Conditions: Hyperlipidemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 37
Healthy volunteers: no

Brief summary:
The purpose of this study is to explore the effects of omega-3-acid ethyl esters (TAK-085) on vascular endothelial function when administered for 8 weeks, as measured by FMD, in patients with hyperlipidemia.

Detailed description:
This is a multicenter, collaborative, randomized, open-label study designed to explore the effects of administration of omega-3-acid ethyl esters (TAK-085) \[2 g (2 g PO QD) or 4 g (2 g PO BID) for 8 weeks\] on vascular endothelial function, as measured by flow-mediated dilation (FMD), in patients receiving a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and have concurrent hypertriglyceridemia.

Considering the potential bias by factors that affect FMD between treatment groups, stratified allocation will be performed with fasting triglyceride (TG) level as a factor.

Arms:
arm 1: A dose of 2 grams of omega-3-acid ethyl esters (TAK-085) will be orally administered once a day immediately after meal. arm 2: A dose of 4 grams of omega-3-acid ethyl esters (TAK-085) will be orally administered twice a day immediately after meal.

Interventions: intervention 1: TAK-085
Intervention descriptions: intervention 1: TAK-085 capsules

Protocol document:
Prot_000.pdf: 
Title: Exploratory study of the effect of omega-3-acid ethyl esters on vascular 
endothelial function in patients with hyperlipidemia by flow mediated dilation 
NCT Number: NCT02824432 
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. 


TAK-085-4001 
Page 1 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
 
PROTOCOL 
 
 
Exploratory study of the effect of omega-3-acid ethyl esters on vascular endothelial 
function in patients with hyperlipidemia by flow mediated dilation 
(Oasis Flow) 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
12-10 Nihonbashi 2-chome, Chuo-ku, Tokyo 
Protocol number 
TAK-085-4001 
Version number/Revision number 
2nd edition 
Study drug: 
Omega-3-acid ethyl esters 
Creation date 
July 7, 2016 
 
 
 
 
 


TAK-085-4001 
Page 2 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
CONFIDENTIAL PROPERTY 
This document is a confidential communication of Takeda. Acceptance of this document constitutes 
agreement by the potential recipient of the drug to be administered 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 research 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. 


TAK-085-4001 
Page 3 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
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 Research, monitoring, registration/allocation center, statistical processing, and audit 


TAK-085-4001 
Page 4 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
shall 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: 
          
 
The Chair of the Clinical Research Steering Committee shall supervise implementation and reporting 
of the clinical research, secure medical guidance of a high degree of professionalism and a high-level 
scientific quality, and revise the research 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 research in accordance with the protocol, including a 
study site that obtains new samples/information from research subjects and provides other study 
sites.  
Researchers, 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: 
A researcher 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 
Research subject: 
A subject (including a dead subject) who meets any of the following:   
PPD


TAK-085-4001 
Page 5 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
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. 
 


TAK-085-4001 
Page 6 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
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 ................................................................................................. 20 
4.0 
INTRODUCTION ................................................................................................. 21 
4.1 
Background ...................................................................................................... 21 
4.2 
Rationale for the proposed research ................................................................ 22 
5.0 
RESEARCH OBJECTIVES AND ENDPOINTS ................................................. 23 
5.1 
Objectives ........................................................................................................ 23 
5.2 
Definition of endpoints .................................................................................... 23 
5.2.1 Primary endpoints ...................................................................................... 23 
5.2.2 Secondary endpoints .................................................................................. 23 
5.2.3 Other endpoints ......................................................................................... 23 
5.2.4 Safety endpoints ........................................................................................ 24 
6.0 
CLINICAL RESEARCH DESIGN ....................................................................... 25 
6.1 
Clinical research design ................................................................................... 25 
6.2 
Rationale for the clinical research design ........................................................ 27 
6.3 
Premature termination of entire clinical research or premature 
termination of clinical research at a study site ................................................ 28 
6.3.1 Premature termination criteria of entire clinical research ......................... 28 
6.3.2 Criteria for premature termination of study sites....................................... 28 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or study at a study site ............................................... 28 
6.4 
Procedures for protocol revision ..................................................................... 28 
7.0 
SELECTION AND WITHDRAWAL CRITERIA OF RESEARCH 
SUBJECTS ............................................................................................................ 30 
7.1 
Inclusion criteria .............................................................................................. 30 
7.2 
Exclusion criteria ............................................................................................. 31 
7.3 
Prohibited concomitant drugs and permitted concomitant drugs .................... 33 


TAK-085-4001 
Page 7 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
7.3.1 Prohibited concomitant drugs .................................................................... 33 
7.3.2 Permitted concomitant drugs ..................................................................... 34 
7.4 
Research subject management ......................................................................... 34 
7.5 
Criteria for discontinuation or withdrawal of a research subject .................... 35 
7.6 
Procedures for discontinuation of individual research subjects ...................... 36 
8.0 
RESEARCH TREATMENT ................................................................................. 37 
8.1 
Study drug ....................................................................................................... 37 
8.1.1 Dose and administration method ............................................................... 37 
8.1.2 Concomitant drug ...................................................................................... 37 
8.1.3 Overdose of the study drug ........................................................................ 37 
8.2 
Allocation of the study drug and administration procedure ............................ 38 
8.3 
Preparation and storage of allocation list ........................................................ 38 
9.0 
CLINICAL STUDY PROTOCOL ........................................................................ 39 
9.1 
Research procedures ........................................................................................ 39 
9.1.1 Informed consent procedure ...................................................................... 39 
9.1.2 Demographic data, medical history, and previous therapeutic drugs ........ 39 
9.1.3 Physical examination ................................................................................. 39 
9.1.4 Weight, height, and BMI ........................................................................... 39 
9.1.5 Vital signs .................................................................................................. 40 
9.1.6 Concomitant drugs ..................................................................................... 40 
9.1.7 Concurrent disease ..................................................................................... 40 
9.1.8 Checking food and drink consumption before the visit ............................. 40 
9.1.9 Laboratory tests ......................................................................................... 41 
9.1.10 Sample collection for exploratory biomarker evaluation .......................... 41 
9.1.11 Flow-mediated dilation (FMD) test ........................................................... 42 
9.1.12 Record of research subjects who are withdrawn before randomization .... 42 
9.1.13 Record of randomization ........................................................................... 43 
9.2 
Drug-taking status of the research subjects ..................................................... 43 
9.3 
Implementation time point of the test and observation items .......................... 43 
9.3.1 Observation period (Visit 1) ...................................................................... 43 
9.3.2 Treatment period (Visit 2) ......................................................................... 44 


TAK-085-4001 
Page 8 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
9.3.3 Treatment period (Visit 3) ......................................................................... 45 
9.3.4 Completion (Visit 4) or discontinuation .................................................... 46 
10.0 
PRETREATMENT EVENT AND ADVERSE EVENTS .................................... 48 
10.1 
Definitions ....................................................................................................... 48 
10.1.1 When pretreatment events are collected .................................................... 48 
10.1.2 Adverse events ........................................................................................... 48 
10.1.3 Considerations for PTEs and adverse events ............................................. 48 
10.1.4 Serious adverse event ................................................................................ 50 
10.1.5 Severity of pretreatment events and adverse events .................................. 51 
10.1.6 Causality of adverse events ....................................................................... 51 
10.1.7 Relationship to study procedures ............................................................... 52 
10.1.8 Date of onset .............................................................................................. 52 
10.1.9 Date of resolution ...................................................................................... 52 
10.1.10Actions taken for the study drug................................................................ 52 
10.1.11Outcome .................................................................................................... 53 
10.2 
Procedures ....................................................................................................... 54 
10.2.1 Collection and reporting of adverse events ............................................... 54 
10.2.2 Collection and reporting of serious adverse events ................................... 55 
10.2.3 Reporting of additional information concerning adverse events ............... 55 
10.3 
Follow-up of serious adverse events ............................................................... 55 
10.3.1 Reporting of serious adverse events, etc., to Ethics Review 
Committee, etc., and regulatory authorities ............................................... 56 
11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY ........................................ 58 
11.1 
Clinical Endpoint Committee .......................................................................... 58 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS ............................... 59 
12.1 
Case report form .............................................................................................. 59 
12.2 
Timing of data entry into the electronic CRF system ...................................... 60 
12.3 
Storage of records ............................................................................................ 60 
13.0 
STATISTICAL ANALYSIS METHODS ............................................................. 61 
13.1 
Statistical and analytical plans ......................................................................... 61 
13.1.1 Analysis set ................................................................................................ 61 


TAK-085-4001 
Page 9 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
13.1.2 Analysis of demographic and other baseline characteristics ..................... 61 
13.1.3 Efficacy analysis ........................................................................................ 61 
13.1.4 Safety analysis ........................................................................................... 65 
13.2 
Criteria for interim analysis and premature discontinuation ........................... 65 
13.3 
Determination of the number of planned research subject .............................. 65 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 67 
14.1 
Monitoring of the study site ............................................................................ 67 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the research protocol. .................................... 67 
14.3 
Quality assurance audits and regulatory agency inspections........................... 67 
15.0 
ETHICAL CONDUCT OF CLINICAL RESEARCH .......................................... 69 
15.1 
Approval of the Ethical Review Board, etc. .................................................... 69 
15.2 
Conflict of interest ........................................................................................... 70 
15.3 
Informed consent and information sheet, and the agreement of the 
research subjects .............................................................................................. 70 
15.4 
Personal information of the research subjects ................................................. 71 
15.5 
Consultation windows for the research subjects or persons related to the 
research concerned .......................................................................................... 72 
15.6 
Financial burden or reward to the research subjects........................................ 72 
15.7 
Benefits and inconveniences to the research subjects ..................................... 72 
15.7.1 Benefits to research subjects...................................................................... 72 
15.7.2 Inconveniences to research subjects .......................................................... 72 
15.8 
Attribution of research results and access rights ............................................. 72 
15.8.1 Attribution of research results ................................................................... 72 
15.8.2 Data access rights ...................................................................................... 72 
15.9 
Reporting of results, Publication, disclosure, and clinical research 
registration policy ............................................................................................ 73 
15.9.1 Reporting of results, publication and disclosure ....................................... 73 
15.9.2 Clinical research registration ..................................................................... 73 
15.9.3 Clinical trial results disclosure .................................................................. 73 
15.10 Insurance and compensation for injury ........................................................... 74 
16.0 
REFERENCES ...................................................................................................... 75 


TAK-085-4001 
Page 10 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
LIST OF IN-TEXT TABLES 
Table 9-a Laboratory tests ................................................................................................. 41 
Table 9-b Exploratory biomarker evaluation..................................................................... 41 
Table 10-a 
Takeda Medically Significant AE List ...................................................... 51 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Outline of clinical research design ............................................................ 27 
LIST OF APPENDICES 
Appendix A  Schedule for Research Procedures ............................................................. 76 
Appendix B  Responsibilities of the Principal Investigator ............................................ 77 


TAK-085-4001 
Page 11 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
2.0 
STUDY SUMMARY 
Sponsor: 
Takeda Pharmaceutical Company Limited 
Study drug: 
Omega-3-acid ethyl esters  
Study title: Exploratory study of the effect of omega-3-acid ethyl esters on vascular endothelial 
function in patients with hyperlipidemia 
Protocol number: TAK-085-4001 
Clinical research design: 
This is a multicenter, collaborative, randomized, open-label study designed to explore the effects of 
administration of omega-3-acid ethyl esters [2 g (2 g PO QD) or 4 g (2 g PO BID) for 8 weeks] on 
vascular endothelial function, as measured by flow-mediated dilation (FMD), in patients receiving a 
hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and have concurrent 
hypertriglyceridemia (hereinafter referred to as TG). 
Considering the potential bias by factors that affect FMD between treatment groups, stratified 
allocation will be performed with fasting TG level as a factor.  
 
Objectives: 
To explore the effects of omega-3-acid ethyl esters on vascular endothelial function when 
administered for 8 weeks, as measured by FMD, in patients with hyperlipidemia.  
Subjects: Patients with hyperlipidemia 
Planned number of research subjects: 
40 patients evaluable for the primary endpoint 
2 g group : 20 subjects 
4 g group : 20 subjects 
Exploratory biomarkers will be measured only for the 
research subjects from whom blood is taken during 
the observation period after approval of the revised 
protocol (the 2nd edition) by the committee such as 
the IEC. 
Number of study sites: 
5 to 10 institutions 
 
Dose and method of administration: 
A dose of 2 g of omega-3-acid ethyl esters will be 
orally administered once or twice a day immediately 
after meal. 
Route of administration: 
Oral 


TAK-085-4001 
Page 12 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
 
Duration of treatment: 
8 weeks 
Duration of evaluation: 
Screening period: 4 weeks 
Treatment period: 8 weeks 
Total: 12 weeks  
Main criteria for inclusion: 
1. 
Patients with the diagnosis of hyperlipidemia and receiving instructions for lifestyle 
improvement 
2. 
Patients with a fasting triglyceride (TG) level of 150 -499 mg/dL at Visit 1 after informed 
consent (Day -29 to Day -1 before start of study drug administration)   
3. 
Patients receiving a stable dose of HMG-CoA reductase inhibitor therapy continuously for at 
least 4 weeks before informed consent at Visit 1 (Day -29 to Day -1 before start of study drug 
administration)    
4. 
Male or postmenopausal female patients 
5. 
Patients who, in the opinion of the principal investigator or the investigator, are capable of 
understanding the content of the clinical research and complying with the research protocol 
requirements.  
6. 
Patients who can provide written informed consent prior to the conduction of the clinical 
research procedures 
7. 
Patients aged ≥20 years at the time of informed consent at Visit 1(Day -28 to Day 0 before the 
start of study drug administration)   
Main criteria for exclusion: 
1. 
Patients with a history of revascularization or those have had coronary artery disease (a 
definitive diagnosis of myocardial infarction, angina) within 24 weeks before informed consent 
at Visit 1 (Day -29 to Day -1 before the start of study drug administration)       
2. 
Patients who have undergo aortic aneurysmectomy within 24 weeks prior to informed consent 
at Visit 1 (Day -29 to Day -1 before the start of study drug administration) or those with 
concurrent aortic aneurysm    
3. 
Patients who have had clinically significant hemorrhagic disorders (e.g., hemophilia, capillary 
fragility, gastrointestinal ulcer, urinary tract hemorrhage, hemoptysis, and vitreous hemorrhage) 
within 24 weeks prior to informed consent at Visit 1 (Day -29 to Day -1 before the start of 
study drug administration) or those who concurrently have the above disorders   
4. 
Patient with a fasting FMD level of 0% measured at the start of study drug administration at 


TAK-085-4001 
Page 13 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
Visit 2 (Day -15 to Day -1 before the start of study drug administration)    
5. 
Patients in whom the type and dosage of HMG-CoA reductase inhibitors, antidiabetic drugs and 
antihypertensive drugs have been changed within 4 weeks prior to informed consent at Visit 1 
(Day -29 to Day -1 before the start of study drug administration)     
6. 
Patients who have started anti dyslipidemic agents within 4 weeks prior to informed consent at 
Visit 1 (Day -29 to Day -1 before the start of study drug administration)    
7. 
Patients requiring a change in the dosage of  dyslipidemia therapeutic, antidiabetic, or 
antihypertensive drugs during the period between informed consent at Visit 1 (Day -29 to Day 
-1 before the start of study drug administration) and the start of study drug administration at 
Visit 2 (Day -15 to Day -1 before the start of study drug administration)  
8. 
Patients with severe hepatic dysfunction 
9. 
Patients with severe renal dysfunction (as an indicator, CKD category ≥G3b, equivalent to an 
A3)  
10. Patients who have been diagnosed with pancreatitis 
11. Patients who have been diagnosed with lipoprotein lipase deficiency, apoprotein C-II 
deficiency, familial hypercholesterolemia, familial combined hyperlipidemia, or familial type 
III hyperlipidemia 
12.  Patients with concurrent Cushing's syndrome, uremia, systemic lupus erythematosus (SLE), 
serum dysproteinemia, or hypothyroidism   
13.  Patients with symptomatic Peripheral Arterial Disease (PAD)  
14. Patients with concurrent hypertension of grade II or higher Note 1)   
Note 1: Patients with systolic blood pressure of ≥160 mm Hg or diastolic BP of ≥100 mm Hg regardless of treatment 
with antihypertensive drugs 
15. 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  
16. Patients with a history of hypersensitivity or allergy for omega-3-acid ethyl esters 
17. Patients who smoke 
18. Patients participating in other clinical studies 
19. Patients who have been determined to be ineligible as subjects in the study by the principal 
investigator or the investigator    


TAK-085-4001 
Page 14 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
Endpoints: 
< Primary endpoint > 
%FMD (fasting) 
Secondary endpoints 
(1) %FMD (4 h postprandial) 
(2) TG level (fasting) 
(3) TG level (4 h postprandial) 
(4) Plasma fatty acid fraction 
<Other endpoints> 
Efficacy endpoint: 
Total cholesterolLDL-C, HDL-C, Remnant-like particle (RLP) cholesterol , Apoprotein B-48, C 
reaction protein (CRP), determination of 8-epi-PGF2α (in urine) 
 
Exploratory endpoints: 
Exploratory biomarker evaluation 
(1) Panel of blood proteins 
PAI1, TFPI, TNF-α, IL-1, IL-6, IL-8, IL-10, INFγ, MCP-1, ICAM1, VCAM1, eSelectin, 
serum amyloid A (SAA), pentraxin 3 (PTX3), FABP4, leptin, adiponectin 
 
(2) Panel of unsaturated fatty acid metabolites 
EPA metabolites (18-HEPE, 5-HEPE, Resolvin E1) 
DHA metabolites [17-HDHA (17-HDoHE), 7-HDHA (7-HDoHE), Resolvin D1, Resolvin 
D2, Resolvin D3, Maresin 1] 
Arachidonic acid metabolites (PGE2, PGD2, PGF2α, TXB2, 6-keto-PGF1α, LTB4) 
 
(3) Panel of lipids 
Phospholipids (glycerophospholipid (phosphatidylcholine, phosphatidylethanolamine, 
phosphatidylglycerol, phosphatidylserine, etc.), sphingophospholipids (sphingomyelin, etc.)), 
sphingolipid (ceramide, ganglioside, sulfatides, etc.), neutral lipids (monoacylglycerol, 
diacylglycerol, triacylglycerol, cholesteryl esters, dolichol, etc.), fatty acids (free fatty acids), 
acylcarnitine, bile acids, ubiquinone, and molecular species related to these biosynthesis and 
metabolism 
<Safety endpoint> 


TAK-085-4001 
Page 15 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
Adverse events, body weight, blood pressure in the sitting position, pulse in the sitting position, 
laboratory tests [fasting plasma glucose (FPG)] 
 
Statistical 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 subjects who satisfy the following criterion: 
• 
Research subjects who were randomized and given at least one dose of the study drug. 
Define SAS as the population of enrolled research subjects who satisfy the following criterion: 
• 
Research subjects who were given at least one dose of the study drug during this clinical 
study.  
(2) Efficacy analysis 
[Primary endpoints] 
%FMD (fasting) 
[Analytical method] 
1) 
Summary statistics by treatment group (number of subjects, mean, SD, 
minimum value, maximum value, quartiles) and a two-sided 95% confidence interval 
for the mean will be calculated at each evaluation time point during the treatment 
period, and a diagram illustrating the change in the mean ± SD will be prepared. 
2) 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point and the same analysis 
as in 1) will be performed.  
3) 
Using fasting TG level at the start of treatment, a stratified analysis on summary 
statistics by treatment group (number of subjects, mean, SD, minimum value, 
maximum value, quartiles) and a two-sided 95% confidence interval for the mean will 
be performed. 
[Secondary endpoints] 
(1) %FMD (4 h postprandial) 
(2) TG level (fasting) 
(3) TG level (4 h postprandial) 
(4) Plasma fatty acid fraction 


TAK-085-4001 
Page 16 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
[Analytical method] 
1) 
Summary statistics by treatment group (number of subjects, mean, SD, 
minimum value, maximum value, quartiles) and a two-sided 95% confidence interval 
for the mean will be calculated at each evaluation time point during the treatment 
period, and a diagram illustrating the change in the mean ± SD will be prepared. 
2) 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point during the treatment 
period and the same analysis as in 1) will be performed.  
3) 
Using fasting TG level at the start of treatment, a stratified analysis on summary 
statistics by treatment group (number of subjects, mean, SD, minimum value, 
maximum value, quartiles) and a two-sided 95% confidence interval for the mean will 
be performed. 
[Other endpoints] 
Efficacy endpoints: 
Total cholesterolLDL-C, HDL-C, Remnant-like particle (RLP) cholesterol , Apoprotein 
B-48,  C reaction protein (CRP), determination of 8-epi-PGF2α (in urine) 
[Analytical method]  
1) 
Summary statistics by treatment group (number of subjects, mean, SD, 
minimum value, maximum value, quartiles) and a two-sided 95% confidence interval 
for the mean will be calculated at each evaluation time point during the treatment 
period, and a diagram illustrating the change in the mean ± SD will be prepared. 
2) 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point and the same analysis 
as in 1) will be performed.  
Exploratory endpoints: 
Exploratory biomarker evaluation 
1) 
Panel of blood proteins 
PAI1, TFPI, TNF-α, IL-1, IL-6, IL-8, IL-10, INFγ, MCP-1, ICAM1, VCAM1, eSelectin, serum 
amyloid A (SAA), pentraxin 3 (PTX3), FABP4, leptin, adiponectin 
 
2) 
Panel of unsaturated fatty acid metabolites 


TAK-085-4001 
Page 17 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
EPA metabolites (18-HEPE, 5-HEPE, Resolvin E1), DHA metabolites [17-HDHA 
(17-HDoHE), 7-HDHA (7-HDoHE), Resolvin D1, Resolvin D2, Resolvin D3, Maresin 1], and 
Arachidonic acid metabolites (PGE2, PGD2, PGF2α, TXB2, 6-keto-PGF1α, LTB4) 
 
 [Analytical method] 
1. 
Summary statistics by treatment group (number of subjects, mean, SD, minimum value, 
maximum value, quartiles) and a two-sided 95% confidence interval for the mean will be 
calculated at each evaluation time point during the observation and treatment period, and a 
diagram illustrating the change in the mean ± SD will be prepared. 
2. 
The change for each treatment group (Treatment Period Visit 2, Visit 3 or Visit 4 - 
Treatment Period Visit 1) will be calculated at each evaluation time point during the 
observation and treatment period and the same analysis as in 1) will be performed. 
3. 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point during the treatment period 
and the same analysis as in 1) will be performed. Moreover, the correlation coefficient will 
be calculated with the change of % FMD for each treatment group, and scatter plots will 
be drawn. 
 
