
Particle Size of LDL (Phospholipid Monitor)  
 
1.2  Secondary Endpoint 
1)  Change of Lipid component by Lipoprotein Fraction in Major Lipid 
(1)Lipoprotein Fraction (CM) 
 
Cholesterol Concentration in CM 
TG Concentration in CM  
Free Cholesterol in CM  
Phospholipid Concentration in CM 
(2)Lipoprotein Fraction in (VLDL) 
Cholesterol Concentration in VLDL 
TG Concentration in VLDL 
Free Cholesterol in VLDL 
Phospholipid Concentration in VLDL 
(3)Lipoprotein Fraction (LDL) 
Cholesterol Concentration in LDL 
TG Concentration in LDL 
Free Cholesterol in LDL 
Phospholipid Concentration in LDL 
(4)Lipoprotein Fraction (HDL) 


 
18 
 
Cholesterol Concentration in HDL 
TG Concentration in HDL 
Free Cholesterol in HDL 
Phospholipid Concentration in HDL 
 
2) Change of fatty acid in all lipid and sd LDL-C 
(1) Fatty acid in all lipid 
Lauric Acid 
Myristic Acid 
Myristoleic Acid 
Palmitic Acid 
Palmitoleic Acid 
Stearic Acid 
Oleic Acid 
Linoleic Acid 
Gamma-linolenic Acid 
Linolenic Acid 
Arachic Acid 
Eicosenoic Acid 
Eicosadienoic Acid 
Eicosatrienoic Acid 
Dihomo-gamma-linolenic Acid 
Arachidonic Acid 
Eicosapentaenoic Acid 
Behenic Acid 
Erucic Acid 
Docosatetraenoic Acid 
Docosapentaenoic Acid 
Lignoceric Acid 
Docosahexaenoic Acid 
Nervonic Acid 
T/T ratio 
EPA/AA ratio 
(EPA+DHA) /AA ratio 
DHA/AA ratio 
(2)sd LDL-C 


 
19 
 
* Exploratory analysis will be performed for the relationship between percent 
change from baseline of sd LDL at week8 and percent change from baseline 
of fatty acid in all lipid. 
 
3) Change of serum lipid, lipid concentration of apolipoprotein and lipoprotein and particle 
number of lipoprotein 
(1) Serum lipid 
Total Cholesterol 
TG 
HDL-C (Direct) 
non-HDL 
(2)Apolipoprotein and Lipoprotein 
Apolipoprotein A1 
Apolipoprotein A2 
Apolipoprotein B 
Apolipoprotein B-48 
Apolipoprotein B-100 
Apolipoprotein C-II 
Apolipoprotein C-III 
Apolipoprotein C- II / C-III 
Apolipoprotein E 
RemL-C  
(3) Particle Number of lipoprotein 
Particle Number in CM Fraction  
Particle Number in VLDL Fraction  
Particle Number in LDL Fraction  
Particle Number in HDL Fraction