3) 
Panel of lipids (fasting) 
Phospholipids (glycerophospholipid (phosphatidylcholine, phosphatidylethanolamine, 
phosphatidylglycerol, phosphatidylserine, etc.), sphingophospholipids (sphingomyelin, etc.)), 
sphingolipid (ceramide, ganglioside, sulfatides, etc.), neutral lipids (monoacylglycerol, 
diacylglycerol, triacylglycerol, cholesteryl esters, dolichol, etc.), fatty acids (free fatty acids), 
acylcarnitine, bile acids, ubiquinone, and molecular species related to these biosynthesis and 
metabolism 
[Analytical method] 
1. 
Summary statistics by treatment group (number of subjects, mean, SD, minimum value, 
maximum value, quartiles) and a two-sided 95% confidence interval for the mean will be 
calculated at each evaluation time point during the observation and treatment period, and a 
diagram illustrating the change in the mean ± SD will be prepared. 
2. 
The change for each treatment group (Treatment Period Visit 2, Visit 3 or Visit 4 - 
Treatment Period Visit 1) will be calculated at each evaluation time point during the 


TAK-085-4001 
Page 18 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
observation and treatment period and the same analysis as in 1) will be performed. 
3. 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point during the treatment period 
and the same analysis as in 1) will be performed. Moreover, the correlation coefficient will 
be calculated with the change of % FMD for each treatment group, and scatter plots will 
be drawn. 
 
4) 
Panel of lipids (4 h postprandial) 
Phospholipids (glycerophospholipid (phosphatidylcholine, phosphatidylethanolamine, 
phosphatidylglycerol, phosphatidylserine, etc.), sphingophospholipids (sphingomyelin, etc.)), 
sphingolipid (ceramide, ganglioside, sulfatides, etc.), neutral lipids (monoacylglycerol, 
diacylglycerol, triacylglycerol, cholesteryl esters, dolichol, etc.), fatty acids (free fatty acids), 
acylcarnitine, bile acids, ubiquinone, and molecular species related to these biosynthesis and 
metabolism 
[Analytical method] 
1. 
Summary statistics by treatment group (number of subjects, mean, SD, minimum value, 
maximum value, quartiles) and a two-sided 95% confidence interval for the mean will be 
calculated at each evaluation time point during the observation and treatment period, and a 
diagram illustrating the change in the mean ± SD will be prepared. 
2. 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point during the treatment period 
and the same analysis as in 1) will be performed. Moreover, the correlation coefficient will 
be calculated with the change of % FMD for each treatment group, and scatter plots will 
be drawn. 
 
(3) Analysis of safety endpoints 
[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 


TAK-085-4001 
Page 19 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
 
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 
 
Tabulation of frequency of serious adverse events 
 
Tabulation of frequency of all adverse events by time of onset 
[Body weight, blood pressure in the sitting position, pulse in the sitting position, laboratory 
tests [fasting plasma glucose (FPG)] 
1) 
Summary statistics of measurements by treatment group at each evaluation time point 
during the treatment period will be calculated and a diagram of the change of individual 
data will be created.  
2) 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point during the treatment period 
and the same analysis as in 1) will be performed.  
3) 
Shift table will be created for assessment results based on reference values for Treatment 
Period Visit 2 and each evaluation time point (Visit 3, Visit 4) during the treatment 
period. 
Rationale for the number of planned research subjects 
The planned sample size is based on the requierment to investigate explore atively the effects of 
omega-3-acid ethyl esters on vascular endothelial function considering the feasibility of this study.  


TAK-085-4001 
Page 20 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
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  
SLE 
systemic lupus erythematosus 
SOC 
System Organ Class 
TG 
triacylglycerol 


TAK-085-4001 
Page 21 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
4.0 
INTRODUCTION 
4.1 
Background 
The efficacy of LDL-lowering regimen using HMG-CoA reductase inhibitor designed to control 
cardiovascular events has been already established, which leads to primary prevention, secondary 
prevention, and risk reduction in high-risk treatment groups.1),2) However, postprandial 
hypertriglyceridemia and the quality of LDL have been receiving attention as an atherosclerotic risk 
factor that remains after the treatment with HMG-CoA reductase inhibitors.  
Although there had been no consensus regarding the significance of triglycerides (TG) as a 
cardiovascular risk, Japan Atherosclerosis Society (JAS) Guidelines for Prevention of 
Atherosclerotic Cardiovascular Diseases (2012) stated that “a number of epidemiological studies 
suggest that elevated triglyceride levels are associated with increased incidence of cardiovascular 
diseases.” TG levels reach the highest 3 to 4 h after meal. Especially, remnant-like lipoprotein (RLP) 
plays an important role to cause the elevation of TG level, and RLP particles contain a greater 
amount of cholesterol, as well as TG, than LDL particles. It has been reported that RLP enhances 
foaming of macrophage and inflammatory reaction3), and TG levels at 2 to 4 h after meals are more 
important than those before meals as a heart disease risk factor. 4)  
As insulin resistance associated with obesity, etc. increases, qualitative changes in LDL, as well as 
elevated levels of TG, are observed. The increase observed in small dense LDL (sdLDL) of small 
particle diameters is considered to enhance the formation of atherosclerotic plaque since this sdLDL 
is easily taken up by macrophages. Therefore, in order to aim at further inhibition of cardiovascular 
events after achieving the lowering of LDL-C with HMG-CoA reductase inhibitors, it is considered 
especially important to lower TG levels/decrease sdLDL. Omega-3 fatty acids including 
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been receiving attention in 
recent years as the drugs having such activities. Since omega 3 fatty acids are not synthesized in the 
body, supplementation from meals (fish) is necessary. EPA and DHA have TG-lowering and 
antiatherosclerosis activities but the mechanism has not been completely elucidated. Omega-3-acid 
ethyl esters (EPA/DHA preparations, Lotriga®) released in 2013 lower TG levels in a 
dose-dependent manner5) and are expected to lead to lowering of RLP, increase in the LDL particle 
size, FMD, and lowering of IL-6 levels.6)   
In JELIS Studies, lowering of TG levels and reduction in major coronary events have been 
demonstrated in the HMG-CoA reductase inhibitor and EPA combination group compared to the 
HMG-CoA reductase inhibitor alone group.7) This clinical study aims at exploring the effects of 
Lotriga® (EPA/DHA preparations) on vascular endothelial function and postprandial 
hypertriglyceridemia assessed by FMD, etc. in patients receiving a 
hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and have concurrent 
hypertriglyceridemia (TG).  


TAK-085-4001 
Page 22 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
Much remains unknown in terms of the changes in endothelial cell-derived cytokines which are well 
known to correlate with progression of arteriosclerosis, as well as the activities of inflammatory cells 
as a chronic inflammation lesion in a cytokine assay panel. In addition, an unfinished work is to 
elucidate an additional mechanism of action by analyzing the in vivo changes in the whole lipids 
after treatment with Lotriga® (EPA/DHA preparations). Thus, blood proteins and lipids/unsaturated 
fatty acid metabolites which are associated with blood vessel inflammation will be measured to 
search for potential biomarkers which may correlate with the change in FMD, and to explore the 
mechanism of TG-lowering and antiatherosclerotic activities by the combination of HMG-CoA 
reductase inhibitor and Lotriga® (EPA/DHA preparations). 
 
4.2 
Rationale for the proposed research 
This clinical study was planned to contribute to the prevention of arteriosclerotic disease by 
exploring the effects of omega-3-acid ethyl esters on vascular endothelial in patients with 
hyperlipidemia. This study was also planned to support the elucidation of mechanism for 
development and prevention of arteriosclerotic disease from the viewpoint of fundamental research, 
by searching for potential biomarkers for endothelial functions after treatment with omega-3-acid 
ethyl esters, and by exploring the mechanism of TG-lowering and antiatherosclerotic activities by 
the combination of HMG-CoA reductase inhibitor and omega-3-acid ethyl esters. 


TAK-085-4001 
Page 23 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
5.0 
RESEARCH OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
The objective of this study is to explore the effects of omega-3-acid ethyl esters on vascular 
endothelial function when administered for 8 weeks, as measured by FMD, in patients with 
hyperlipidemia. 
5.2 
Definition of endpoints 
5.2.1 Primary endpoints 
%FMD (fasting) 
5.2.2 Secondary endpoints 
(1) %FMD (4 h postprandial) 
(2) TG level (fasting) 
(3) TG level (4 h postprandial) 
(4) Plasma fatty acid fraction 
5.2.3 Other endpoints 
Efficacy endpoints: 
total cholesterol, LDL-C, HDL-C, Remnant-like particle (RLP) cholesterol , apoprotein B-48, 
C-reactive protein (CRP), determination of 8-epi-PGF2α (in urine) 
 
Exploratory endpoints: 
Exploratory biomarker evaluation 
 
(1) 
Panel of blood proteins 
PAI1, TFPI, TNF-α, IL-1, IL-6, IL-8, IL-10, INFγ, MCP-1, ICAM1, VCAM1, eSelectin, serum 
amyloid A (SAA), pentraxin 3 (PTX3), FABP4, leptin, adiponectin 
 
(2) 
Panel of unsaturated fatty acid metabolites 
EPA metabolites (18-HEPE, 5-HEPE, Resolvin E1) 
DHA metabolites [17-HDHA (17-HDoHE), 7-HDHA (7-HDoHE), Resolvin D1, Resolvin D2, 
Resolvin D3, Maresin 1] 
Arachidonic acid metabolites (PGE2, PGD2, PGF2α, TXB2, 6-keto-PGF1α, LTB4) 
 
(3) 
Panel of lipids 


TAK-085-4001 
Page 24 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
Phospholipids (glycerophospholipid (phosphatidylcholine, phosphatidylethanolamine, 
phosphatidylglycerol, phosphatidylserine, etc.), sphingophospholipids (sphingomyelin, etc.)), 
sphingolipid (ceramide, ganglioside, sulfatides, etc.), neutral lipids (monoacylglycerol, 
diacylglycerol, triacylglycerol, cholesteryl esters, dolichol, etc.), fatty acids (free fatty acids), 
acylcarnitine, bile acids, ubiquinone, and molecular species related to these biosynthesis and 
metabolism 
5.2.4 Safety endpoints 
Adverse events, body weight, blood pressure in the sitting position, pulse in the sitting position, 
laboratory tests [fasting plasma glucose (FPG)] 
 


TAK-085-4001 
Page 25 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
6.0 
CLINICAL RESEARCH DESIGN 
6.1 
Clinical research design 
< Clinical research design > 
This is a multicenter, collaborative, randomized, open-label study designed to explore the effects of 
administration of omega-3-acid ethyl esters [2 g (2 g PO QD) or 4 g (2 g PO BID) for 8 weeks] on 
vascular endothelial function, as measured by FMD, in patients receiving a 
hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and have concurrent 
hypertriglyceridemia. 
Considering the potential bias by factors that affect FMD between treatment groups, stratified 
allocation will be performed with fasting TG as a factor.  
Research TREATMENT 
(1) Study drug: 
Omega-3-acid ethyl esters 
(2) Dosage regimen 
Omega-3-acid ethyl esters will be orally administered [2 g (2 g PO QD) or 4 g (2 g PO BID)] 
immediately after meal for 8 weeks in patients with hyperlipidemia . 
(3) Duration of treatment: 
8 weeks 
Planned number of research subjects: 
40 patients evaluable for the primary endpoint 
2 g group: 20 subjects 
4 g group: 20 subjects 
Number of study sites: 
5 to 10 institutions 
< Duration of the treatment and number of visits of by subjects > 
(1) Duration of treatment: 
The duration of the treatment period is 8 weeks. Research subjects should visit the hospital at the 
time of informed consent at Visit 1 (Day-29 to Day -1 before the start of study drug) and from the 
start of study drug administration at Visit 2 (Day -15 to Day -1 from the start of study drug 
administration) to completion of study drug administration [Visit 4 (Week 8)].  


TAK-085-4001 
Page 26 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
(2) Number of visits 
Observation period: 1 visit 
Treatment period: 3 to 6 visits 
The FMD measurement during the treatment period will be performed by a physician or 
laboratory technician who completed the FMD measurement training. Therefore, only for the 
FMD measurement, subjects are expected to go to a testing laboratory other than the one they 
normally visit for examinations. In that case, a total of 3 visits for the FMD measurement will 
be added to the total of 3 visits for examinations from Treatment Period Visit 2 (Day -15 to 
Day -1 before the start of study drug administration) to Visit 4 (Week 8). Therefore, the 
number of visits during the treatment period will be a minimum of 3 and a maximum of 6.  
 
 
 
 


TAK-085-4001 
Page 27 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
Figure 6 (a) shows an outline of the clinical research design. Refer to Appendix A for schedule of 
examinations, observations, and assessments. 
Figure 6.a 
Outline of clinical research design 
< Outline of clinical research> 
Duration of treatment:8 weeks 
Number of visits: 4 to 7 visits 
 
(a) FMD measurement will be performed by a physician or laboratory technician who completed 
the FMD measurement training.  
6.2 
Rationale for the clinical research design 
<Rationale> 
Since this study aims at exploring the effects of oral administration of omega-3-acid ethyl esters 
in clinical practice (2 g once a day or twice a day for 8 weeks) on vascular endothelial function, 
the study was designed as an open-label comparing FMD before and after omega-3-acid 
administration without including control groups.  
< Rationale for the dose and dosing regimen > 
In accordance with the approved dosage and administration of omega-3-acid ethyl esters, dose 
and dosing regimen of omega-3-acid ethyl esters were set at 2 g (2 g PO QD) and 4 g (2 g PO 
BID) in this study. 
< Rationale for the duration of study > 
Visit
1
Week
-4
Allowable
range
-29
Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor
4
0
4
8
-15to-1
14to41
42to70
Omega-3-acid ethyl esters 2 g (2 g PO QD) -
Omega-3-acid ethyl esters 4 g (2 g PO BID) -
FMD(a)
FMD(a)
FMD(a)
Explanation using
informed consent
information sheet
(the informed
Start of study drug
treatment
Eligibility screening
2
3


TAK-085-4001 
Page 28 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
Since improvement of FMD was observed after a 2-month administration of omega-3-acid ethyl 
esters in the studies conducted outside Japan investigating the effect of omega-3-acid ethyl esters 
on FMD,8) it was considered that the effect of omega-3-acid ethyl esters on FMD can be 
examined with an 8-week administration and the duration of the treatment period was, therefore, 
set at 8 weeks in this clinical study.  
< Rationale for the planned sample size > 
See Section 13.3.  
6.3 
Premature termination of entire clinical research or premature termination 
of clinical research at a study site 
6.3.1 Premature termination criteria of entire clinical research 
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 research subject participation in the study. 
 
When there is serious deviation from Ethical Guidelines or ICH-GCP for medical and health 
research 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 in significant violation of 
the ethical guidelines, protocol, or contractual agreement for medical and health research involving 
human subjects, or is unable to ensure proper conduct of the research. 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or study at a study site 
In the event that the sponsor or a study site committee such as an ethics review committee 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. 
6.4 
Procedures for protocol revision 
If the protocol needs to be revised, the sponsor shall consider and decide whether to revise the 
protocol. 


TAK-085-4001 
Page 29 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
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 IEC, as necessary according to institutional regulations for review, and 
obtain approval from the director of the entity. 


TAK-085-4001 
Page 30 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
7.0 
SELECTION AND WITHDRAWAL CRITERIA OF RESEARCH 
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 research subjects shall be determined in accordance with the following criteria. 
1. 
Patients with the diagnosis of hyperlipidemia and receiving instructions for lifestyle 
improvement 
2. 
Patients with a fasting triglyceride (TG) level of 150 – 499 mg/dL at Visit 1 after informed 
consent (Day -29 to Day -1 before start of study drug administration) 
3. 
Patients receiving a stable dose of HMG-CoA reductase inhibitor therapy continuously for 
at least 4 weeks at the time of informed consent at Visit 1 (Day -29 to Day -1 before start 
of study drug administration)   
4. 
Male or postmenopausal female patients 
5. 
Patients who, in the opinion of the principal investigator or the investigator, are capable of 
understanding the content of the clinical research and complying with the research 
protocol requirements. 
6. 
Patients who can provide written informed consent prior to the conduction of the clinical 
research procedures 
7. 
Patients aged ≥20 years at the time of informed consent at Visit 1(Day -29 to Day -1 
before the start of study drug administration)  
[Rationale for the inclusion criteria] 
1. This was set as a target condition in this clinical study.  
2. This was set according to the diagnostic criteria for hypertriglyceridemia in “Japan 
Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular 
Diseases 2012.” 
3. This was set for an accurate assessment of the efficacy.  
4. This was set in consideration of the effect of female hormones on FMD. 
5.6. These were set as fundamental items for the research. 
7. This was set considering the age ≥20 years as the age where patients are capable of making a 
decision to participate in this clinical study.  


TAK-085-4001 
Page 31 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
7.2 
Exclusion criteria 
Research subjects meeting any of the criteria below shall not be included in this research. 
1. Patients with a history of revascularization or those have had coronary artery disease (a 
definitive diagnosis of myocardial infarction, angina) within 24 weeks before informed 
consent at Visit 1 (Day -29 to Day -1 before the start of study drug administration)    （  
2. Patients who have undergo aortic aneurysmectomy within 24 weeks prior to informed 
consent at Visit 1 (Day -29 to Day -1 before the start of study drug administration) or 
those with concurrent aortic aneurysm    
3. Patients who have had clinically significant hemorrhagic disorders (e.g., hemophilia, 
capillary fragility, gastrointestinal ulcer, urinary tract hemorrhage, hemoptysis, and 
vitreous hemorrhage) within 24 weeks prior to informed consent at Visit 1 (Day -29 to 
Day -1 before the start of study drug administration) or those who concurrently have the 
above disorders  
4. Patient with a fasting FMD level of 0% measured at the start of study drug administration 
at Visit 2 (Day -15 to Day -1 before the start of study drug administration)   
5. Patients in whom the type and dosage of HMG-CoA reductase inhibitors, antidiabetic drugs 
and antihypertensive drugs have been changed within 4 weeks prior to informed consent at 
Visit 1 (Day -29 to Day -1 before the start of study drug administration)    
6. Patients who have started anti dyslipidemic agents within 4 weeks prior to informed 
consent at Visit 1 (Day -29 to Day -1 before the start of study drug administration)    
7. Patients requiring a change in the dosage of  dyslipidemia therapeutic, antidiabetic, or 
antihypertensive drugs during the period between informed consent at Visit 1 (Day -29 to 
Day -1 before the start of study drug administration) and the start of study drug 
administration at Visit 2 (Day -15 to Day -1 before the start of study drug administration)  
8. Patients with severe hepatic dysfunction 
9. Patients with  severe renal dysfunction (as an indicator, CKD category ≥G3b, equivalent to 
an A3)  
10. Patients who have been diagnosed with pancreatitis 
11. Patients who have been diagnosed with lipoprotein lipase deficiency, apoprotein C-II 
deficiency, familial hypercholesterolemia, familial combined hyperlipidemia, or familial 
type III hyperlipidemia  


TAK-085-4001 
Page 32 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
12. Patients with concurrent Cushing's syndrome, uremia, systemic lupus erythematosus (SLE), 
serum dysproteinemia, or hypothyroidism    
13. Patients with symptomatic Peripheral Arterial Disease (PAD) 
14. Patients with concurrent hypertension of grade II or higher Note 1)   
Note 1: Patients with systolic blood pressure of ≥160 mm Hg or diastolic BP of ≥100 mm Hg regardless of 
treatment with antihypertensive drugs  
15. 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 Note 2)  
16. Patients with a history of hypersensitivity or allergy for omega 3-acid ethyl esters -  
17. Patients who smoke 
18. Patients participating in other clinical studies 
19. Patients who have been determined to be ineligible as subjects 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] 
1.2.8.16 These were set in consideration of safety of the research subjects. 
3 This was set because EPA-E, a component of the study drug, has an antiplatelet action and 
may impair hemostasis in patients.  


TAK-085-4001 
Page 33 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
4.5.6.7.9.14. 17 These were set because it was considered that drug efficacy evaluation would be 
affected.  
10. This was set because acute pancreatitis may occur in patients with significant 
hypertriglyceridemia.  
11. This was set to exclude patients with hypertriglyceridemia attributed to a genetic 
predisposition. 
12. This was set to exclude an underline condition commonly seen in patients with secondary 
hypertriglyceridemia.  
13.15 These were set in consideration of safety of the research subjects and for an accurate 
assessment of the efficacy. 
18.19 These were set as fundamental items for the research.  
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 6 (Week 8)].  
(*: Concomitant drugs prohibited in the package insert of hydroxymethylglutaryl-coenzyme A 
(HMG-CoA) reductase inhibitor taken at the time of informed consent are included.)  
1. Eicosapentaenoic acid (EPA) preparations or EPA/DHA preparations (including 
supplements) 
2. Antidyslipidemic agents (except for HMG-CoA reductase inhibitor taken at the time of the 
informed consent)  
Anion exchange resin 
Fibrates 
Ezetimibe  
Nicotinic acid derivatives 
Probucol 
Phytosterols 
Evolocumab 


TAK-085-4001 
Page 34 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
Others (elastase ES, dextran sulfate sodium, polyenephosphatidylcholine, pantethine) 
3. Pancreatic hormones 
Insulin preparation 
4. Androgens 
Testosterone, methyltestosterone 
5. Follicle hormone and luteinizing hormone 
Estrogen and progestogen 
6. Systemic steroids 
<Rationale> 
1to 6 These were set because it was considered that efficacy evaluation of the study drug would 
be affected by these drugs.  
7.3.2 Permitted concomitant drugs 
Drugs other than those prohibited for concomitant use may be taken during the study period. 
However, for HMG-CoA reductase inhibitors, antidiabetic drugs (except for insulin) and 
antihypertensive drugs, dosage change, 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 
Research subject management 
The principal investigator or investigator shall instruct research subjects regarding the following: 
(1) Guidance for research subjects for improving lifestyle shall be made constant during the clinical 
study and its content shall not be changed. Research subjects shall be instructed to avoid 
excessive exercise as much as possible during the study period.  
(2) Research subjects shall be instructed not to consume alcohol after 9:00 pm two days before the 
hospital visit, and not to consume food after 9:00 pm on the day before the hospital visit. 
Although water can be taken as desired on the day of blood collection, research subjects shall 
be instructed to visit the hospital in a fasting state in order that fasting morning samples can be 
collected.  
(3) Research 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) Research subjects shall be instructed to visit the hospital according to the schedule and take the 
test as prescribed during the study period. 


TAK-085-4001 
Page 35 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
(5) Research 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.)  
(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, 
research subjects shall be instructed to promptly report in the event of an adverse drug reaction, 
such as bleeding.  
(7) Research subjects must notify the principal investigator or investigator in advance if they 
receive treatment from other physicians. If treated by other physicians, the research subjects 
shall be instructed to promptly report the details of the treatment.  
7.5 
Criteria for discontinuation or withdrawal of a research subject 
The principal investigator or investigator shall record the main reason for discontinuation of protocol 
treatment on the case report form according to the classification described below. Refer to Section 
9.1.11 for research subjects who withdraw from the research before randomization. 
1. Pretreatment Event (PTE) or adverse event  
When the research subject had a pretreatment event (PTE) or an adverse event that requires 
withdrawal of the research subject from the study because continued participation in the study 
would impose an unacceptable risk to the research subject’s health, or when the research subject 
is unwilling to continue study participation because of the PTE or adverse event. 
2. Major protocol deviation  
When it is discovered after randomization that a research subject does not meet the eligibility 
criteria or is not adhering to the protocol, and continued participation in the research would 
impose an unacceptable risk to the research subject’s health.  
3. Lost to follow-up 
When the research subject failed to make visits and could not be contacted despite the attempts 
to contact the research subject. 
4. Voluntary termination 
When the research subject wishes to withdraw from the research. The reason for discontinuation 
shall be obtained to the extent possible. 
5. Research termination 
When the sponsor or a committee such as the IEC or regulatory authority has decided to 
terminate the study. Refer to Section 6.3.1 for details.  


TAK-085-4001 
Page 36 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
6. Lack of efficacy  
When efficacy of the study drug is not evident and continuation of the research may pose an 
unacceptable risk to the research subjects in the opinion of the principal investigator or 
investigator.  
7. 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 research subjects 
The principal investigator or investigator shall terminate a research subject’s research participation 
when the research subject meets the criteria described in Section 7.5. Individual research subjects 
may discontinue their research participation without giving a reason at any time during the research. 
Should a research subject’s participation be discontinued, the primary reason for termination shall be 
recorded on 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. 


TAK-085-4001 
Page 37 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
8.0 
RESEARCH 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 
Omega-3-acid ethyl esters will be orally administered [2 g (2 g PO QD) or 4 g (2 g PO BID)] 
immediately after meal. In principle, the dosage prescribed to the research subject should not be 
changed until the end of the study. Since the research subject should in a fasting state at the time of 
visit, the drug to be taken after breakfast should be taken immediately after the first meal 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 drug 
HMG-CoA reductase inhibitors, antidiabetic drugs (except for insulin) or antihypertensive drugs 
taken at the time of informed consent should continue to be taken without a change in dosage and 
administration during the study period.  
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 research 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, “Pretreatment Event and Adverse Events.”P  
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 SAEs.” 


TAK-085-4001 
Page 38 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
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 research subjects. The principal investigator or the designee shall notify the information required 
for allocation in addition to the research subject identification code. Then, drugs that should be 
administered to each research subject will be notified through the Case Registration Web System. 
The principal investigator or investigator shall prescribe the study drug 2 g [(2 g PO QD) or 4 g (2 g 
PO BID)] according to the notification, and record the dose administered for each research 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 research. 
Using fasting TG values 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. 
 


TAK-085-4001 
Page 39 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
9.0 
CLINICAL STUDY PROTOCOL 
9.1 
Research procedures 
The principal investigator or investigator shall collect data in accordance with the procedure below. 
In principle, tests other than FMD measurement, observations, and evaluations of research subjects 
shall be performed by the same principal investigator or investigator. FMD measurement shall be 
performed by a physician or laboratory technician who has completed the FMD measurement 
training. The study schedule is provided in Appendix A. 
9.1.1 Informed consent procedure 
The procedures for obtaining informed consent are described in Section 15.3. 
Consent shall be obtained from the research subject before initiation of research procedures. 
Research subject code is given to each research subject from whom informed consent was acquired 
and who was randomized. The research subject ID code shall be used throughout the research period 
and shall not be changed. 
9.1.2 Demographic data, medical history, and previous therapeutic drugs 
Demographic data shall be collected regarding date of birth, gender, time (year/month) of onset of 
dyslipidemia (or diagnosis), last menstrual period (year), frequency of consumption of fish (almost 
every day, once/2 days, 1 to 2 times/week, almost never), smoking and drinking history, and vessel 
diameter.  
 Medical history data shall be collected regarding clinically problematic diseases or symptoms that 
disappeared or were terminated within 1 year from informed consent. When the symptoms or disease 
continues, it shall be considered as a concurrent disease (Refer to Section 9.1.7). 
Previous therapeutic drug data shall be collected regarding all drugs used within 4 weeks before the 
informed consent 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 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: 


TAK-085-4001 
Page 40 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
 Height = 176 cm, 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  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 research subjects shall be included. At 
every hospital visit of the research subject, the status of use (drug name, route of administration) of 
the drugs (including vitamin compound, over-the-counter medication, and Chinese medicine) used, 
other than the study drug, from the time of informed consent to the completion of the clinical 
research shall be monitored. 
9.1.7 Concurrent disease 
A concurrent disease shall be defined as a disease or symptom that is present at the time of the 
research subject’s informed consent Clinically problematic laboratory test data, ECG findings, and 
abnormal physical examination findings observed immediately after the acquisition of the informed 
consent and examination 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 Checking food and drink consumption before the visit 
At each study visit, the principal investigator, investigator, etc., physician for FMD measurement, or 
laboratory technician for FMD measurement will check the food and drink consumption of the 
research subject before the visit. 
• 
Alcohol should not be consumed from 9:00 pm two days before the hospital visit to the time of 
the fasting test, and food should not be consumed from 9:00 pm on the day before to the time of 
the fasting test.  
• 
Eating/drinking to excess and extreme change in dietary content should be avoided on the day 
before the fasting test. 


TAK-085-4001 
Page 41 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
9.1.9 Laboratory tests 
The following laboratory tests shall be performed according to the observation schedule (Appendix 
A). Samples will be taken under ≥10-h fasting for the fasting test and at 4 h after consumption of a 
prescribed meal (allowable range ± 30 min) for the 4-h postprandial test. 
The principal investigator or investigator shall evaluate and keep the reported laboratory test results. 
Table 9-a Laboratory tests 
Serum chemistry 
(fasting) 
Serum chemistry 
(4 h postprandial) 
Urinalysis 
(fasting) 
TG 
Total cholesterol 
LDL-C 
HDL-C 
Remnant-like particle (RLP) 
cholesterol 
Apoprotein B-48 
high-sensitivity C-reactive 
protein (hs-CRP)   
Fasting plasma glucose (FPG) 
Plasma fatty acid fraction 
(Dihomo-gamma-linolenic 
acid、Arachidonic acid、
Eicosapentaenoic acid、
Docosahexaenoic acid、
EPA/AAratio、DHA/AAratio） 
TG 
Total cholesterol 
LDL-C 
HDL-C 
Remnant-like particle (RLP) 
cholesterol 
Apoprotein B-48  
 
Determination of 
8-epi-PGF2α 
The principal investigator shall keep laboratory test reference values, including the historical data. 
9.1.10 Sample collection for exploratory biomarker evaluation 
Evaluation of the following biomarkers shall be performed in Integrated Technology Research 
Laboratories, Takeda Pharmaceutical Company Limited, according to the observation schedule 
(Appendix A). Samples will be taken under ≥10-h fasting for the fasting test and at 4 h after 
consumption of a prescribed meal (allowable range ± 30 min) for the 4-h postprandial test. 
The member (exploratory biomarker evaluation ) of Steering Committeewill evaluate the results 
from panels of blood proteins, lipids, and unsaturated fatty acid metabolites. 
Table 9-b Exploratory biomarker evaluation 
(fasting) 
(4 h postprandial) 


TAK-085-4001 
Page 42 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
Panel of blood proteins: 
PAI1, TFPI, TNF-α, IL-1, IL-6, IL-8, IL-10, INFγ, MCP-1, ICAM1, 
VCAM1, eSelectin, serum amyloid A (SAA), pentraxin 3 (PTX3), 
FABP4, leptin, adiponectin 
 
Panel of unsaturated fatty acid metabolites: 
EPA metabolites (18-HEPE, 5-HEPE, Resolvin E1) 
DHA metabolites [17-HDHA (17-HDoHE), 7-HDHA (7-HDoHE), 
Resolvin D1, Resolvin D2, Resolvin D3, Maresin 1] 
Arachidonic acid metabolites (PGE2, PGD2, PGF2α, TXB2, 
6-keto-PGF1α, LTB4) 
 
Panel of lipids: 
Phospholipids (glycerophospholipid (phosphatidylcholine, 
phosphatidylethanolamine, phosphatidylglycerol, 
phosphatidylserine, etc.), sphingophospholipids (sphingomyelin, 
etc.)), sphingolipid (ceramide, ganglioside, sulfatides, etc.), neutral 
lipids (monoacylglycerol, diacylglycerol, triacylglycerol, cholesteryl 
esters, dolichol, etc.), fatty acids (free fatty acids), acylcarnitine, bile 
acids, ubiquinone, and molecular species related to these 
biosynthesis and metabolism  
Panel of lipids: 
Phospholipids 
(glycerophospholipid 
(phosphatidylcholine, 
phosphatidylethanolamine, 
phosphatidylglycerol, 
phosphatidylserine, etc.), 
sphingophospholipids 
(sphingomyelin, etc.)), 
sphingolipid (ceramide, 
ganglioside, sulfatides, etc.), 
neutral lipids (monoacylglycerol, 
diacylglycerol, triacylglycerol, 
cholesteryl esters, dolichol, etc.), 
fatty acids (free fatty acids), 
acylcarnitine, bile acids, 
ubiquinone, and molecular 
species related to these 
biosynthesis and metabolism 
 
9.1.11 Flow-mediated dilation (FMD) test  
FMD tests shall be performed according to the observation schedule (Appendix A) based on the 
Procedure for FMD Measurement provided separately. The fasting test will be performed under 
≥10-h fasting and the 4-h postprandial test will be performed 4 h after consumption of a prescribed 
meal (allowable range ±30 min). FMD measurement will be performed by a physician or laboratory 
technician who completed the FMD measurement training. 
9.1.12 Record of research subjects who are withdrawn before randomization 
A CFR shall be created for all research 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 
• 
Sex 
• 
Eligibility 
• 
PTE/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: 
• 
PTE adverse events 


TAK-085-4001 
Page 43 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
• 
Not satisfying at least one of the inclusion criteria or meeting any of the exclusion criteria 
• 
Serious deviation from the protocol 
• 
Lost to follow-up 
• 
Voluntary discontinuation (specify the reason) 
• 
Discontinuation of the entire study 
• 
Others (specify the reason) 
Research subject ID numbers assigned to research subjects withdrawn from the research before 
{randomization shall not be reused. 
9.1.13 Record of randomization 
Research subjects to be randomized shall meet all of the inclusion criteria and shall not meet any of 
the exclusion criteria according to Section 8.2. The principal investigator or investigator shall 
specify the reason why the subject cannot be randomized / transferred to the treatment period. 
9.2 
Drug-taking status of the research subjects 
The principal investigator or investigator shall confirm the drug-taking status of the study drug of the 
research subject at every visit. Throughout the clinical research period, drug-taking status will be 
checked through interview for two categories, “compliance of at least 50% of the prescribed dose or 
compliance of < 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 research 
subject may be withdrawn from the research if appropriate for the circumstances. 
9.3 
Implementation time point of the test and observation items 
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 Observation period (Visit 1) 
At Visit 1 (Day -29 to Day -1 before study drug administration), the study shall be explained using 
the informed consent form to the research subjects who meet the inclusion criteria (except for 2) in 
Section 7.1 and do not meet any of the exclusion criteria (except for 4 and 7) 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 study drug 
administration) are shown below.  
• 
Informed consent procedure 
• 
Demographic data, medical history, previous treatment drug(s) 
• 
Physical examination 


TAK-085-4001 
Page 44 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
• 
Height, weight and BMI 
• 
Vital signs 
• 
Concomitant drugs 
• 
Concurrent disease 
• 
Laboratory tests (fasting) 
• 
Exploratory biomarker evaluation (fasting) 
Items to be checked: Food and drink consumption before visit: 
o 
Alcohol should not be consumed from 9:00 pm two days before the hospital visit to the 
time of visit and food should not be consumed from 9:00 pm on the day before to the 
time of visit. 
o 
Eating/drinking to excess and extreme change in dietary content should be avoided on 
the day before the hospital visit. 
9.3.2 Treatment period (Visit 2) 
1. Laboratory tests/FMD measurement 
Research subjects shall take the following tests at a designated medical institution for FMD 
measurement. 
• 
Laboratory tests [fasting and 4-h postprandial (allowable range ±30 min)]   
• 
Exploratory biomarker evaluation [fasting and 4-h postprandial (allowable range ±30 min)] 
• 
FMD test [fasting and 4-h postprandial (allowable range ±30 min)]    
Items to be checked: Food and drink consumption before visit   
o 
Alcohol should not be consumed from 9:00 pm two days before the hospital visit to the 
time of visit and food should not be consumed from 9:00 pm on the day before to the 
time of visit.  
o 
Eating/drinking to excess and extreme change in dietary content should be avoided on 
the day before the hospital visit. 
 
Research subjects shall visit the study site after undergoing prescribed tests at a designated medical 
institution for FMD measurements. 
 
2. Implementation of examination 
 Based on the results of the tests/observations at Visit 1 (Day -29 to Day -1 before the start of study 
drug administration) and the FMD test results (fasting) at Visit 2 (Day -15 to Day -1 before the start 
of study drug administration), the principal investigator or the investigator shall perform the 
following tests, observations, and evaluations in research subjects who meet the inclusion criteria 
and do not meet any of the exclusion criteria.  


TAK-085-4001 
Page 45 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
• 
Physical examination 
• 
Vital signs 
• 
Concomitant drugs 
• 
Pretreatment Event 
 
The principal investigator or the investigator shall give notification to the registration center 
(accessing to the Case Registration Web System) regarding research subjects in whom all the tests at 
Visit 2 (Day -15 to Day -1 before study drug administration), observation results, and evaluation 
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 research subject to take the drug starting from the next day.  
 
The research subject with a fasting FMD level of 0% shall be withdrawn from this study based on 
Section 7.2.  
Refer to Section 9.1.11 for preparation of records relating to the research subjects withdrawn before 
randomization. 
9.3.3 Treatment period (Visit 3) 
1. Research subjects shall undergo the following tests at Visit 3 (Day 14 to Day 41 after the study 
drug administration) at a designated medical institution for FMD measurements.  
• 
FMD test (fasting) 
• 
Laboratory tests [fasting and 4-h postprandial (allowable range ± 30 min)] 
• 
Exploratory biomarker evaluation [fasting and 4-h postprandial (allowable range ±30 min)] 
 
 Food and drink consumption before the visit will be checked. 
o 
Alcohol should not be consumed from 9:00 pm two days before the hospital visit to the 
time of visit and food should not be consumed from 9:00 pm on the day before to the 
time of visit. 
o 
Eating/drinking to excess and extreme change in dietary content should be avoided on 
the day before the hospital visit. 
 
2. The principal investigator and the investigator shall perform the following tests, observations, 
and evaluations at Visit 3 (Day 14 to Day 41 after the study drug administration). 
• 
Physical examination 
• 
Vital signs 
• 
Concomitant drugs 


TAK-085-4001 
Page 46 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
• 
Study drug compliance 
• 
Adverse Events 
Tests, observations, and evaluations of (1) and (2) at Visit 3 may be performed in any order  
[so long as the completion of all the contents falls within the allowable range (Day 14 to Day 41 
after the study drug administration)]. 
9.3.4 Completion (Visit 4) or discontinuation 
1. Visit 4 shall be the last VISIT, and research subjects shall undergo the following tests at the 
designated medical institution for FMD measurement within the allowable range of Visit 4 (42 
to 70 days after the study drug administration). If the study drug administration is discontinued, 
research subjects should, to the extent possible, undergo tests within 3 days from the last dose 
taken. 
• 
FMD test [fasting and 4-h postprandial (allowable range ± 30 min)]  
• 
Laboratory tests [fasting and 4-h postprandial (allowable range ± 30 min)] 
• 
Exploratory biomarker evaluation [fasting and 4-h postprandial (allowable range ±30 min)] 
 
 Food and drink consumption before the visit will be checked. 
o 
Alcohol should not be consumed from 9:00 pm two days before the hospital visit to the 
time of visit and food should not be consumed from 9:00 pm on the day before to the 
time of visit. 
o 
Eating/drinking to excess and extreme change in dietary content should be avoided on 
the day before the hospital visit. 
 
2. The principal investigator and the investigator shall perform the following tests, observations, 
and evaluations at Visit 4 (Day 42 to Day 70 days after the study drug administration). If the 
study drug administration is discontinued, research subjects should, to the extent possible, 
undergo tests, observations, and evaluations required for the last visit within 3 days from the last 
dose taken.  
• 
Physical examination 
• 
Vital signs  
• 
Concomitant drugs 
• 
Study drug compliance 
• 
Adverse Events 
Since the principal investigator or the investigator is required to confirm safety of the tests, 
observations, and evaluations at Visit 4 or at discontinuation, FMD test and laboratory tests in (1) 
shall be performed first, and tests, observations, and evaluations in (2) shall be performed last.  


TAK-085-4001 
Page 47 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
At completion of the clinical research, the status of all research subjects administered the study drug 
shall be recorded on the CRF. 
 


TAK-085-4001 
Page 48 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
10.0 
PRETREATMENT EVENT AND ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 When pretreatment events are collected 
A Pretreatment Event (PTE) is defined as any unfavorable medical event that occurs to a research 
subject prior to administration of study drug but after the acquisition of informed consent. PTEs are 
not limited to events with clear causal relationship with treatment with the concerned drug. 
10.1.2 Adverse events 
An adverse event is defined as any untoward medical occurrence in a patient or a research 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 relate d to the 
pharmaceutical product (including the study drug) or not. 
10.1.3 Considerations for PTEs and 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 a PTE or 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: 
PTEs or 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: 


TAK-085-4001 
Page 49 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
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 research subject). Retest and/or 
continued monitoring of an abnormality are not considered medical practice. Also, repeated or 
additional 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 symptoms that had been present since before before the 
informed consent) : A disease or symptoms that had been present since before the acquisition of 
informed consent shall be regarded as a concurrent disease and not an adverse event. When a 
concurrent medical condition 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 research 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 research 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 research 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 / severity of PTEs:  
If the research subject experiences changes in the severity of an adverse event / a severity of PTE, 
the event shall be recorded once, at its peak severity. 
Previously planned surgery or treatment:  
Preplanned surgeries or interventions that were scheduled before study treatment shall not be 


TAK-085-4001 
Page 50 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
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 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 research 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. 
10.1.4 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 
research 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 research 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 
were more severe. 


TAK-085-4001 
Page 51 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
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 
When a PTE meets any of the above criteria for SAEs, it shall be reported in accordance with a 
procedure similar to that for serious adverse events (Refer to Section 10.2.2 and 10.3). 
10.1.5 Severity of pretreatment events and 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. 
10.1.6 Causality of adverse events 
The causal relationship of each PTE and 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 
An adverse event that does not follow a temporal sequence from administration of 


TAK-085-4001 
Page 52 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
related 
the study drug. Very likely due to other factors such as underlying disease, 
concurrent diseases, or concomitant drugs/treatment. 
10.1.7 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.” 
10.1.8 Date of onset 
The date of onset of adverse event shall be determined according to the following rules: 
Adverse event, etc. 
Date of onset 
Signs, symptoms, diseases 
(diagnoses) 
The date on which the first signs/symptoms were noted by the 
research 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 or PTE 
The date on which the first worsening of diseases/symptoms was 
noted by the research subject and/or the principal investigator or 
investigator. 
Onset of a test abnormality 
after the start of the study drug 
administration 
(in case of PTE) 
(in case of AE) 
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. 
10.1.9 Date of resolution 
The date of resolution of an adverse event, etc. is the date on which the research subject recovered 
(including resolution with sequelae). If a research subject died due to the adverse event, etc. 
concerned, it shall be the date of death. The adverse event shall be recorded as “ongoing” if the 
research subject has not yet recovered by the end of the study. 
10.1.10 Actions taken for the study drug 
Actions taken for the study drug shall be classified or defined as shown below. 


TAK-085-4001 
Page 53 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
Drug withdrawn 
The study drug is discontinued because of an adverse event (including 
withdrawal by the research subject at his/her own discretion). 
The case in which the study drug administration is continued after withdrawal 
from the study shall be categorized into “Dose not changed.” 
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 research subject. 
Unknown 
It has not been possible to determine what action has been taken because the 
research 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. 
10.1.11 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 research 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 research 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 
“Direct relationship” means that the concerned adverse event was the cause of 
death, or the concerned adverse event 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 research 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 


TAK-085-4001 
Page 54 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
change of hospitals or relocation, etc. 
10.2 
Procedures 
10.2.1 Collection and reporting of adverse events 
10.2.1.1 Adverse event collection period  
The collection of PTEs shall start after the acquisition of informed consent and continue until the 
start of the study drug administration at Visit 2 (Day -15 to Day -1 before the start of study drug 
administration). If withdrawal was decided before the start of administration of the study drug, the 
collection of PTEs shall be terminated at that point. 
Collection of the adverse events shall commence at the start of administration of the study drug to 
research subjects [at Visit 2 (Day -15 to Day -1 before the start of study drug administration)] and 
continue until completion of the treatment period [Visit 4 (Week 8)] or at 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. 
When a PTE corresponds to a serious criterion, the principal investigator or investigator shall follow 
up all research subjects experiencing the PTE until the symptom resolve, any clinically significant 
abnormal laboratory values have returned to the baseline after acquisition of informed consent, or 
there is a satisfactory explanation for the change (permanent and irreversible PTEs). When the PTE 
does not correspond to a serious criterion, irrespective of the causal relationship with the procedure, 
follow-up of the research subject is not required by the protocol. 
The principal investigator or investigator shall follow up all research 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. Name of adverse event, date of onset, date of resolution, grade, 
causal relationship with the study drug (i.e. "Unrelated" or "Related"), action taken for the study 
drug, outcome, relationship to study procedures, and severity shall be recorded.  


TAK-085-4001 
Page 55 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
Follow-up period of PTEs meeting any of the criteria for AEs and SAEs 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. When a serious PTE develops, it shall also be 
reported in accordance with a procedure similar to that for serious adverse events. 
At the time of onset of a serious adverse event or after notification of the onset by the research 
subject, the principal investigator shall report the serious adverse event to the head 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 of after notification of the onset. Further, 
the investigator shall submit a formal report within 10 calendar days to the sponsor. 
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 
• 
Research subject ID number 
• 
Name of investigator or the subinvestigator 
• 
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 investigator or the subinvestigator shall confirm the necessary 
additional information and enter in the 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, the investigator or 
subinvestigator 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 


TAK-085-4001 
Page 56 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
at the research implementing entity (e.g., ECG charts, laboratory test values, discharge summary, 
postmortem results) shall be sent to the sponsor or the committee such as the IEC upon request. 
The investigator or the subinvestigator shall follow-up all serious adverse events, etc., until recovery 
is confirmed, or the final outcome is determined. In addition, serious PTEs shall also be followed, in 
accordance with procedure similar to that for serious adverse events. 
10.3.1 Reporting of serious adverse events, etc., to Ethics Review Committee, etc., 
and regulatory authorities 
When the head of study site receives a report of a serious adverse event from the principal 
investigator, the head of study site shall consult the Ethics Review Committee, etc., and notify the 
study sites that are conducting the clinical research 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 research (study drug) cannot be ruled out and is unexpected, the head 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 Minister of 
Health, Labour and Welfare, and notify other study sites conducting the clinical research. (The chief 
executive of the research implementing entity may report it to the Minister of Health, Labour and 
Welfare via the sponsor, and notify it to other clinical research implementing entities via the 
sponsor.) Serious PTEs shall also be reported in accordance with the same procedure as that for the 
serious adverse events. (No need to report to the Minister of Health, Labour and Welfare.) 
• 
Actions taken for serious adverse events (discontinuation of new enrollment, revision of 
informed consent form, re-consents to other research subjects, etc.) 
• 
Date of review, summery of review, result, necessary action, etc., related to Ethics Review 
Committee, etc. 
• 
Notification to other research implementing entities 
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 
investigators, and the head 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 


TAK-085-4001 
Page 57 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
the study drug risk-benefit, continuation of study drug administration, or continuation of clinical 
research. The research implementing entity shall submit copies of emergency report documents to 
the Ethics Review Committee, etc. 


TAK-085-4001 
Page 58 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY 
11.1 
Clinical Endpoint Committee 
The Central Assessment Committee members shall be independent specialists who have appropriate 
experience in the assessment of the parameters set as the endpoints of this research. 
REGARDING THE PRIMARY ENDPOINT “%FMD (FASTING)” AND THE SECONDARY 
ENDPOINT “%FMD (4 H POSTPRANDIAL)”,THE CENTRAL ASSESSMENT COMMITTEE 
SHALL CONFIRM THE VALIDITY OF THE ASSESSMENT OF THE MEASUREMENT 
RESULTS ACCORDING TO THE PROCEDURE defined separately on the measured images 
reported from the FMD measuring study sites or measuring institutes. 
The assessment results from the committee members shall be entered into the clinical research 
database and used for the analysis of endpoints. 
 


TAK-085-4001 
Page 59 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
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, PTE, medical history and concurrent disease shall be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs shall be coded using the WHO (World 
Health Organization) Drug Dictionary. 
12.1 
Case report form 
The principal investigator or investigator shall complete a CRF for each research subject who has 
signed the informed consent form. 
The sponsor or the designee shall provide access rights to the electric CRF system to the study site. 
Before use of the electric CRF 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 investigator the designee shall ensure the accuracy and completeness of the CRF, and provide an 
electronic signature on the relevant page of the case report form. 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 (except for the data included in the source 
documents). 
• 
Eligibility, completioin status, reason for discontinuation, the seriousness, severity, relation 
to study drug and study procedures outcome 
The following data shall not be recorded directly into the CRFs.  
• 
Laboratory test values 
• 
FMD/Vessel caliber measurement results   
• 
Measurement results from panels of blood proteins, unsaturated fatty acid metabolites, and 
lipids 
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) of change or 
correction on the CRF provided by the sponsor shall be used. The principal investigator shall 


TAK-085-4001 
Page 60 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
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. 
The sponsor or the designee shall confirm that the CRFs are completed appropriately according to 
the procedures set by research. The sponsor or the designee shall have access to the medical records 
of the research 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 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 electronic CRF system 
The sponsor or the designee shall request the principal investigator and investigator to promptly 
enter data into the EDC following enrolment of the research 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 research subject 
ID code, medical records, clinical study worksheets (if used), original signed and dated informed 
consent forms, the record of change or correction on the CRF (copy), and electric copies of 
electronic CRF 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 research 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. 


TAK-085-4001 
Page 61 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
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 before the acquisition of the informed 
consent of the earliest research 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 research. 
13.1.1 Analysis set 
Two analysis sets, “Full Analysis Set；FAS” and “Safety Analysis Set；SAS” are used in this 
research. The FAS primarily used for efficacy analysis will be defined as “research subjects who 
have been randomized and received the study drug at least once”, and the SAS as “research subjects 
who have received the study drug at least once during the clinical research”.  
13.1.2 Analysis of demographic and other baseline characteristics 
From “SAS” primary research subject background items will be tabulated. 
13.1.3 Efficacy analysis 
From FAS the following shall be analyzed. 
13.1.3.1 Analysis of primary endpoints 
%FMD(fasting) 
[Analytical method] 
1) 
Summary statistics by treatment group (number of subjects, mean, SD, minimum value, 
maximum value, quartiles) and a two-sided 95% confidence interval for the mean will be 
calculated at each evaluation time point during the treatment period, and a diagram 
illustrating the change in the mean ± SD will be prepared. 
2) 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment Period 
Visit 2) will be calculated at each evaluation time point during the treatment period and the 
same analysis as in 1) will be performed.  
3) 
Using fasting TG at the start of treatment, a stratified analysis on summary statistics by 
treatment group (number of subjects, mean, SD, minimum value, maximum value, quartiles) 
and a two-sided 95% confidence interval for the mean will be performed. 


TAK-085-4001 
Page 62 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
 
13.1.3.2 Analysis of secondary endpoints 
① %FMD (4 h postprandial) 
② TG level (fasting) 
③ TG level (4 h postprandial) 
④ Plasma fatty acid fraction 
 
[Analytical method] 
1) 
Summary statistics by treatment group (number of subjects, mean, SD, minimum value, 
maximum value, quartiles) and a two-sided 95% confidence interval for the mean will be 
calculated at each evaluation time point during the treatment period, and a diagram 
illustrating the change in the mean ± SD will be prepared. 
2) 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point during the treatment period 
and the same analysis as in 1) will be performed.  
3) 
Using fasting TG at the start of treatment, a stratified analysis on summary statistics by 
treatment group (number of subjects, mean, SD, minimum value, maximum value, 
quartiles) and a two-sided 95% confidence interval for the mean will be performed. 
13.1.3.3 Analysis of other endpoints 
Efficacy endpoints: 
Total cholesterol, LDL-C, LDL-C, Remnant-like particle (RLP) cholesterol , Apoprotein B-48, 
C-reactive protein (CRP), 8-epi-PGF2α quantitative (urinary) 
Analytical method 
1) 
Summary statistics by treatment group (number of subjects, mean, SD, minimum value, 
maximum value, quartiles) and a two-sided 95% confidence interval for the mean will be 
calculated at each evaluation time point during the treatment period, and a diagram 
illustrating the change in the mean ± SD will be prepared. 
2) 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point during the treatment period 
and the same analysis as in 1) will be performed.  
Exploratory endpoints: 
Exploratory biomarker evaluation 


TAK-085-4001 
Page 63 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
(1) Panel of blood proteins 
PAI1, TFPI, TNF-α, IL-1, IL-6, IL-8, IL-10, INFγ, MCP-1, ICAM1, VCAM1, eSelectin, serum 
amyloid A (SAA), pentraxin 3 (PTX3), FABP4, leptin, adiponectin 
 
(2) Panel of unsaturated fatty acid metabolites 
EPA metabolites (18-HEPE, 5-HEPE, Resolvin E1), DHA metabolites [17-HDHA 
(17-HDoHE), 7-HDHA (7-HDoHE), Resolvin D1, Resolvin D2, Resolvin D3, Maresin 1], and 
Arachidonic acid metabolites (PGE2, PGD2, PGF2α, TXB2, 6-keto-PGF1α, LTB4) 
 
Analytical method 
1. 
Summary statistics by treatment group (number of subjects, mean, SD, minimum value, 
maximum value, quartiles) and a two-sided 95% confidence interval for the mean will be 
calculated at each evaluation time point during the observation and treatment period, and a 
diagram illustrating the change in the mean ± SD will be prepared. 
2. 
The change for each treatment group (Treatment Period Visit 2, Visit 3 or Visit 4 - 
Treatment Period Visit 1) will be calculated at each evaluation time point during the 
observation and treatment period and the same analysis as in 1) will be performed. 
3. 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point during the treatment period 
and the same analysis as in 1) will be performed. Moreover, the correlation coefficient will 
be calculated with the change of % FMD for each treatment group and drawn a scatter 
plot. 
 
(3) Panel of lipids (fasting) 
Phospholipids (glycerophospholipid (phosphatidylcholine, phosphatidylethanolamine, 
phosphatidylglycerol, phosphatidylserine, etc.), sphingophospholipids (sphingomyelin, etc.)), 
sphingolipid (ceramide, ganglioside, sulfatides, etc.), neutral lipids (monoacylglycerol, 
diacylglycerol, triacylglycerol, cholesteryl esters, dolichol, etc.), fatty acids (free fatty acids), 
acylcarnitine, bile acids, ubiquinone, and molecular species related to these biosynthesis and 
metabolism 
Analytical method 


TAK-085-4001 
Page 64 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
1. 
Summary statistics by treatment group (number of subjects, mean, SD, minimum value, 
maximum value, quartiles) and a two-sided 95% confidence interval for the mean will be 
calculated at each evaluation time point during the observation and treatment period, and a 
diagram illustrating the change in the mean ± SD will be prepared. 
2. 
The change for each treatment group (Treatment Period Visit 2, Visit 3 or Visit 4 - 
Treatment Period Visit 1) will be calculated at each evaluation time point during the 
observation and treatment period and the same analysis as in 1) will be performed. 
3. 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point during the treatment period 
and the same analysis as in 1) will be performed. Moreover, the correlation coefficient will 
be calculated with the change of % FMD for each treatment group, and scatter plots will 
be drawn. 
 
(4) Panel of lipids (4 h postprandial) 
Phospholipids (glycerophospholipid (phosphatidylcholine, phosphatidylethanolamine, 
phosphatidylglycerol, phosphatidylserine, etc.), sphingophospholipids (sphingomyelin, etc.)), 
sphingolipid (ceramide, ganglioside, sulfatides, etc.), neutral lipids (monoacylglycerol, 
diacylglycerol, triacylglycerol, cholesteryl esters, dolichol, etc.), fatty acids (free fatty acids), 
acylcarnitine, bile acids, ubiquinone, and molecular species related to these biosynthesis and 
metabolism 
Analytical method 
1. 
Summary statistics by treatment group (number of subjects, mean, SD, minimum value, 
maximum value, quartiles) and a two-sided 95% confidence interval for the mean will be 
calculated at each evaluation time point during the observation and treatment period, and a 
diagram illustrating the change in the mean ± SD will be prepared. 
2. 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point during the treatment period 
and the same analysis as in 1) will be performed. Moreover, the correlation coefficient will 
be calculated with the change of % FMD for each treatment group, and scatter plots will 
be drawn. 
 


TAK-085-4001 
Page 65 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
13.1.4 Safety analysis 
From Safety Analysis Set (SAS) the following will be analyzed.  
(1) Adverse events 
The following analysis will be performed for each treatment group. Adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by System 
Organ Class and Preferred Term. 
 
Tabulation of frequencies 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 
 
Tabulation of frequency of serious adverse events 
 
Tabulation of frequency of all adverse events by time of onset 
(2) Body weight, blood pressure in the sitting position, pulse in the sitting position, laboratory tests 
[fasting plasma glucose (FPG)] 
1) 
Summary statistics of measurements by treatment group at each evaluation time point 
during the treatment period will be calculated and a diagram of the change of individual 
data will be created. 
2) 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point during the treatment period 
and the same analysis as in 1) will be performed.  
3) 
Regarding evaluation results based on standard values, shift tables of treatment period Visit 
2 and assessment time points of treatment period (Visit 3, Visit 4) will be prepared. 
13.2 
Criteria for interim analysis and premature discontinuation 
No interim analysis is planned. 
13.3 
Determination of the number of planned research subject 
40 patients evaluable for the primary endpoint  
(Omega-3-acid ethyl esters 2 g: 20 patients, Omega-3-acid ethyl esters 4 g: 20 patients)  


TAK-085-4001 
Page 66 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
Exploratory biomarkers will be measured only for the research subjects from whom blood is taken 
during the observation period after approval of the revised protocol (the 2nd edition) by the 
committee such as the IEC. 
 
[Rationale for the number of planned research subjects] 
The planned sample size is based on the feasibility to explore the effects of omega-3-acid ethyl 
esters on vascular endothelial function. 


TAK-085-4001 
Page 67 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
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 research 
to confirm that the research is conducted in accordance with all specifications in the research 
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 Ethics Review Committee, etc., have access to the source documents. 
The sponsor or the designee shall access the records, including the list of research subject ID 
numbers, medical records of the research subjects, and signed and dated original consent forms to 
confirm that the research is appropriately conducted in compliance with the research protocol. Also, 
confirm the consistency between CRF and the related source documents. The principal investigator, 
investigator, and other personnel involved in the research shall spare sufficient time to facilitate 
monitoring procedures during visits to the study site. 
Detailed procedures for monitoring shall be described separately in the procedure. 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the research protocol. 
The principal investigator or investigator shall record all deviations from Ethical Guidelines for 
Medical and Health Research Involving Human Subjects, and research protocol. 
If any deviation is found, the principal investigator shall promptly notify the chief executive of the 
study site for the clinical research 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 study site for approval of the committee 
such as the IEC. 
14.3 
Quality assurance audits and regulatory agency inspections 
The study site may be research subject to audits by the sponsor or the designee. 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 research. In addition, this research 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 


TAK-085-4001 
Page 68 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
promptly. The principal investigator and the chief executive of the study site shall ensure that the 
auditor has access to all the research-related source documents. 


TAK-085-4001 
Page 69 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
15.0 
ETHICAL CONDUCT OF CLINICAL RESEARCH 
This research shall be conducted with the highest respect for the individual participants (i.e., 
research subjects) according to the research protocol, and the ethical principles that have their origin 
in the Declaration of Helsinki, 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 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 research, 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 Ethics Review Committee for the protocol’s review and approval. In addition to the 
research protocol, a copy of the informed consent form and information sheet, written materials 
related to research 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 
Ethics Review Committee to obtain approval. The sponsor or the designee must obtain written 
approval of the protocol and subject informed consent from the study site committee such as the 
Ethics Review Committee before commencement of the study. The study site committee such as the 
Ethics Review Committee’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) 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 IEC, for example, revision of the 
protocol, revision of the informed consent form and information sheet, revision of materials related 
to research subject recruitment, reports on safety in accordance with the regulatory requirements, 
reports on status of implementation of the research at intervals determined by a study site committee 
such as the Ethics Review Committee, and submission of the study completion report. The sponsor 
or the designee shall obtain written approval from the Ethics Review Committee, etc. related to the 
above mentioned items and all related materials. 


TAK-085-4001 
Page 70 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
15.2 
Conflict of interest 
These clinical studies shall be conducted with the support of the research client. 
Prior to the conduction of this clinical research, the principal investigators involved in this clinical 
research shall ensure appropriate management of any conflicts (COI) in the conduct of the research 
in accordance with the rules of the study site.8)-12) 
The study site shall observe all requirements that the Ethical Review Board, etc. prescribe. This will 
include self-declaration of COI, clinical research protocol, informed consent and information sheet.  
15.3 
Informed consent and information sheet, and the agreement of the research 
subjects 
The informed consent and information sheet 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 research subjects in this 
clinical research (both in and outside Japan: supply to a third party), and disclosure. The informed 
consent form and the information sheet will explain in detail the nature of the research, its objectives, 
and potential risks and benefits. The informed consent form and the information sheet will detail the 
requirements of the participant and the fact that research 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 research subject information sheet by the committee such as the IEC. The 
informed consent form and information sheet must be approved by the committee prior to use. 
The informed consent form and information sheet shall be written in language that can be easily 
understood by the potential research subjects. The principal investigator or investigator shall be 
responsible for providing detailed explanation of the informed consent form and information sheet to 
the potential subjects. Information should be given in both oral and written form whenever possible 
and in manner deemed appropriate by the committee such as the IEC. 
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 subjects. If the potential 
subject decides to participate, the informed consent form must be signed and dated by the potential 
subject prior to entering into the research. The principal investigator or investigator shall instruct the 
potential subject or representative to sign using their legal names, not 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 research. 


TAK-085-4001 
Page 71 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
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 research 
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 research 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 research subject when the informed 
consent form is revised. The date of obtaining new consent shall be recorded in the research 
subject’s medical record, and a copy of the revised consent form shall be provided to the research 
subject. 
Exploratory biomarkers will be measured only for the research subjects from whom blood is taken 
during the observation period after approval of the revised protocol (the 2nd edition) and the revised 
informed consent form by the committee such as the IEC. Exploratory biomarkers should not be 
measured for the research subjects from whom blood collection is completed before the approval of 
the revised protocol (the 2nd edition) and the revised informed consent form by the committee such 
as the IEC, even if a re-written informed consent is obtained from them. 
 
15.4 
Personal information of the research subjects 
The sponsor or the designee shall affirm the principle of the protection of research subjects' 
private/personal information. Throughout this study, research subject ID numbers shall be used to 
link the subject's source data to the sponsor's research database and research-related documents. 
Limited information on research subjects such as gender, age, and date of birth may be used within 
the scope of all applicable laws and regulations for identification of research subjects and 
confirmation of accuracy of research subject ID number. 
For verification of the conduct of the research 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 research sponsor’s designee, representatives of regulatory 
authorities, designated auditors, and committees such as the Ethical Review Board direct access to 
research subjects’ original medical records (source data or documents), including laboratory test 
results, admission and discharge records during a subject’s research participation, and autopsy 
reports. The principal investigator or investigator shall obtain specific authorization of the research 
subject as part of the informed consent process for access to research subject's original medical 
records by research sponsor’s designee and representatives of regulatory authorities (see Section 
15.3). 


TAK-085-4001 
Page 72 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
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 
research subject, other personal information not recorded on the CRF of the research subject). 
15.5 
Consultation windows for the research subjects or persons related to the 
research concerned 
The principal investigator shall establish a contact service to respond to inquiries concerning this 
clinical research from research subjects or concerned people. Details of the contacts for inquiries 
will be described in the ICF. 
15.6 
Financial burden or reward to the research subjects 
Of the expenses for this clinical research, the sponsor shall offer compensation for medical treatment 
not covered by health insurance as research expenses. The research 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 research to the research subjects at each visit from the research funds. 
Details of the financial burden on the research subjects and rewards shall be described in the 
informed consent form and information sheet. 
15.7 
Benefits and inconveniences to the research subjects 
15.7.1 Benefits to research subjects 
By participating in this clinical research, the research subjects may understand one’s own condition 
of vascular endothelial function in detail. 
15.7.2 Inconveniences to research subjects 
By participating in this clinical research the burden of the research subject may increase as number 
of visits will increase compared to daily medical care. 
15.8 
Attribution of research results and access rights 
15.8.1 Attribution of research results 
The research results and data obtained from this research shall belong to the sponsor. 
15.8.2 Data access rights 
Access rights for all data and information generated from this research will be given to personnel 
approved by the sponsor. In addition, secondary use (meta-analysis, etc.) of the data obtained in this 


TAK-085-4001 
Page 73 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
clinical research may be possible if used in such a way that the data shall not be linked to personal 
identification information. 
15.9 
Reporting of results, Publication, disclosure, and clinical research 
registration policy 
15.9.1 Reporting of results, publication and disclosure 
The principal investigator shall report a written summary of results of the research to the chief 
executive of the study site and provide the sponsor with all the results and data obtained from the 
research. Only the sponsor may disclose the research information to other principal investigators, 
investigators or regulatory authorities during the research period, except when required by laws and 
regulations. The sponsor shall be responsible for publication of the research protocol and 
research-related results (including the public web site) except for other cases permitted in the 
research contract. 
During research period and after the end of research, 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 research (including data and information 
provided by the principal investigator) without obtaining agreement of the principal investigator. 
The investigator or the subinvestigator should obtain the prior written approval from the sponsor 
when publishing the information obtained in this research at an academic conference, etc. 
15.9.2 Clinical research registration 
To ensure that information on clinical research 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 research 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 research. On 
such websites, the research location (city, country), 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 research 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. 


TAK-085-4001 
Page 74 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
15.10 Insurance and compensation for injury 
In case of injuries, each research subject in the clinical research 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 research subjects. 
Healthy injury in a research 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. 


TAK-085-4001 
Page 75 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
16.0 
REFERENCES 
1. 
Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in 
men with hypercholesterolemia. 
N Engl J Med. 1995; 333: 1301-1307. 
2. 
Fraley AE, Schwartz GG, Olsson AG, et al. Relationship of oxidized phospholipids and 
biomarkers of oxidized low-density lipoprotein with cardiovascular risk factors, 
inflammatory biomarkers, and effect of statin therapy in patients with acute coronary 
syndromes:  Results from the MIRACL (Myocardial Ischemia Reduction With Aggressive 
Cholesterol Lowering) trial. 
J Am Coll Cardiol. 2009; 53（23）: 2186-2196. 
3. 
Fujioka Y, Ishikawa Y. Remnant lipoproteins as strong key particles to atherogenesis.  
J Atheroscler Thromb. 2009 : 16 ; 145-154. 
4. 
Nordestgaard BG, Benn M, Schnohr P, et al. Nonfasting triglycerides and risk of myocardial 
infarction, ischemic heart disease, and death in men and women. JAMA. 2007; 298:  
299-308. 
5. 
Tatsuno I, Saito Y, Kudou K, Ootake J. 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. 
6. 
Tousoulis D, Plastiras A, Siasos G, 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. 
7. 
Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major 
coronary events in hypercholesterolaemic patients（JELIS）: a randomised open-label, blinded 
endpoint analysis.  
Lancet. 2007 ; 369 : 1090-1098. 
8. 
Report of the Working Group on Conflict of Interest (Ministry of Education, Culture, Sports, 
Science and Technology dated November 1, 2002) 
9. 
Guidelines for determining the conflict of interest polity for clinical research (Review group 
for ethical aspects of clinical research and conflict of interest, March 2006) 
10. Guidelines on the Management of COI in Health and Labor Scirences Research (No. 
0331001, science, issued on March 31, 2008, and approved by the Chief of the Health 
Sciences Division)    
11. Guidelines for management of COI in medical research (COI Committee of Japan 
Association of Medical Sciences, February 2011) 
12. 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, Japanese Respiratory Society, Japanese Society 
of Hematology, Japanese Society of Allergology, Japanese Association for Infectious 
Diseases, Aug 2011) 


TAK-085-4001 
Page 76 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
Appendix A  Schedule for Research Procedures 
 
(a) Eating/drinking to excess and extreme change in dietary content should be avoided on the day before the hospital 
visit. 
(b) All concomitant drugs will be recorded. 
 (c) Time window ± 30 minutes   
 (d)To be performed before test at Visit 2  
(e) To be performed by the physician or the clinical laboratory technician who has finished the FMD measurement 
training   
(f) To be performed after consent has been obtained. 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. 
(g) To be performed to the extent possible 
(h) To be investigated only for "FMD/Vessel caliber measurement results" obtained from the FMP measurement 
before fasting 
Observation
period
Week
-4
0
4
8
Day
-29
-1(f)
28
56
Allowable range
(Day)
-29 to -1
-15 to -1
14 to 41
42 to 70
Up to 3 days
after the last
dose
1
2
3
4
X
X
X
X
X(h)
X(d)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X(d)
X
X
X
X
X(d)
X
X
X
X
X(d)
X(d)
X
X
X
X
X
X
X
X
X(d)
X
X
X
X
X(d)
X
X
X
X
X(d)
X
X
X
X
X(d)
X
X
X
X
X
X
X
X
X(e)
X(e)
X(e)
X(e)
X(e)
X(e)
X(e)
X
X
X
X
X
(X)
←X→
←X→
←X
←X
Drug compliance
PTE and adverse events assessment
　Urinalysis (fasting)
FMD
  FMD (fasting)
　FMD (4 h postprandial)  (c)
Prescription of the study drug
Exploratory biomarker evaluation
  Panel of blood proteins
  Panel of unsaturated fatty acid metabolites
  Panel of lipids (fasting)
  Panel of lipids (4 h postprandial)(c)
　Serum chemistry (4 h postprandial)(c)
Demographic data, medical history,
previous therapeutic drugs
Physical examination
 Confirmation of food and drink
consumption before visit　(a)
Height
Body weight
BMI
Vital signs
Concomitant drugs (b)
Concurrent disease
Laboratory tests
　Serum chemistry (fasting)
Inclusion/Exclusion criteria
Treatment period
 
Discontinuation
(g)
Time of visit
VISIT Number
Informed consent procedure


TAK-085-4001 
Page 77 of 77
2nd edition 
July 7, 2016
 
CONFIDENTIAL 
Appendix B  Responsibilities of the Principal Investigator 
1. 
Appropriately To appropriately conduct the clinical research in compliance with this research 
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 research subjects. 
2. 
Prepare To prepare a list of any other investigators and/or research collaborators when certain 
important research-related activities are divided by investigators and/or research collaborators, 
and submit the list to the sponsor as required. 
3. 
To prepare the informed consent form 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 
subinvestigators and study collaborators, and give guidance and supervision. 
6. 
To select research 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 research. 
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 research according to the study site. 
10. To ensure, together with the chief executive of the study site, that sufficient medical care is 
provided to research subjects for all research-related clinically problematic adverse events 
throughout the period of subjects’ research participation and thereafter. 
11. When a research subject is treated at another medical institution or department, to inform the 
acting physician at the medical institution or department in writing of the research subject’s 
study participation and research completion/discontinuation after obtaining the research 
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. 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 
collaborator from source data, {electronically sign/ sign or write name/affix a seal, and submit 
them to the sponsor. 
15. To discuss a revision of the protocol, etc., when proposed by the sponsor. 
16. To report the research completion in writing to the chief executive of the study site. 


TAK-085-4001 
Page 1 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
 
PROTOCOL 
 
 
Exploratory study of the effect of omega-3-acid ethyl esters on vascular endothelial 
function in patients with hyperlipidemia by flow mediated dilation 
(Oasis Flow) 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
12-10 Nihonbashi 2-chome, Chuo-ku, Tokyo 
Protocol number 
TAK-085-4001 
Version number/Revision number 
First edition 
Study drug: 
Omega-3-acid ethyl esters 
Creation date 
March 29, 2016 
 
 
 
 
 


TAK-085-4001 
Page 2 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
CONFIDENTIAL PROPERTY 
This document is a confidential communication of Takeda. Acceptance of this document constitutes 
agreement by the potential recipient of the drug to be administered 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 research 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. 


TAK-085-4001 
Page 3 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
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 Research, monitoring, registration/allocation center, statistical processing, and audit 


TAK-085-4001 
Page 4 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
shall 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: 
          
 
The Chair of the Clinical Research Steering Committee shall supervise implementation and reporting 
of the clinical research, secure medical guidance of a high degree of professionalism and a high-level 
scientific quality, and revise the research 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 research in accordance with the protocol, including a 
study site that obtains new samples/information from research subjects and provides other study 
sites.  
Researchers, 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: 
A researcher 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 
Research subject: 
A subject (including a dead subject) who meets any of the following:   
PPD


TAK-085-4001 
Page 5 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
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. 
 


TAK-085-4001 
Page 6 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
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 ................................................................................................. 18 
4.0 
INTRODUCTION ................................................................................................. 19 
4.1 
Background ...................................................................................................... 19 
4.2 
Rationale for the proposed research ................................................................ 20 
5.0 
RESEARCH OBJECTIVES AND ENDPOINTS ................................................. 21 
5.1 
Objectives ........................................................................................................ 21 
5.2 
Definition of endpoints .................................................................................... 21 
5.2.1 Primary endpoints ...................................................................................... 21 
5.2.2 Secondary endpoints .................................................................................. 21 
5.2.3 Other endpoints ......................................................................................... 21 
5.2.4 Safety endpoints ........................................................................................ 21 
6.0 
CLINICAL RESEARCH DESIGN ....................................................................... 22 
6.1 
Clinical research design ................................................................................... 22 
6.2 
Rationale for the clinical research design ........................................................ 24 
6.3 
Premature termination of entire clinical research or premature 
termination of clinical research at a study site ................................................ 25 
6.3.1 Premature termination criteria of entire clinical research ......................... 25 
6.3.2 Criteria for premature termination of study sites....................................... 25 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or study at a study site ............................................... 25 
6.4 
Procedures for protocol revision ..................................................................... 25 
7.0 
SELECTION AND WITHDRAWAL CRITERIA OF RESEARCH 
SUBJECTS ............................................................................................................ 27 
7.1 
Inclusion criteria .............................................................................................. 27 
7.2 
Exclusion criteria ............................................................................................. 28 


TAK-085-4001 
Page 7 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
7.3 
Prohibited concomitant drugs and permitted concomitant drugs .................... 30 
7.3.1 Prohibited concomitant drugs .................................................................... 30 
7.3.2 Permitted concomitant drugs ..................................................................... 31 
7.4 
Research subject management ......................................................................... 31 
7.5 
Criteria for discontinuation or withdrawal of a research subject .................... 32 
7.6 
Procedures for discontinuation of individual research subjects ...................... 33 
8.0 
RESEARCH TREATMENT ................................................................................. 34 
8.1 
Study drug ....................................................................................................... 34 
8.1.1 Dose and administration method ............................................................... 34 
8.1.2 Concomitant drug ...................................................................................... 34 
8.1.3 Overdose of the study drug ........................................................................ 34 
8.2 
Allocation of the study drug and administration procedure ............................ 35 
8.3 
Preparation and storage of allocation list ........................................................ 35 
9.0 
CLINICAL STUDY PROTOCOL ........................................................................ 36 
9.1 
Research procedures ........................................................................................ 36 
9.1.1 Informed consent procedure ...................................................................... 36 
9.1.2 Demographic data, medical history, and previous therapeutic drugs ........ 36 
9.1.3 Physical examination ................................................................................. 36 
9.1.4 Weight, height, and BMI ........................................................................... 36 
9.1.5 Vital signs .................................................................................................. 37 
9.1.6 Concomitant drugs ..................................................................................... 37 
9.1.7 Concurrent disease ..................................................................................... 37 
9.1.8 Checking food and drink consumption before the visit ............................. 37 
9.1.9 Laboratory tests ......................................................................................... 38 
9.1.10 Flow-mediated dilation (FMD) test ........................................................... 38 
9.1.11 Record of research subjects who are withdrawn before randomization .... 38 
9.1.12 Record of randomization ........................................................................... 39 
9.2 
Drug-taking status of the research subjects ..................................................... 39 
9.3 
Implementation time point of the test and observation items .......................... 39 
9.3.1 Observation period (Visit 1) ...................................................................... 39 
9.3.2 Treatment period (Visit 2) ......................................................................... 40 


TAK-085-4001 
Page 8 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
9.3.3 Treatment period (Visit 3) ......................................................................... 41 
9.3.4 Completion (Visit 4) or discontinuation .................................................... 42 
10.0 
PRETREATMENT EVENT AND ADVERSE EVENTS .................................... 43 
10.1 
Definitions ....................................................................................................... 43 
10.1.1 When pretreatment events are collected .................................................... 43 
10.1.2 Adverse event ............................................................................................ 43 
10.1.3 Considerations for PTEs and adverse events ............................................. 43 
10.1.4 Serious adverse event ................................................................................ 45 
10.1.5 Severity of pretreatment events and adverse events .................................. 46 
10.1.6 Causality of pretreatment events and adverse events ................................ 46 
10.1.7 Relationship to study procedures ............................................................... 47 
10.1.8 Date of onset .............................................................................................. 47 
10.1.9 Date of resolution ...................................................................................... 47 
10.1.10Actions taken for the study drug................................................................ 47 
10.1.11Outcome .................................................................................................... 48 
10.2 
Procedures ....................................................................................................... 49 
10.2.1 Collection and reporting of adverse events ............................................... 49 
10.2.2 Collection and reporting of serious adverse events ................................... 50 
10.2.3 Reporting of additional information concerning adverse events ............... 50 
10.3 
Follow-up of serious adverse events ............................................................... 50 
10.3.1 Reporting of serious adverse events, etc., to Ethics Review 
Committee, etc., and regulatory authorities ............................................... 51 
11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY ........................................ 53 
11.1 
Clinical Endpoint Committee .......................................................................... 53 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS ............................... 54 
12.1 
Case report form .............................................................................................. 54 
12.2 
Timing of data entry into the electronic CRF system ...................................... 55 
12.3 
Storage of records ............................................................................................ 55 
13.0 
STATISTICAL ANALYSIS METHODS ............................................................. 56 
13.1 
Statistical and analytical plans ......................................................................... 56 
13.1.1 Analysis set ................................................................................................ 56 


TAK-085-4001 
Page 9 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
13.1.2 Analysis of demographic and other baseline characteristics ..................... 56 
13.1.3 Efficacy analysis ........................................................................................ 56 
13.1.4 Safety analysis ........................................................................................... 57 
13.2 
Criteria for interim analysis and premature discontinuation ........................... 58 
13.3 
Determination of the number of planned research subject .............................. 58 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 60 
14.1 
Monitoring of the study site ............................................................................ 60 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the research protocol. .................................... 60 
14.3 
Quality assurance audits and regulatory agency inspections........................... 60 
15.0 
ETHICAL CONDUCT OF CLINICAL RESEARCH .......................................... 62 
15.1 
Approval of the Ethical Review Board, etc. .................................................... 62 
15.2 
Conflict of interest ........................................................................................... 63 
15.3 
Informed consent and information sheet, and the agreement of the 
research subjects .............................................................................................. 63 
15.4 
Personal information of the research subjects ................................................. 64 
15.5 
Consultation windows for the research subjects or persons related to the 
research concerned .......................................................................................... 64 
15.6 
Financial burden or reward to the research subjects........................................ 65 
15.7 
Benefits and inconveniences to the research subjects ..................................... 65 
15.7.1 Benefits to research subjects...................................................................... 65 
15.7.2 Inconveniences to research subjects .......................................................... 65 
15.8 
Attribution of research results and access rights ............................................. 65 
15.8.1 Attribution of research results ................................................................... 65 
15.8.2 Data access rights ...................................................................................... 65 
15.9 
Reporting of results, Publication, disclosure, and clinical research 
registration policy ............................................................................................ 65 
15.9.1 Reporting of results, publication and disclosure ....................................... 65 
15.9.2 Clinical research registration ..................................................................... 66 
15.9.3 Clinical trial results disclosure .................................................................. 66 
15.10 Insurance and compensation for injury ........................................................... 66 
16.0 
REFERENCES ...................................................................................................... 67 


TAK-085-4001 
Page 10 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
LIST OF IN-TEXT TABLES 
Table 9.a 
Laboratory tests ......................................................................................... 38 
Table 10.a 
Takeda Medically Significant AE List ...................................................... 46 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Outline of clinical research design ............................................................ 24 
LIST OF APPENDICES 
Appendix A  Schedule for Research Procedures ............................................................. 68 
Appendix B  Responsibilities of the Principal Investigator ............................................ 69 


TAK-085-4001 
Page 11 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
2.0 
STUDY SUMMARY 
Sponsor: 
Takeda Pharmaceutical Company Limited 
Study drug: 
Omega-3-acid ethyl esters  
Study title: Exploratory study of the effect of omega-3-acid ethyl esters on vascular endothelial 
function in patients with hyperlipidemia 
Protocol number: TAK-085-4001 
Clinical research design: 
This is a multicenter, collaborative, randomized, open-label study designed to explore the effects of 
administration of omega-3-acid ethyl esters [2 g (2 g PO QD) or 4 g (2 g PO BID) for 8 weeks] on 
vascular endothelial function, as measured by flow-mediated dilation (FMD), in patients receiving a 
hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and have concurrent 
hypertriglyceridemia (hereinafter referred to as TG). 
Considering the potential bias by factors that affect FMD between treatment groups, stratified 
allocation will be performed with fasting TG level as a factor.  
 
Objectives: 
To explore the effects of omega-3-acid ethyl esters on vascular endothelial function when 
administered for 8 weeks, as measured by FMD, in patients with hyperlipidemia.  
Subjects: Patients with hyperlipidemia 
Planned number of research subjects: 
40 patients evaluable for the primary endpoint 
2 g group : 20 subjects 
4 g group : 20 subjects 
Number of study sites: 
5 to 10 institutions 
 
Dose and method of administration: 
A dose of 2 g of omega-3-acid ethyl esters will be 
orally administered once or twice a day immediately 
after meal. 
 
Route of administration: 
Oral 
Duration of treatment: 
8 weeks 
Duration of evaluation: 
Screening period: 4 weeks 
Treatment period: 8 weeks 
Total: 12 weeks  


TAK-085-4001 
Page 12 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
Main criteria for inclusion: 
1. 
Patients with the diagnosis of hyperlipidemia and receiving instructions for lifestyle 
improvement 
2. 
Patients with a fasting triglyceride (TG) level of 150 -499 mg/dL at Visit 1 after informed 
consent (Day -29 to Day -1 before start of study drug administration)   
3. 
Patients receiving a stable dose of HMG-CoA reductase inhibitor therapy continuously for at 
least 4 weeks before informed consent at Visit 1 (Day -29 to Day -1 before start of study drug 
administration)    
4. 
Male or postmenopausal female patients 
5. 
Patients who, in the opinion of the principal investigator or the investigator, are capable of 
understanding the content of the clinical research and complying with the research protocol 
requirements.  
6. 
Patients who can provide written informed consent prior to the conduction of the clinical 
research procedures 
7. 
Patients aged ≥20 years at the time of informed consent at Visit 1(Day -28 to Day 0 before the 
start of study drug administration)   
Main criteria for exclusion: 
1. 
Patients with a history of revascularization or those have had coronary artery disease (a 
definitive diagnosis of myocardial infarction, angina) within 24 weeks before informed consent 
at Visit 1 (Day -29 to Day -1 before the start of study drug administration)       
2. 
Patients who have undergo aortic aneurysmectomy within 24 weeks prior to informed consent 
at Visit 1 (Day -29 to Day -1 before the start of study drug administration) or those with 
concurrent aortic aneurysm    
3. 
Patients who have had clinically significant hemorrhagic disorders (e.g., hemophilia, capillary 
fragility, gastrointestinal ulcer, urinary tract hemorrhage, hemoptysis, and vitreous hemorrhage) 
within 24 weeks prior to informed consent at Visit 1 (Day -29 to Day -1 before the start of 
study drug administration) or those who concurrently have the above disorders   
4. 
Patient with a fasting FMD level of 0% measured at the start of study drug administration at 
Visit 2 (Day -15 to Day -1 before the start of study drug administration)    
5. 
Patients in whom the type and dosage of HMG-CoA reductase inhibitors, antidiabetic drugs and 
antihypertensive drugs have been changed within 4 weeks prior to informed consent at Visit 1 
(Day -29 to Day -1 before the start of study drug administration)     
6. 
Patients who have started anti dyslipidemic agents within 4 weeks prior to informed consent at 


TAK-085-4001 
Page 13 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
Visit 1 (Day -29 to Day -1 before the start of study drug administration)    
7. 
Patients requiring a change in the dose of  dyslipidemia therapeutic, antidiabetic, or 
antihypertensive drugs during the period between informed consent at Visit 1 (Day -29 to Day 
-1 before the start of study drug administration) and the start of study drug administration at 
Visit 2 (Day -15 to Day -1 before the start of study drug administration)  
8. 
Patients with severe hepatic dysfunction 
9. 
Patients with severe renal dysfunction (as an indicator, CKD category ≥G3b, equivalent to an 
A3)  
10. Patients who have been diagnosed with pancreatitis 
11. Patients who have been diagnosed with lipoprotein lipase deficiency, apoprotein C-II 
deficiency, familial hypercholesterolemia, familial combined hyperlipidemia, or familial type 
III hyperlipidemia 
12.  Patients with concurrent Cushing's syndrome, uremia, systemic lupus erythematosus (SLE), 
serum dysproteinemia, or hypothyroidism   
13.  Patients with symptomatic Peripheral Arterial Disease (PAD)  
14. Patients with concurrent hypertension of grade II or higher Note 1)   
Note 1: Patients with systolic blood pressure of ≥160 mm Hg or diastolic BP of ≥100 mm Hg regardless of treatment 
with antihypertensive drugs 
15. 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 Note 2)  
16. Patients with a history of hypersensitivity or allergy for omega-3-acid ethyl esters 
17. Patients who smoke 
18. Patients participating in other clinical studies 
19. Patients who have been determined to be ineligible as subjects in the study by the principal 
investigator or the investigator    
Endpoints: 
< Primary endpoint > 
%FMD (fasting) 
Secondary endpoints 
(1) %FMD (4 h postprandial) 


TAK-085-4001 
Page 14 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
(2) TG level (fasting) 
(3) TG level (4 h postprandial) 
(4) Plasma fatty acid fraction 
<Safety endpoint> 
Adverse events, body weight, blood pressure in the sitting position, pulse in the sitting position, 
laboratory tests [fasting plasma glucose (FPG)] 
<Other endpoints> 
Efficacy endpoint: 
(1) Total cholesterolLDL-C, HDL-C, Remnant-like particle (RLP) cholesterol , Apoprotein B-48, 
C reaction protein (CRP), determination of 8-epi-PGF2α (in urine) 
(2)  
Statistical 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 subjects who satisfy the following criterion: 
• 
Research subjects who were randomized and given at least one dose of the study drug. 
Define SAS as the population of enrolled research subjects who satisfy the following criterion: 
• 
Research subjects who were given at least one dose of the study drug during this clinical 
study.  
(2) Efficacy analysis 
[Primary endpoints] 
%FMD (fasting) 
[Analytical method] 
1) 
Summary statistics by treatment group (number of subjects, mean, SD, 
minimum value, maximum value, quartiles) and a two-sided 95% confidence interval 
for the mean will be calculated at each evaluation time point during the treatment 
period, and a diagram illustrating the change in the mean ± SD will be prepared. 
2) 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point and the same analysis 
as in 1) will be performed.  
3) 
Using fasting TG level at the start of treatment, a stratified analysis on summary 


TAK-085-4001 
Page 15 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
statistics by treatment group (number of subjects, mean, SD, minimum value, 
maximum value, quartiles) and a two-sided 95% confidence interval for the mean will 
be performed. 
[Secondary endpoints] 
(1) %FMD (4 h postprandial) 
(2) TG level (fasting) 
(3) TG level (4 h postprandial) 
(4) Plasma fatty acid fraction 
[Analytical method] 
1) 
Summary statistics by treatment group (number of subjects, mean, SD, 
minimum value, maximum value, quartiles) and a two-sided 95% confidence interval 
for the mean will be calculated at each evaluation time point during the treatment 
period, and a diagram illustrating the change in the mean ± SD will be prepared. 
2) 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point during the treatment 
period and the same analysis as in 1) will be performed.  
3) 
Using fasting TG level at the start of treatment, a stratified analysis on summary 
statistics by treatment group (number of subjects, mean, SD, minimum value, 
maximum value, quartiles) and a two-sided 95% confidence interval for the mean will 
be performed. 
[Other endpoints] 
Efficacy endpoints: 
Total cholesterolLDL-C, HDL-C, Remnant-like particle (RLP) cholesterol , Apoprotein 
B-48,  C reaction protein (CRP), determination of 8-epi-PGF2α (in urine) 
[Analytical method]  
1) 
Summary statistics by treatment group (number of subjects, mean, SD, 
minimum value, maximum value, quartiles) and a two-sided 95% confidence interval 
for the mean will be calculated at each evaluation time point during the treatment 
period, and a diagram illustrating the change in the mean ± SD will be prepared. 
2) 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point and the same analysis 
as in 1) will be performed.  


TAK-085-4001 
Page 16 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
1. 
Exploratory endpoints: 
(1) Panel of blood proteins 
PAI1, TFPI, TNF-α, IL-1, IL-6, IL-8, IL-10, INFγ, MCP-1, ICAM1, VCAM1, eSelectin, 
SAA, PTX3, FABP4, leptin, adiponectin 
 
(1) 
Panel of lipids 
Phospholipids, sphingolipids, neutral lipids, fatty acids (free fatty acids), acylcarnitine, 
bile acids 
 
(2) 
Panel of unsaturated fatty acid metabolites 
EPA metabolites (18-HEPE, 5-HEPE, Resolvin E1) 
DHA metabolites [17-HDHA (17-HDoHE), 7-HDHA (7-HDoHE), Resolvin D1, Resolvin 
D2, Resolvin D3, Maresin 1] 
Arachidonic acid metabolites (PGE2, PGD2, PGF2α, TXB2, 6-keto-PGF1α, LTB4) 
 
[Analytical method] 
Summary statistics by treatment group (number of subjects, mean, SD, minimum  
(3) Analysis of safety endpoints 
[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 
 
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 
[Body weight, blood pressure in the sitting position, pulse in the sitting position, laboratory 


TAK-085-4001 
Page 17 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
tests [fasting plasma glucose (FPG)] 
1) 
Summary statistics of measurements by treatment group at each evaluation time point 
during the treatment period will be calculated and a diagram of the change of individual 
data will be created.  
2) 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point during the treatment period 
and the same analysis as in 1) will be performed.  
3) 
Shift table will be created for assessment results based on reference values for Treatment 
Period Visit 2 and each evaluation time point (Visit 3, Visit 4) during the treatment 
period. 
Rationale for the number of planned research subjects 
The planned sample size is based on the requierment to investigate explore atively the effects of 
omega-3-acid ethyl esters on vascular endothelial function considering the feasibility of this study. 


TAK-085-4001 
Page 18 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
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  
SLE 
systemic lupus erythematosus 
SOC 
System Organ Class 
TG 
triacylglycerol 


TAK-085-4001 
Page 19 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
4.0 
INTRODUCTION 
4.1 
Background 
The efficacy of LDL-lowering regimen using HMG-CoA reductase inhibitor designed to control 
cardiovascular events has been already established, which leads to primary prevention, secondary 
prevention, and risk reduction in high-risk treatment groups.1),2) However, postprandial 
hypertriglyceridemia and the quality of LDL have been receiving attention as an atherosclerotic risk 
factor that remains after the treatment with HMG-CoA reductase inhibitors.  
Although there had been no consensus regarding the significance of triglycerides (TG) as a 
cardiovascular risk, Japan Atherosclerosis Society (JAS) Guidelines for Prevention of 
Atherosclerotic Cardiovascular Diseases (2012) stated that “a number of epidemiological studies 
suggest that elevated triglyceride levels are associated with increased incidence of cardiovascular 
diseases.” TG levels reach the highest 3 to 4 h after meal. Especially, remnant-like lipoprotein (RLP) 
plays an important role to cause the elevation of TG level, and RLP particles contain a greater 
amount of cholesterol, as well as TG, than LDL particles. It has been reported that RLP enhances 
foaming of macrophage and inflammatory reaction3), and TG levels at 2 to 4 h after meals are more 
important than those before meals as a heart disease risk factor. 4)  
As insulin resistance associated with obesity, etc. increases, qualitative changes in LDL, as well as 
elevated levels of TG, are observed. The increase observed in small dense LDL (sdLDL) of small 
particle diameters is considered to enhance the formation of atherosclerotic plaque since this sdLDL 
is easily taken up by macrophages. Therefore, in order to aim at further inhibition of cardiovascular 
events after achieving the lowering of LDL-C with HMG-CoA reductase inhibitors, it is considered 
especially important to lower TG levels/decrease sdLDL. Omega-3 fatty acids including 
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been receiving attention in 
recent years as the drugs having such activities. Since omega 3 fatty acids are not synthesized in the 
body, supplementation from meals (fish) is necessary. EPA and DHA have TG-lowering and 
antiatherosclerosis activities but the mechanism has not been completely elucidated. Omega-3-acid 
ethyl esters (EPA/DHA preparations, Lotriga®) released in 2013 lower TG levels in a 
dose-dependent manner5) and are expected to lead to lowering of RLP, increase in the LDL particle 
size, FMD, and lowering of IL-6 levels.6)   
In JELIS Studies, lowering of TG levels and reduction in major coronary events have been 
demonstrated in the HMG-CoA reductase inhibitor and EPA combination group compared to the 
HMG-CoA reductase inhibitor alone group.7) This clinical study aims at exploring the effects of 
Lotriga® (EPA/DHA preparations) on vascular endothelial function and postprandial 
hypertriglyceridemia assessed by FMD, etc. in patients receiving a 
hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and have concurrent 
hypertriglyceridemia (TG).  


TAK-085-4001 
Page 20 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
4.2 
Rationale for the proposed research 
This clinical study was planned to contribute to the prevention of arteriosclerotic disease by 
exploring the effects of omega-3-acid ethyl esters on vascular endothelial in patients with 
hyperlipidemia. 


TAK-085-4001 
Page 21 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
5.0 
RESEARCH OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
The objective of this study is to explore the effects of omega-3-acid ethyl esters on vascular 
endothelial function when administered for 8 weeks, as measured by FMD, in patients with 
hyperlipidemia. 
5.2 
Definition of endpoints 
5.2.1 Primary endpoints 
%FMD (fasting) 
5.2.2 Secondary endpoints 
(1) %FMD (4 h postprandial) 
(2) TG level (fasting) 
(3) TG level (4 h postprandial) 
(4) Plasma fatty acid fraction 
5.2.3 Other endpoints 
Efficacy endpoints: 
total cholesterol, LDL-C, HDL-C, Remnant-like particle (RLP) cholesterol , apoprotein B-48, 
C-reactive protein (CRP), determination of 8-epi-PGF2α (in urine) 
5.2.4 Safety endpoints 
Adverse events, body weight, blood pressure in the sitting position, pulse in the sitting position, 
laboratory tests [fasting plasma glucose (FPG)] 
 


TAK-085-4001 
Page 22 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
6.0 
CLINICAL RESEARCH DESIGN 
6.1 
Clinical research design 
< Clinical research design > 
This is a multicenter, collaborative, randomized, open-label study designed to explore the effects of 
administration of omega-3-acid ethyl esters [2 g (2 g PO QD) or 4 g (2 g PO BID) for 8 weeks] on 
vascular endothelial function, as measured by FMD, in patients receiving a 
hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor and have concurrent 
hypertriglyceridemia. 
Considering the potential bias by factors that affect FMD between treatment groups, stratified 
allocation will be performed with fasting TG as a factor.  
Research TREATMENT 
(1) Study drug: 
Omega-3-acid ethyl esters 
(2) Dosage regimen 
Omega-3-acid ethyl esters will be orally administered [2 g (2 g PO QD) or 4 g (2 g PO BID)] 
immediately after meal for 8 weeks in patients with hyperlipidemia . 
(3) Duration of treatment: 
8 weeks 
Planned number of research subjects: 
40 patients evaluable for the primary endpoint 
2 g group: 20 subjects 
4 g group: 20 subjects 
Number of study sites: 
5 to 10 institutions 
< Duration of the treatment and number of visits of by subjects > 
(1) Duration of treatment: 
The duration of the treatment period is 8 weeks. Research subjects should visit the hospital at the 
time of informed consent at Visit 1 (Day-29 to Day -1 before the start of study drug) and from the 
start of study drug administration at Visit 2 (Day -15 to Day -1 from the start of study drug 
administration) to completion of study drug administration [Visit 4 (Week 8)].  


TAK-085-4001 
Page 23 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
(2) Number of visits 
Observation period: 1 visit 
Treatment period: 3 to 6 visits 
The FMD measurement during the treatment period will be performed by a physician or 
laboratory technician who completed the FMD measurement training. Therefore, only for the 
FMD measurement, subjects are expected to go to a testing laboratory other than the one they 
normally visit for examinations. In that case, a total of 3 visits for the FMD measurement will 
be added to the total of 3 visits for examinations from Treatment Period Visit 2 (Day -15 to 
Day -1 before the start of study drug administration) to Visit 4 (Week 8). Therefore, the 
number of visits during the treatment period will be a minimum of 3 and a maximum of 6.  
 
 
 
 


TAK-085-4001 
Page 24 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
Figure 6 (a) shows an outline of the clinical research design. Refer to Appendix A for schedule of 
examinations, observations, and assessments. 
Figure 6.a 
Outline of clinical research design 
< Outline of clinical research> 
Duration of treatment:8 weeks 
Number of visits: 4 to 7 visits 
 
(a) FMD measurement will be performed by a physician or laboratory technician who completed 
the FMD measurement training.  
6.2 
Rationale for the clinical research design 
<Rationale> 
Since this study aims at exploring the effects of oral administration of omega-3-acid ethyl esters 
in clinical practice (2 g once a day or twice a day for 8 weeks) on vascular endothelial function, 
the study was designed as an open-label comparing FMD before and after omega-3-acid 
administration without including control groups.  
< Rationale for the dose and dosing regimen > 
In accordance with the approved dosage and administration of omega-3-acid ethyl esters, dose 
and dosing regimen of omega-3-acid ethyl esters were set at 2 g (2 g PO QD) and 4 g (2 g PO 
BID) in this study. 
< Rationale for the duration of study > 
Visit
1
Week
-4
Allowable
range
-29
Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor
4
0
4
8
-15to-1
14to41
42to70
Omega-3-acid ethyl esters 2 g (2 g PO QD) -
Omega-3-acid ethyl esters 4 g (2 g PO BID) -
FMD(a)
FMD(a)
FMD(a)
Explanation using
informed consent
information sheet
(the informed
Start of study drug
treatment
Eligibility screening
2
3


TAK-085-4001 
Page 25 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
Since improvement of FMD was observed after a 2-month administration of omega-3-acid ethyl 
esters in the studies conducted outside Japan investigating the effect of omega-3-acid ethyl esters 
on FMD,8) it was considered that the effect of omega-3-acid ethyl esters on FMD can be 
examined with an 8-week administration and the duration of the treatment period was, therefore, 
set at 8 weeks in this clinical study.  
< Rationale for the planned sample size > 
See Section 13.3.  
6.3 
Premature termination of entire clinical research or premature termination 
of clinical research at a study site 
6.3.1 Premature termination criteria of entire clinical research 
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 research subject participation in the study. 
 
When there is serious deviation from Ethical Guidelines or ICH-GCP for medical and health 
research 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 in significant violation of 
the ethical guidelines, protocol, or contractual agreement for medical and health research involving 
human subjects, or is unable to ensure proper conduct of the research. 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or study at a study site 
In the event that the sponsor or a study site committee such as an ethics review committee 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. 
6.4 
Procedures for protocol revision 
If the protocol needs to be revised, the sponsor shall consider and decide whether to revise the 
protocol. 


TAK-085-4001 
Page 26 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
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 IEC, as necessary according to institutional regulations for review, and 
obtain approval from the director of the entity. 


TAK-085-4001 
Page 27 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
7.0 
SELECTION AND WITHDRAWAL CRITERIA OF RESEARCH 
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 research subjects shall be determined in accordance with the following criteria. 
1. 
Patients with the diagnosis of hyperlipidemia and receiving instructions for lifestyle 
improvement 
2. 
Patients with a fasting triglyceride (TG) level of 150 – 499 mg/dL at Visit 1 after informed 
consent (Day -29 to Day -1 before start of study drug administration) 
3. 
Patients receiving a stable dose of HMG-CoA reductase inhibitor therapy continuously for 
at least 4 weeks at the time of informed consent at Visit 1 (Day -29 to Day -1 before start 
of study drug administration)   
4. 
Male or postmenopausal female patients 
5. 
Patients who, in the opinion of the principal investigator or the investigator, are capable of 
understanding the content of the clinical research and complying with the research 
protocol requirements. 
6. 
Patients who can provide written informed consent prior to the conduction of the clinical 
research procedures 
7. 
Patients aged ≥20 years at the time of informed consent at Visit 1(Day -29 to Day -1 
before the start of study drug administration)  
[Rationale for the inclusion criteria] 
1. This was set as a target condition in this clinical study.  
2. This was set according to the diagnostic criteria for hypertriglyceridemia in “Japan 
Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular 
Diseases 2012.” 
3. This was set for an accurate assessment of the efficacy.  
4. This was set in consideration of the effect of female hormones on FMD. 
5.6. These were set as fundamental items for the research. 
7. This was set considering the age ≥20 years as the age where patients are capable of making a 
decision to participate in this clinical study.  


TAK-085-4001 
Page 28 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
7.2 
Exclusion criteria 
Research subjects meeting any of the criteria below shall not be included in this research. 
1. Patients with a history of revascularization or those have had coronary artery disease (a 
definitive diagnosis of myocardial infarction, angina) within 24 weeks before informed 
consent at Visit 1 (Day -29 to Day -1 before the start of study drug administration)    （  
2. Patients who have undergo aortic aneurysmectomy within 24 weeks prior to informed 
consent at Visit 1 (Day -29 to Day -1 before the start of study drug administration) or 
those with concurrent aortic aneurysm    
3. Patients who have had clinically significant hemorrhagic disorders (e.g., hemophilia, 
capillary fragility, gastrointestinal ulcer, urinary tract hemorrhage, hemoptysis, and 
vitreous hemorrhage) within 24 weeks prior to informed consent at Visit 1 (Day -29 to 
Day -1 before the start of study drug administration) or those who concurrently have the 
above disorders  
4. Patient with a fasting FMD level of 0% measured at the start of study drug administration 
at Visit 2 (Day -15 to Day -1 before the start of study drug administration)   
5. Patients in whom the type and dosage of HMG-CoA reductase inhibitors, antidiabetic drugs 
and antihypertensive drugs have been changed within 4 weeks prior to informed consent at 
Visit 1 (Day -29 to Day -1 before the start of study drug administration)    
6. Patients who have started anti dyslipidemic agents within 4 weeks prior to informed 
consent at Visit 1 (Day -29 to Day -1 before the start of study drug administration)    
7. Patients requiring a change in the dose of  dyslipidemia therapeutic, antidiabetic, or 
antihypertensive drugs during the period between informed consent at Visit 1 (Day -29 to 
Day -1 before the start of study drug administration) and the start of study drug 
administration at Visit 2 (Day -15 to Day -1 before the start of study drug administration)  
8. Patients with severe hepatic dysfunction 
9. Patients with  severe renal dysfunction (as an indicator, CKD category ≥G3b, equivalent to 
an A3)  
10. Patients who have been diagnosed with pancreatitis 
11. Patients who have been diagnosed with lipoprotein lipase deficiency, apoprotein C-II 
deficiency, familial hypercholesterolemia, familial combined hyperlipidemia, or familial 
type III hyperlipidemia  


TAK-085-4001 
Page 29 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
12. Patients with concurrent Cushing's syndrome, uremia, systemic lupus erythematosus (SLE), 
serum dysproteinemia, or hypothyroidism    
13. Patients with symptomatic Peripheral Arterial Disease (PAD) 
14. Patients with concurrent hypertension of grade II or higher Note 1)   
Note 1: Patients with systolic blood pressure of ≥160 mm Hg or diastolic BP of ≥100 mm Hg regardless of 
treatment with antihypertensive drugs  
15. 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 Note 2)  
16. Patients with a history of hypersensitivity or allergy for omega 3-acid ethyl esters -  
17. Patients who smoke 
18. Patients participating in other clinical studies 
19. Patients who have been determined to be ineligible as subjects 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] 
1.2.8.16 These were set in consideration of safety of the research subjects. 
3 This was set because EPA-E, a component of the study drug, has an antiplatelet action and 
may impair hemostasis in patients.  


TAK-085-4001 
Page 30 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
4.5.6.7.9.14. 17 These were set because it was considered that drug efficacy evaluation would be 
affected.  
10. This was set because acute pancreatitis may occur in patients with significant 
hypertriglyceridemia.  
11. This was set to exclude patients with hypertriglyceridemia attributed to a genetic 
predisposition. 
12. This was set to exclude an underline condition commonly seen in patients with secondary 
hypertriglyceridemia.  
13.15 These were set in consideration of safety of the research subjects and for an accurate 
assessment of the efficacy. 
18.19 These were set as fundamental items for the research.  
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 6 (Week 8)].  
(*: Concomitant drugs prohibited in the package insert of hydroxymethylglutaryl-coenzyme A 
(HMG-CoA) reductase inhibitor taken at the time of informed consent are included.)  
1. Eicosapentaenoic acid (EPA) preparations or EPA/DHA preparations (including 
supplements) 
2. Antidyslipidemic agents (except for HMG-CoA reductase inhibitor taken at the time of the 
informed consent)  
Anion exchange resin 
Fibrates 
Ezetimibe  
Nicotinic acid derivatives 
Probucol 
Phytosterols 
Others (elastase ES, dextran sulfate sodium, polyenephosphatidylcholine, pantethine) 
3. Pancreatic hormones 


TAK-085-4001 
Page 31 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
Insulin preparation 
4. Androgens 
Testosterone, methyltestosterone 
5. Follicle hormone and luteinizing hormone 
Estrogen and progestogen 
6. Systemic steroids 
<Rationale> 
1to 6 These were set because it was considered that efficacy evaluation of the study drug would 
be affected by these drugs.  
7.3.2 Permitted concomitant drugs 
Drugs other than those prohibited for concomitant use may be taken during the study period. 
However, for HMG-CoA reductase inhibitors, antidiabetic drugs (except for insulin) and 
antihypertensive drugs, dose change, 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 
Research subject management 
The principal investigator or investigator shall instruct research subjects regarding the following: 
(1) Guidance for research subjects for improving lifestyle shall be made constant during the clinical 
study and its content shall not be changed. Research subjects shall be instructed to avoid 
excessive exercise as much as possible during the study period.  
(2) Research subjects shall be instructed not to consume alcohol after 9:00 pm two days before the 
hospital visit, and not to consume food after 9:00 pm on the day before the hospital visit. 
Although water can be taken as desired on the day of blood collection, research subjects shall 
be instructed to visit the hospital in a fasting state in order that fasting morning samples can be 
collected.  
(3) Research 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) Research subjects shall be instructed to visit the hospital according to the schedule and take the 
test as prescribed during the study period. 
(5) Research 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.)  


TAK-085-4001 
Page 32 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
(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, 
research subjects shall be instructed to promptly report in the event of an adverse drug reaction, 
such as bleeding.  
(7) Research subjects must notify the principal investigator or investigator in advance if they 
receive treatment from other physicians. If treated by other physicians, the research subjects 
shall be instructed to promptly report the details of the treatment.  
7.5 
Criteria for discontinuation or withdrawal of a research subject 
The principal investigator or investigator shall record the main reason for discontinuation of protocol 
treatment on the case report form according to the classification described below. Refer to Section 
9.1.11 for research subjects who withdraw from the research before randomization. 
1. Pretreatment Event (PTE) or adverse event  
When the research subject had a pretreatment event (PTE) or an adverse event that requires 
withdrawal of the research subject from the study because continued participation in the study 
would impose an unacceptable risk to the research subject’s health, or when the research subject 
is unwilling to continue study participation because of the PTE or adverse event. 
2. Major protocol deviation  
When it is discovered after randomization that a research subject does not meet the eligibility 
criteria or is not adhering to the protocol, and continued participation in the research would 
impose an unacceptable risk to the research subject’s health.  
3. Lost to follow-up 
When the research subject failed to make visits and could not be contacted despite the attempts 
to contact the research subject. 
4. Voluntary termination 
When the research subject wishes to withdraw from the research. The reason for discontinuation 
shall be obtained to the extent possible. 
5. Research termination 
When the sponsor or a committee such as the IEC or regulatory authority has decided to 
terminate the study. Refer to Section 6.3.1 for details.  
6. Lack of efficacy  
When efficacy of the study drug is not evident and continuation of the research may pose an 


TAK-085-4001 
Page 33 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
unacceptable risk to the research subjects in the opinion of the principal investigator or 
investigator.  
7. 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 research subjects 
The principal investigator or investigator shall terminate a research subject’s research participation 
when the research subject meets the criteria described in Section 7.5. Individual research subjects 
may discontinue their research participation without giving a reason at any time during the research. 
Should a research subject’s participation be discontinued, the primary reason for termination shall be 
recorded on 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. 


TAK-085-4001 
Page 34 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
8.0 
RESEARCH 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 
Omega-3-acid ethyl esters will be orally administered [2 g (2 g PO QD) or 4 g (2 g PO BID)] 
immediately after meal. In principle, the dosage prescribed to the research subject should not be 
changed until the end of the study. Since the research subject should in a fasting state at the time of 
visit, the drug to be taken after breakfast should be taken immediately after the first meal 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 drug 
HMG-CoA reductase inhibitors, antidiabetic drugs (except for insulin) or antihypertensive drugs 
taken at the time of informed consent should continue to be taken without a change in dosage and 
administration during the study period.  
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 research 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, “Pretreatment Event and Adverse Events.”P  
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 SAEs.” 


TAK-085-4001 
Page 35 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
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 research subjects. The principal investigator or the designee shall notify the information required 
for allocation in addition to the research subject identification code. Then, drugs that should be 
administered to each research subject will be notified through the Case Registration Web System. 
The principal investigator or investigator shall prescribe the study drug 2 g [(2 g PO QD) or 4 g (2 g 
PO BID)] according to the notification, and record the dose administered for each research 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 research. 
Using fasting TG values 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. 
 


TAK-085-4001 
Page 36 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
9.0 
CLINICAL STUDY PROTOCOL 
9.1 
Research procedures 
The principal investigator or investigator shall collect data in accordance with the procedure below. 
In principle, tests other than FMD measurement, observations, and evaluations of research subjects 
shall be performed by the same principal investigator or investigator. FMD measurement shall be 
performed by a physician or laboratory technician who has completed the FMD measurement 
training. The study schedule is provided in Appendix A. 
9.1.1 Informed consent procedure 
The procedures for obtaining informed consent are described in Section 15.3. 
Consent shall be obtained from the research subject before initiation of research procedures. 
Research subject code is given to each research subject from whom informed consent was acquired 
and who was randomized. The research subject ID code shall be used throughout the research period 
and shall not be changed. 
9.1.2 Demographic data, medical history, and previous therapeutic drugs 
Demographic data shall be collected regarding date of birth, gender, time (year/month) of onset of 
dyslipidemia (or diagnosis), last menstrual period (year), frequency of consumption of fish (almost 
every day, once/2 days, 1 to 2 times/week, almost never), smoking and drinking history, and vessel 
diameter.  
 Medical history data shall be collected regarding clinically problematic diseases or symptoms that 
disappeared or were terminated within 1 year from informed consent. When the symptoms or disease 
continues, it shall be considered as a concurrent disease (Refer to Section 9.1.7). 
Previous therapeutic drug data shall be collected regarding all drugs used within 4 weeks before the 
informed consent 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 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: 


TAK-085-4001 
Page 37 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
 Height = 176 cm, 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  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 research subjects shall be included. At 
every hospital visit of the research subject, the status of use (drug name, route of administration) of 
the drugs (including vitamin compound, over-the-counter medication, and Chinese medicine) used, 
other than the study drug, from the time of informed consent to the completion of the clinical 
research shall be monitored. 
9.1.7 Concurrent disease 
A concurrent disease shall be defined as a disease or symptom that is present at the time of the 
research subject’s informed consent Clinically problematic laboratory test data, ECG findings, and 
abnormal physical examination findings observed immediately after the acquisition of the informed 
consent and examination 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 Checking food and drink consumption before the visit 
At each study visit, the principal investigator, investigator, etc., physician for FMD measurement, or 
laboratory technician for FMD measurement will check the food and drink consumption of the 
research subject before the visit. 
• 
Alcohol should not be consumed from 9:00 pm two days before the hospital visit to the time of 
the fasting test, and food should not be consumed from 9:00 pm on the day before to the time of 
the fasting test.  
• 
Eating/drinking to excess and extreme change in dietary content should be avoided on the day 
before the fasting test. 


TAK-085-4001 
Page 38 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
9.1.9 Laboratory tests 
The following laboratory tests shall be performed according to the observation schedule (Appendix 
A). The fasting test will be performed under ≥10-h fasting and the 4-h postprandial test will be 
performed 4 h after consumption of a prescribed meal (allowable range ± 30 min). 
The principal investigator or investigator shall evaluate and keep the reported laboratory test results. 
Table 9.a Laboratory tests 
Serum chemistry 
(fasting) 
Serum chemistry 
(4 h postprandial) 
Urinalysis 
(fasting) 
TG 
Total cholesterol 
LDL-C 
HDL-C 
Remnant-like particle (RLP) 
cholesterol 
Apoprotein B-48 
high-sensitivity C-reactive 
protein (hs-CRP)   
Fasting plasma glucose (FPG) 
Plasma fatty acid fraction 
TG 
Total cholesterol 
LDL-C 
HDL-C 
Remnant-like particle (RLP) 
cholesterol 
Apoprotein B-48  
 
Determination of 
8-epi-PGF2α 
The principal investigator shall keep laboratory test reference values, including the historical data. 
9.1.10 Flow-mediated dilation (FMD) test  
FMD tests shall be performed according to the observation schedule (Appendix A) based on the 
Procedure for FMD Measurement provided separately. The fasting test will be performed under 
≥10-h fasting and the 4-h postprandial test will be performed 4 h after consumption of a prescribed 
meal (allowable range ±30 min). FMD measurement will be performed by a physician or laboratory 
technician who completed the FMD measurement training. 
9.1.11 Record of research subjects who are withdrawn before randomization 
A CFR shall be created for all research 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 
• 
Sex 
• 
Eligibility 
• 
PTE/adverse events (with details, if any) 


TAK-085-4001 
Page 39 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
• 
Reason for discontinuation 
The primary reason for withdrawal before randomization shall be recorded on the CRF according to 
the following classification: 
• 
PTE adverse events 
• 
Not satisfying at least one of the inclusion criteria or meeting any of the exclusion criteria 
• 
Serious deviation from the protocol 
• 
Lost to follow-up 
• 
Voluntary discontinuation (specify the reason) 
• 
Discontinuation of the entire study 
• 
Others (specify the reason) 
Research subject ID numbers assigned to research subjects withdrawn from the research before 
{randomization shall not be reused. 
9.1.12 Record of randomization 
Research subjects to be randomized shall meet all of the inclusion criteria and shall not meet any of 
the exclusion criteria according to Section 8.2. The principal investigator or investigator shall 
specify the reason why the subject cannot be randomized / transferred to the treatment period. 
9.2 
Drug-taking status of the research subjects 
The principal investigator or investigator shall confirm the drug-taking status of the study drug of the 
research subject at every visit. Throughout the clinical research period, drug-taking status will be 
checked through interview for two categories, “compliance of at least 50% of the prescribed dose or 
compliance of < 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 research 
subject may be withdrawn from the research if appropriate for the circumstances. 
9.3 
Implementation time point of the test and observation items 
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 Observation period (Visit 1) 
At Visit 1 (Day -29 to Day -1 before study drug administration), the study shall be explained using 
the informed consent form to the research subjects who meet the inclusion criteria (except for 2) in 
Section 7.1 and do not meet any of the exclusion criteria (except for 4 and 7) in Section 7.2, and 
consent shall be obtained in accordance with Section 15.3. - . 


TAK-085-4001 
Page 40 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
Tests, observations, and evaluations to be performed at Visit 1 (Day -29 to Day -1 before study drug 
administration) are shown below.  
• 
Informed consent procedure 
• 
Demographic data, medical history, previous treatment drug(s) 
• 
Physical examination 
• 
Height, weight and BMI 
• 
Vital signs 
• 
Concomitant drugs 
• 
Concurrent disease 
Laboratory tests (fasting)Items to be checked: Food and drink consumption before visit: 
o 
Alcohol should not be consumed from 9:00 pm two days before the hospital visit to the 
time of visit and food should not be consumed from 9:00 pm on the day before to the 
time of visit. 
o 
Eating/drinking to excess and extreme change in dietary content should be avoided on 
the day before the hospital visit. 
9.3.2 Treatment period (Visit 2) 
1. Laboratory tests/FMD measurement 
Research subjects shall take the following tests at a designated medical institution for FMD 
measurement. 
• 
Laboratory tests [fasting and 4-h postprandial (allowable range ±30 min)]  FMD test 
[fasting and 4-h postprandial (allowable range ±30 min)]    
Items to be checked: Food and drink consumption before visit   
o 
Alcohol should not be consumed from 9:00 pm two days before the hospital visit to the 
time of visit and food should not be consumed from 9:00 pm on the day before to the 
time of visit.  
o 
Eating/drinking to excess and extreme change in dietary content should be avoided on 
the day before the hospital visit. 
 
Research subjects shall visit the study site after undergoing prescribed tests at a designated medical 
institution for FMD measurements. 
 
2. Implementation of examination 
 Based on the results of the tests/observations at Visit 1 (Day -29 to Day -1 before the start of study 
drug administration) and the FMD test results (fasting) at Visit 2 (Day -15 to Day -1 before the start 
of study drug administration), the principal investigator or the investigator shall perform the 


TAK-085-4001 
Page 41 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
following tests, observations, and evaluations in research subjects who meet the inclusion criteria 
and do not meet any of the exclusion criteria.  
• 
Physical examination 
• 
Vital signs 
• 
Concomitant drugs 
• 
Pretreatment Event 
 
The principal investigator or the investigator shall give notification to the registration center 
(accessing to the Case Registration Web System) regarding research subjects in whom all the tests at 
Visit 2 (Day -15 to Day -1 before study drug administration), observation results, and evaluation 
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 research subject to take the drug starting from the next day.  
 
The research subject with a fasting FMD level of 0% shall be withdrawn from this study based on 
Section 7.2.  
Refer to Section 9.1.11 for preparation of records relating to the research subjects withdrawn before 
randomization. 
9.3.3 Treatment period (Visit 3) 
1. Research subjects shall undergo the following tests at Visit 3 (Day 14 to Day 41 after the study 
drug administration) at a designated medical institution for FMD measurements.  
• 
FMD test (fasting) 
Laboratory tests [fasting and 4-h postprandial (allowable range ± 30 min)] 
 Food and drink consumption before the visit will be checked. 
o 
Alcohol should not be consumed from 9:00 pm two days before the hospital visit to the 
time of visit and food should not be consumed from 9:00 pm on the day before to the 
time of visit. 
o 
Eating/drinking to excess and extreme change in dietary content should be avoided on 
the day before the hospital visit. 
 
2. The principal investigator and the investigator shall perform the following tests, observations, 
and evaluations at Visit 3 (Day 14 to Day 41 after the study drug administration). 
• 
Physical examination 
• 
Vital signs 
• 
Concomitant drugs 


TAK-085-4001 
Page 42 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
• 
Study drug compliance 
• 
Adverse Events 
Tests, observations, and evaluations of (1) and (2) at Visit 3 may be performed in any order  
[so long as the completion of all the contents falls within the allowable range (Day 14 to Day 41 
after the study drug administration)]. 
9.3.4 Completion (Visit 4) or discontinuation 
1. Visit 4 shall be the last VISIT, and research subjects shall undergo the following tests at the 
designated medical institution for FMD measurement within the allowable range of Visit 4 (42 
to 70 days after the study drug administration). If the study drug administration is discontinued, 
research subjects should, to the extent possible, undergo tests within 3 days from the last dose 
taken. 
• 
FMD test [fasting and 4-h postprandial (allowable range ± 30 min)]  
Laboratory tests [fasting and 4-h postprandial (allowable range ± 30 min)] 
 Food and drink consumption before the visit will be checked. 
o 
Alcohol should not be consumed from 9:00 pm two days before the hospital visit to the 
time of visit and food should not be consumed from 9:00 pm on the day before to the 
time of visit. 
o 
Eating/drinking to excess and extreme change in dietary content should be avoided on 
the day before the hospital visit. 
 
2. The principal investigator and the investigator shall perform the following tests, observations, 
and evaluations at Visit 4 (Day 42 to Day 70 days after the study drug administration). If the 
study drug administration is discontinued, research subjects should, to the extent possible, 
undergo tests, observations, and evaluations required for the last visit within 3 days from the last 
dose taken.  
• 
Physical examination 
• 
Vital signs  
• 
Concomitant drugs 
• 
Study drug compliance 
• 
Adverse Events 
Since the principal investigator or the investigator is required to confirm safety of the tests, 
observations, and evaluations at Visit 4 or at discontinuation, FMD test and laboratory tests in (1) 
shall be performed first, and tests, observations, and evaluations in (2) shall be performed last.  
At completion of the clinical research, the status of all research subjects administered the study drug 
shall be recorded on the CRF. 
 


TAK-085-4001 
Page 43 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
10.0 
PRETREATMENT EVENT AND ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 When pretreatment events are collected 
A Pretreatment Event (PTE) is defined as any unfavorable medical event that occurs to a research 
subject prior to administration of study drug but after the acquisition of informed consent. PTEs are 
not limited to events with clear causal relationship with treatment with the concerned drug. 
10.1.2 Adverse events 
An adverse event is defined as any untoward medical occurrence in a patient or a research 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 relate d to the 
pharmaceutical product (including the study drug) or not. 
10.1.3 Considerations for PTEs and 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 a PTE or 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: 
PTEs or 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: 


TAK-085-4001 
Page 44 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
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 research subject). Retest and/or 
continued monitoring of an abnormality are not considered medical practice. Also, repeated or 
additional 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 symptoms that had been present since before before the 
informed consent) : A disease or symptoms that had been present since before the acquisition of 
informed consent shall be regarded as a concurrent disease and not an adverse event. When a 
concurrent medical condition 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 research 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 research 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 research 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 / severity of PTEs:  
If the research subject experiences changes in the severity of an adverse event / a severity of PTE, 
the event shall be recorded once, at its peak severity. 
Previously planned surgery or treatment:  
Preplanned surgeries or interventions that were scheduled before study treatment shall not be 


TAK-085-4001 
Page 45 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
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 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 research 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. 
10.1.4 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 
research 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 research 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 
were more severe. 


TAK-085-4001 
Page 46 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
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 
When a PTE meets any of the above criteria for SAEs, it shall be reported in accordance with a 
procedure similar to that for serious adverse events (Refer to Section 10.2.2 and 10.3). 
10.1.5 Severity of pretreatment events and 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. 
10.1.6 Causality of adverse events 
The causal relationship of each PTE and 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 
An adverse event that does not follow a temporal sequence from administration of 


TAK-085-4001 
Page 47 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
related 
the study drug. Very likely due to other factors such as underlying disease, 
concurrent diseases, or concomitant drugs/treatment. 
10.1.7 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.” 
10.1.8 Date of onset 
The date of onset of adverse event shall be determined according to the following rules: 
Adverse event, etc. 
Date of onset 
Signs, symptoms, diseases 
(diagnoses) 
The date on which the first signs/symptoms were noted by the 
research 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 or PTE 
The date on which the first worsening of diseases/symptoms was 
noted by the research subject and/or the principal investigator or 
investigator. 
Onset of a test abnormality 
after the start of the study drug 
administration 
(in case of PTE) 
(in case of AE) 
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. 
10.1.9 Date of resolution 
The date of resolution of an adverse event, etc. is the date on which the research subject recovered 
(including resolution with sequelae). If a research subject died due to the adverse event, etc. 
concerned, it shall be the date of death. The adverse event shall be recorded as “ongoing” if the 
research subject has not yet recovered by the end of the study. 
10.1.10 Actions taken for the study drug 
Actions taken for the study drug shall be classified or defined as shown below. 


TAK-085-4001 
Page 48 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
Drug withdrawn 
The study drug is discontinued because of an adverse event (including 
withdrawal by the research subject at his/her own discretion). 
The case in which the study drug administration is continued after withdrawal 
from the study shall be categorized into “Dose not changed.” 
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 research subject. 
Unknown 
It has not been possible to determine what action has been taken because the 
research 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. 
10.1.11 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 research 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 research 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 
“Direct relationship” means that the concerned adverse event was the cause of 
death, or the concerned adverse event 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 research 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 


TAK-085-4001 
Page 49 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
change of hospitals or relocation, etc. 
10.2 
Procedures 
10.2.1 Collection and reporting of adverse events 
10.2.1.1 Adverse event collection period  
The collection of PTEs shall start after the acquisition of informed consent and continue until the 
start of the study drug administration at Visit 2 (Day -15 to Day -1 before the start of study drug 
administration). If withdrawal was decided before the start of administration of the study drug, the 
collection of PTEs shall be terminated at that point. 
Collection of the adverse events shall commence at the start of administration of the study drug to 
research subjects [at Visit 2 (Day -15 to Day -1 before the start of study drug administration)] and 
continue until completion of the treatment period [Visit 4 (Week 8)] or at 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. 
When a PTE corresponds to a serious criterion, the principal investigator or investigator shall follow 
up all research subjects experiencing the PTE until the symptom resolve, any clinically significant 
abnormal laboratory values have returned to the baseline after acquisition of informed consent, or 
there is a satisfactory explanation for the change (permanent and irreversible PTEs). When the PTE 
does not correspond to a serious criterion, irrespective of the causal relationship with the procedure, 
follow-up of the research subject is not required by the protocol. 
The principal investigator or investigator shall follow up all research 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. Name of adverse event, date of onset, date of resolution, grade, 
causal relationship with the study drug (i.e. "Unrelated" or "Related"), action taken for the study 
drug, outcome, relationship to study procedures, and severity shall be recorded.  


TAK-085-4001 
Page 50 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
Follow-up period of PTEs meeting any of the criteria for AEs and SAEs 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. When a serious PTE develops, it shall also be 
reported in accordance with a procedure similar to that for serious adverse events. 
At the time of onset of a serious adverse event or after notification of the onset by the research 
subject, the principal investigator shall report the serious adverse event to the head 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 of after notification of the onset. Further, 
the investigator shall submit a formal report within 10 calendar days to the sponsor. 
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 
• 
Research subject ID number 
• 
Name of investigator or the subinvestigator 
• 
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 investigator or the subinvestigator shall confirm the necessary 
additional information and enter in the 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, the investigator or 
subinvestigator 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 


TAK-085-4001 
Page 51 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
at the research implementing entity (e.g., ECG charts, laboratory test values, discharge summary, 
postmortem results) shall be sent to the sponsor or the committee such as the IEC upon request. 
The investigator or the subinvestigator shall follow-up all serious adverse events, etc., until recovery 
is confirmed, or the final outcome is determined. In addition, serious PTEs shall also be followed, in 
accordance with procedure similar to that for serious adverse events. 
10.3.1 Reporting of serious adverse events, etc., to Ethics Review Committee, etc., 
and regulatory authorities 
When the head of study site receives a report of a serious adverse event from the principal 
investigator, the head of study site shall consult the Ethics Review Committee, etc., and notify the 
study sites that are conducting the clinical research 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 research (study drug) cannot be ruled out and is unexpected, the head 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 Minister of 
Health, Labour and Welfare, and notify other study sites conducting the clinical research. (The chief 
executive of the research implementing entity may report it to the Minister of Health, Labour and 
Welfare via the sponsor, and notify it to other clinical research implementing entities via the 
sponsor.) Serious PTEs shall also be reported in accordance with the same procedure as that for the 
serious adverse events. (No need to report to the Minister of Health, Labour and Welfare.) 
• 
Actions taken for serious adverse events (discontinuation of new enrollment, revision of 
informed consent form, re-consents to other research subjects, etc.) 
• 
Date of review, summery of review, result, necessary action, etc., related to Ethics Review 
Committee, etc. 
• 
Notification to other research implementing entities 
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 
investigators, and the head 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 


TAK-085-4001 
Page 52 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
the study drug risk-benefit, continuation of study drug administration, or continuation of clinical 
research. The research implementing entity shall submit copies of emergency report documents to 
the Ethics Review Committee, etc. 


TAK-085-4001 
Page 53 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY 
11.1 
Clinical Endpoint Committee 
The Central Assessment Committee members shall be independent specialists who have appropriate 
experience in the assessment of the parameters set as the endpoints of this research. 
REGARDING THE PRIMARY ENDPOINT “%FMD (FASTING)” AND THE SECONDARY 
ENDPOINT “%FMD (4 H POSTPRANDIAL)”,THE CENTRAL ASSESSMENT COMMITTEE 
SHALL CONFIRM THE VALIDITY OF THE ASSESSMENT OF THE MEASUREMENT 
RESULTS ACCORDING TO THE PROCEDURE defined separately on the measured images 
reported from the FMD measuring study sites or measuring institutes. 
The assessment results from the committee members shall be entered into the clinical research 
database and used for the analysis of endpoints. 
 


TAK-085-4001 
Page 54 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
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, PTE, medical history and concurrent disease shall be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs shall be coded using the WHO (World 
Health Organization) Drug Dictionary. 
12.1 
Case report form 
The principal investigator or investigator shall complete a CRF for each research subject who has 
signed the informed consent form. 
The sponsor or the designee shall provide access rights to the electric CRF system to the study site. 
Before use of the electric CRF 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 investigator the designee shall ensure the accuracy and completeness of the CRF, and provide an 
electronic signature on the relevant page of the case report form. 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 (except for the data included in the source 
documents). 
• 
Eligibility, completioin status, reason for discontinuation, the seriousness, severity, relation 
to study drug and study procedures outcome 
The following data shall not be recorded directly into the CRFs.  
• 
Laboratory test values 
FMD/Vessel caliber measurement results  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) 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. 


TAK-085-4001 
Page 55 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
The sponsor or the designee shall confirm that the CRFs are completed appropriately according to 
the procedures set by research. The sponsor or the designee shall have access to the medical records 
of the research 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 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 electronic CRF system 
The sponsor or the designee shall request the principal investigator and investigator to promptly 
enter data into the EDC following enrolment of the research 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 research subject 
ID code, medical records, clinical study worksheets (if used), original signed and dated informed 
consent forms, the record of change or correction on the CRF (copy), and electric copies of 
electronic CRF 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 research 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. 


TAK-085-4001 
Page 56 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
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 before the acquisition of the informed 
consent of the earliest research 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 research. 
13.1.1 Analysis set 
Two analysis sets, “Full Analysis Set；FAS” and “Safety Analysis Set；SAS” are used in this 
research. The FAS primarily used for efficacy analysis will be defined as “research subjects who 
have been randomized and received the study drug at least once”, and the SAS as “research subjects 
who have received the study drug at least once during the clinical research”.  
13.1.2 Analysis of demographic and other baseline characteristics 
From “SAS” primary research subject background items will be tabulated. 
13.1.3 Efficacy analysis 
From FAS the following shall be analyzed. 
13.1.3.1 Analysis of primary endpoints 
%FMD(fasting) 
[Analytical method] 
1) 
Summary statistics by treatment group (number of subjects, mean, SD, minimum value, 
maximum value, quartiles) and a two-sided 95% confidence interval for the mean will be 
calculated at each evaluation time point during the treatment period, and a diagram 
illustrating the change in the mean ± SD will be prepared. 
2) 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment Period 
Visit 2) will be calculated at each evaluation time point during the treatment period and the 
same analysis as in 1) will be performed.  
3) 
Using fasting TG at the start of treatment, a stratified analysis on summary statistics by 
treatment group (number of subjects, mean, SD, minimum value, maximum value, quartiles) 
and a two-sided 95% confidence interval for the mean will be performed. 


TAK-085-4001 
Page 57 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
 
13.1.3.2 Analysis of secondary endpoints 
① %FMD (4 h postprandial) 
② TG level (fasting) 
③ TG level (4 h postprandial) 
④ Plasma fatty acid fraction 
 
[Analytical method] 
1) 
Summary statistics by treatment group (number of subjects, mean, SD, minimum value, 
maximum value, quartiles) and a two-sided 95% confidence interval for the mean will be 
calculated at each evaluation time point during the treatment period, and a diagram 
illustrating the change in the mean ± SD will be prepared. 
2) 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point during the treatment period 
and the same analysis as in 1) will be performed.  
3) 
Using fasting TG at the start of treatment, a stratified analysis on summary statistics by 
treatment group (number of subjects, mean, SD, minimum value, maximum value, 
quartiles) and a two-sided 95% confidence interval for the mean will be performed. 
13.1.3.3 Analysis of other endpoints 
Efficacy endpoints: 
Total cholesterol, LDL-C, LDL-C, Remnant-like particle (RLP) cholesterol , Apoprotein B-48, 
C-reactive protein (CRP), 8-epi-PGF2α quantitative (urinary) 
Analytical method 
1) 
Summary statistics by treatment group (number of subjects, mean, SD, minimum value, 
maximum value, quartiles) and a two-sided 95% confidence interval for the mean will be 
calculated at each evaluation time point during the treatment period, and a diagram 
illustrating the change in the mean ± SD will be prepared. 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment Period 
Visit 2) will be calculated at each evaluation time point during the treatment period and the 
same analysis as in 1) will be performed.   
13.1.4 Safety analysis 
From Safety Analysis Set (SAS) the following will be analyzed.  


TAK-085-4001 
Page 58 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
(1) Adverse events 
The following analysis will be performed for each treatment group. Adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by System 
Organ Class and Preferred Term. 
 
Tabulation of frequencies 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 
 
Tabulation of frequency of serious adverse events 
 
Tabulation of frequency of all adverse events by time of onset 
(2) Body weight, blood pressure in the sitting position, pulse in the sitting position, laboratory tests 
[fasting plasma glucose (FPG)] 
1) 
Summary statistics of measurements by treatment group at each evaluation time point 
during the treatment period will be calculated and a diagram of the change of individual 
data will be created. 
2) 
The change for each treatment group (Treatment Period Visit 3 or Visit 4 - Treatment 
Period Visit 2) will be calculated at each evaluation time point during the treatment period 
and the same analysis as in 1) will be performed.  
3) 
Regarding evaluation results based on standard values, shift tables of treatment period Visit 
2 and assessment time points of treatment period (Visit 3, Visit 4) will be prepared. 
13.2 
Criteria for interim analysis and premature discontinuation 
No interim analysis is planned. 
13.3 
Determination of the number of planned research subject 
40 patients evaluable for the primary endpoint  
(Omega-3-acid ethyl esters 2 g: 20 patients, Omega-3-acid ethyl esters 4 g: 20 patients)  
 
[Rationale for the number of planned research subjects] 


TAK-085-4001 
Page 59 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
The planned sample size is based on the feasibility to explore the effects of omega-3-acid ethyl 
esters on vascular endothelial function.  


TAK-085-4001 
Page 60 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
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 research 
to confirm that the research is conducted in accordance with all specifications in the research 
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 Ethics Review Committee, etc., have access to the source documents. 
The sponsor or the designee shall access the records, including the list of research subject ID 
numbers, medical records of the research subjects, and signed and dated original consent forms to 
confirm that the research is appropriately conducted in compliance with the research protocol. Also, 
confirm the consistency between CRF and the related source documents. The principal investigator, 
investigator, and other personnel involved in the research shall spare sufficient time to facilitate 
monitoring procedures during visits to the study site. 
Detailed procedures for monitoring shall be described separately in the procedure. 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the research protocol. 
The principal investigator or investigator shall record all deviations from Ethical Guidelines for 
Medical and Health Research Involving Human Subjects, and research protocol. 
If any deviation is found, the principal investigator shall promptly notify the chief executive of the 
study site for the clinical research 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 study site for approval of the committee 
such as the IEC. 
14.3 
Quality assurance audits and regulatory agency inspections 
The study site may be research subject to audits by the sponsor or the designee. 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 research. In addition, this research 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 


TAK-085-4001 
Page 61 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
promptly. The principal investigator and the chief executive of the study site shall ensure that the 
auditor has access to all the research-related source documents. 


TAK-085-4001 
Page 62 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
15.0 
ETHICAL CONDUCT OF CLINICAL RESEARCH 
This research shall be conducted with the highest respect for the individual participants (i.e., 
research subjects) according to the research protocol, and the ethical principles that have their origin 
in the Declaration of Helsinki, 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 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 research, 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 Ethics Review Committee for the protocol’s review and approval. In addition to the 
research protocol, a copy of the informed consent form and information sheet, written materials 
related to research 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 
Ethics Review Committee to obtain approval. The sponsor or the designee must obtain written 
approval of the protocol and subject informed consent from the study site committee such as the 
Ethics Review Committee before commencement of the study. The study site committee such as the 
Ethics Review Committee’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) 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 IEC, for example, revision of the 
protocol, revision of the informed consent form and information sheet, revision of materials related 
to research subject recruitment, reports on safety in accordance with the regulatory requirements, 
reports on status of implementation of the research at intervals determined by a study site committee 
such as the Ethics Review Committee, and submission of the study completion report. The sponsor 
or the designee shall obtain written approval from the Ethics Review Committee, etc. related to the 
above mentioned items and all related materials. 


TAK-085-4001 
Page 63 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
15.2 
Conflict of interest 
These clinical studies shall be conducted with the support of the research client. 
Prior to the conduction of this clinical research, the principal investigators involved in this clinical 
research shall ensure appropriate management of any conflicts (COI) in the conduct of the research 
in accordance with the rules of the study site.8)-12) 
The study site shall observe all requirements that the Ethical Review Board, etc. prescribe. This will 
include self-declaration of COI, clinical research protocol, informed consent and information sheet.  
15.3 
Informed consent and information sheet, and the agreement of the research 
subjects 
The informed consent and information sheet 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 research subjects in this 
clinical research (both in and outside Japan: supply to a third party), and disclosure. The informed 
consent form and the information sheet will explain in detail the nature of the research, its objectives, 
and potential risks and benefits. The informed consent form and the information sheet will detail the 
requirements of the participant and the fact that research 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 research subject information sheet by the committee such as the IEC. The 
informed consent form and information sheet must be approved by the committee prior to use. 
The informed consent form and information sheet shall be written in language that can be easily 
understood by the potential research subjects. The principal investigator or investigator shall be 
responsible for providing detailed explanation of the informed consent form and information sheet to 
the potential subjects. Information should be given in both oral and written form whenever possible 
and in manner deemed appropriate by the committee such as the IEC. 
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 subjects. If the potential 
subject decides to participate, the informed consent form must be signed and dated by the potential 
subject prior to entering into the research. The principal investigator or investigator shall instruct the 
potential subject or representative to sign using their legal names, not 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 research. 


TAK-085-4001 
Page 64 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
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 research 
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 research 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 research subject when the informed 
consent form is revised. The date of obtaining new consent shall be recorded in the research 
subject’s medical record, and a copy of the revised consent form shall be provided to the research 
subject. 
15.4 
Personal information of the research subjects 
The sponsor or the designee shall affirm the principle of the protection of research subjects' 
private/personal information. Throughout this study, research subject ID numbers shall be used to 
link the subject's source data to the sponsor's research database and research-related documents. 
Limited information on research subjects such as gender, age, and date of birth may be used within 
the scope of all applicable laws and regulations for identification of research subjects and 
confirmation of accuracy of research subject ID number. 
For verification of the conduct of the research 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 research sponsor’s designee, representatives of regulatory 
authorities, designated auditors, and committees such as the Ethical Review Board direct access to 
research subjects’ original medical records (source data or documents), including laboratory test 
results, admission and discharge records during a subject’s research participation, and autopsy 
reports. The principal investigator or investigator shall obtain specific authorization of the research 
subject as part of the informed consent process for access to research subject's original medical 
records by research 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 
research subject, other personal information not recorded on the CRF of the research subject). 
15.5 
Consultation windows for the research subjects or persons related to the 
research concerned 
The principal investigator shall establish a contact service to respond to inquiries concerning this 
clinical research from research subjects or concerned people. Details of the contacts for inquiries 
will be described in the ICF. 


TAK-085-4001 
Page 65 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
15.6 
Financial burden or reward to the research subjects 
Of the expenses for this clinical research, the sponsor shall offer compensation for medical treatment 
not covered by health insurance as research expenses. The research 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 research to the research subjects at each visit from the research funds. 
Details of the financial burden on the research subjects and rewards shall be described in the 
informed consent form and information sheet. 
15.7 
Benefits and inconveniences to the research subjects 
15.7.1 Benefits to research subjects 
By participating in this clinical research, the research subjects may understand one’s own condition 
of vascular endothelial function in detail. 
15.7.2 Inconveniences to research subjects 
By participating in this clinical research the burden of the research subject may increase as number 
of visits will increase compared to daily medical care. 
15.8 
Attribution of research results and access rights 
15.8.1 Attribution of research results 
The research results and data obtained from this research shall belong to the sponsor. 
15.8.2 Data access rights 
Access rights for all data and information generated from this research will be given to personnel 
approved by the sponsor. In addition, secondary use (meta-analysis, etc.) of the data obtained in this 
clinical research may be possible if used in such a way that the data shall not be linked to personal 
identification information. 
15.9 
Reporting of results, Publication, disclosure, and clinical research 
registration policy 
15.9.1 Reporting of results, publication and disclosure 
The principal investigator shall report a written summary of results of the research to the chief 
executive of the study site and provide the sponsor with all the results and data obtained from the 
research. Only the sponsor may disclose the research information to other principal investigators, 
investigators or regulatory authorities during the research period, except when required by laws and 


TAK-085-4001 
Page 66 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
regulations. The sponsor shall be responsible for publication of the research protocol and 
research-related results (including the public web site) except for other cases permitted in the 
research contract. 
During research period and after the end of research, 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 research (including data and information 
provided by the principal investigator) without obtaining agreement of the principal investigator. 
The investigator or the subinvestigator should obtain the prior written approval from the sponsor 
when publishing the information obtained in this research at an academic conference, etc. 
15.9.2 Clinical research registration 
To ensure that information on clinical research 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 research 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 research. On 
such websites, the research location (city, country), 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 research 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 research subject in the clinical research 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 research subjects. 
Healthy injury in a research 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. 


TAK-085-4001 
Page 67 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
16.0 
REFERENCES 
1. 
Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in 
men with hypercholesterolemia. 
N Engl J Med. 1995; 333: 1301-1307. 
2. 
Fraley AE, Schwartz GG, Olsson AG, et al. Relationship of oxidized phospholipids and 
biomarkers of oxidized low-density lipoprotein with cardiovascular risk factors, 
inflammatory biomarkers, and effect of statin therapy in patients with acute coronary 
syndromes:  Results from the MIRACL (Myocardial Ischemia Reduction With Aggressive 
Cholesterol Lowering) trial. 
J Am Coll Cardiol. 2009; 53（23）: 2186-2196. 
3. 
Fujioka Y, Ishikawa Y. Remnant lipoproteins as strong key particles to atherogenesis.  
J Atheroscler Thromb. 2009 : 16 ; 145-154. 
4. 
Nordestgaard BG, Benn M, Schnohr P, et al. Nonfasting triglycerides and risk of myocardial 
infarction, ischemic heart disease, and death in men and women. JAMA. 2007; 298:  
299-308. 
5. 
Tatsuno I, Saito Y, Kudou K, Ootake J. 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. 
6. 
Tousoulis D, Plastiras A, Siasos G, 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. 
7. 
Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major 
coronary events in hypercholesterolaemic patients（JELIS）: a randomised open-label, blinded 
endpoint analysis.  
Lancet. 2007 ; 369 : 1090-1098. 
8. 
Report of the Working Group on Conflict of Interest (Ministry of Education, Culture, Sports, 
Science and Technology dated November 1, 2002) 
9. 
Guidelines for determining the conflict of interest polity for clinical research (Review group 
for ethical aspects of clinical research and conflict of interest, March 2006) 
10. Guidelines on the Management of COI in Health and Labor Scirences Research (No. 
0331001, science, issued on March 31, 2008, and approved by the Chief of the Health 
Sciences Division)    
11. Guidelines for management of COI in medical research (COI Committee of Japan 
Association of Medical Sciences, February 2011) 
12. 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, Japanese Respiratory Society, Japanese Society 
of Hematology, Japanese Society of Allergology, Japanese Association for Infectious 
Diseases, Aug 2011) 


TAK-085-4001 
Page 68 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
Appendix A  Schedule for Research Procedures 
 
(a) Eating/drinking to excess and extreme change in dietary content should be avoided on the day before the hospital 
visit. 
(b) All concomitant drugs will be recorded. 
(c) Hematology, urinalysis, and other details will be entered below: 
• Hematology 
(Fasting): TG, total cholesterol, LDL-cholesterol, HDL-cholesterol , Remnant-like particle (RLP) cholesterol , 
apoprotein B-48, C-reactive protein (CRP), fasting plasma glucose (FPG), plasma fatty acid fraction 
(4 hours postprandial): TG, total cholesterol, LDL-C, HDL-cholesterol, Remnant-like particle (RLP) 
cholesterol , apoprotein B-48    
• Urinalysis: Quantitative 8-epi-PGF2α  
(d) Time window ± 30 minutes   
(e) To be performed before test at Visit 2  
(f) To be performed by the physician or the clinical laboratory technician who has finished the FMD measurement 
training   
(g) To be performed after consent has been obtained. 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. 
(h) To be performed to the extent possible 
Observation
period
Week
-4
0
4
8
Day
-29
-1(g)
28
56
Allowable range
(Day)
-29 to -1
-15 to -1
14 to 41
42 to 70
Up to 3 days
after the last
dose
1
2
3
4
X
X
X
X
X(e)
X
X
X
X
X
X
X
X
X
X
X
X
X(e)
X
X
X
X
X(e)
X
X
X
X
X(e)
X
X(e)
X
X
X
X
X
X
X
X
X(e)
X
X
X
X
X
X
X
X
X(f)
X(f)
X(f)
X(f)
X(f)
X(f)
X(f)
X
X
X
X
X
X)
←X→
←X→
←X
←X
Inclusion/Exclusion criteria
Treatment period
 
Discontinuation
(h)
Time of visit
VISIT Number
Informed consent procedure
　Serum chemistry (4 h postprandial)(d)
Demographic data, medical history,
previous therapeutic drugs
Physical examination
 Confirmation of food and drink
consumption before visit　(a)
Height
Body weight
BMI
Vital signs
Concomitant drugs (b)
Concurrent disease
Laboratory tests (c)
　Serum chemistry (fasting)
Drug compliance
PTE and adverse events assessment
　Urinalysis (fasting)
　Other tests
FMD
　FMD (fasting)
　FMD (4 h postprandial)  (d)
Prescription of the study drug
X(i) 
(X) 


TAK-085-4001 
Page 69 of 69
First edition 
March 29, 2016
 
CONFIDENTIAL 
Appendix B  Responsibilities of the Principal Investigator 
1. 
Appropriately To appropriately conduct the clinical research in compliance with this research 
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 research subjects. 
2. 
Prepare To prepare a list of any other investigators and/or research collaborators when certain 
important research-related activities are divided by investigators and/or research collaborators, 
and submit the list to the sponsor as required. 
3. 
To prepare the informed consent form 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 
subinvestigators and study collaborators, and give guidance and supervision. 
6. 
To select research 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 research. 
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 research according to the study site. 
10. To ensure, together with the chief executive of the study site, that sufficient medical care is 
provided to research subjects for all research-related clinically problematic adverse events 
throughout the period of subjects’ research participation and thereafter. 
11. When a research subject is treated at another medical institution or department, to inform the 
acting physician at the medical institution or department in writing of the research subject’s 
study participation and research completion/discontinuation after obtaining the research 
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. 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 
collaborator from source data, {electronically sign/ sign or write name/affix a seal, and submit 
them to the sponsor. 
15. To discuss a revision of the protocol, etc., when proposed by the sponsor. 
16. To report the research completion in writing to the chief executive of the study site. 

SAP_001.pdf: 
Title: Exploratory study of the effect of omega-3-acid ethyl esters on vascular 
endothelial function in patients with hyperlipidemia by flow mediated dilation 
NCT Number: NCT02824432 
Statistical analysis plan Approve Date: 14-Nov-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. 


 
 
 
 
 
Exploratory study of the effect of omega-3-acid ethyl esters on vascular endothelial 
function in patients with hyperlipidemia by flow mediated dilation 
(Protocol number:  TAK-085-4001)  
 
Statistical Analysis Plan 
(Ver.4.0:  14 Nov 2017) 
 
 
Sponsor:  Takeda Pharmaceutical Company Limited 
 
 
 
 
 
Authorizer:   
 
Takeda Pharmaceutical Company Limited 
 
 
Biostatistics Manager:  
PPD
PPD
PPD
PPD


目次 
1. 
DEFINITIONS of TERMS ................................................................................................. 1 
2. 
TIME WINDOW ............................................................................................................... 1 
3. 
ANALYSIS SET ................................................................................................................ 1 
4. 
CONSIDERATIONS for ANALYSIS .................................................................................. 2 
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 ............................................................. 4 
6.3. Treatment Compliance ..................................................................................................... 7 
7. 
EFFICACY EVALUATIONS ............................................................................................. 8 
7.1. Primary Endpoint and the Analytical Methods ................................................................... 8 
7.2. Secondary Endpoints and the Analytical Methods .............................................................. 8 
7.3. Analysis of other endpoints .............................................................................................. 9 
8. 
SAFETY EVALUATION ................................................................................................... 9 
8.1. Frequency of Adverse Event Occurrence ........................................................................... 9 
8.2. Other Endpoints and the Analytical Methods ................................................................... 12 
9. 
LISTING......................................................................................................................... 13 
10. 
CONSIDERATIONS on STATISTICAL ANALYSIS ...................................................... 14 
10.1. Adjustments for Covariates .......................................................................................... 14 
10.2. Handling of Dropouts or Missing Data .......................................................................... 14 
10.3. Criteria for Interim Analysis and Early Discontinuation ................................................. 14 
10.4. Multicenter Studies...................................................................................................... 14 
10.5. Multiple Comparisons/Multiplicity ............................................................................... 14 
10.6. Examination of Subgroups ........................................................................................... 14 
11. 
REVISION HISTORY .................................................................................................. 15 
 


 
1 
 
1. 
DEFINITIONS of TERMS 
・ Summary Statistics:  Number of subjects, mean, SDs, maximum values, minimum values, 
and quartiles 
・ Treatment Group:  Omega-3-acid ethyl esters 2g, Omega-3-acid ethyl esters 4g 
 
2. 
TIME WINDOW 
For each inspection, observation and evaluation item, evaluable data is handled according to the 
following table. When there are multiple data that can be evaluated at the same visit, the one 
with the closest inspection date, observation, and evaluation date to the reference date is adopted, 
and if the difference from the reference date is the same, the later data is adopted. 
 
< FMD (Fasting, 4h postprandial) > 
Visit 
Reference implementation date 
Time Allowance 
Days after the 
Administration 
Start of Treatment Period 
Days after the Administration: -1 
-15 to -1 
Treatment period 4 week 
Days after the Administration: 28 
1 to 41 
Treatment period 8 week 
Days after the Administration: 56 
42 to 70 
 
< Other than FMD > 
Visit 
Reference implementation date 
Time Allowance 
Days after the 
Administration 
Start of Treatment Period 
Days after the Administration: -1 
-29 to -1 
Treatment period 4 week 
Days after the Administration: 28 
1 to 41 
Treatment period 8 week 
Days after the Administration: 56 
42 to 70 
 
・ The reference implementation date and the number of days after administration in the 
treatment period are indicated as “Day -1” for the day before study drug administration and 
“Day 1” for the administration day. As the administration is started from the day after the 
visit, 4 weeks of the treatment period and 8 weeks of the treatment period are 28 days and 
56 days after the study drug administration. 
 
3. 
ANALYSIS SET 
・ Full Analysis Set 
The subjects who were randomized and given at least one dose of the study drug. 


 
2 
 
・ Safety Analysis Set 
The subjects who are given at least one dose of the study drug. 
 
4. 
CONSIDERATIONS for ANALYSIS 
・ Confidence coefficient  
95% (two-sided estimation) 
・ Display digit 
 [Mean, Confidence coefficient, Quartiles] 
Round statistics off to the 1 digits lower than significant digits of the data. 
 [Standard Deviation] 
Round statistics off 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 statistics off to 1 decimal places. 
 
5. 
OTHER DATA HANDLING 
[Data Handling for Study Drug] 
・ Duration of Treatment 
Duration of Treatment = Date of the Last Dose - Date of the First Dose + 1 
 
[Data Handling for Adverse Event] 
・ Adverse Events  
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). 
・ Time to Occurrence of Adverse Event 
Time to Occurrence of Adverse Event = Onset Date of Adverse Event - Date of the First 
Dose + 1  
・ Non-serious Adverse Events 
Adverse events, excluding serious adverse events (protocol 10.1.4), shall be non-serious 
adverse events in the case of an incidence of over 5% in at least one treatment group. 
 
[Data Handling for Duration of Dyslipidemia (year)] 
・ Duration of Dyslipidemia (year) 


 
3 
 
Duration of Dyslipidemia (year) = (Date of Informed Consent (year/month) – Onset Date of 
Dyslipidemia (year/month)) / 12 (rounded off to two decimal places) 
If only the month of the onset of dyslipidemia is unknown, the month of the onset of 
dyslipidemia is regarded as “January”. 
 
 
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 
Version of MedDRA 
Version of SAS 
Analysis Methods:  For the above analysis variables, the following analysis is 
performed. 
(1) Show above items. 
 
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 variables, the following analysis is 
performed. 
(1) Frequency Count 
6.1.3. Subject Disposition 
6.1.3.1. 
Study completion status 
Analysis Set:  Randomized subjects 
Analysis Variables:  Study completion status 
[Complete, Incomplete (and the reason)] 
Analysis Methods:  For the above analysis variables, the following analysis is 
performed for each treatment group and all subjects in the 
analysis set. 
(1) Frequency Count 
 
 


 
4 
 
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 variables, the following analysis is 
performed for each treatment group and all subjects in the 
analysis set. 
(1) Frequency Count 
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. 
 
6.1.4.2. 
Datasets Analyzed 
Analysis Set:  Randomized subjects 
Analysis Variables:  Subjects excluded from analysis datasets  
[Reason of exclusion] 
Full Analysis Set    [Adopted] 
Safety Analysis Set  [Adopted] 
Analysis Methods:  For the above analysis variables, the following analysis is 
performed for each treatment group (both (1) and (2)) and all 
subjects (for (2)) in the analysis set. For analysis (1), Subjects 
applicable for multiple categories will be counted once in 
each category. 
(1) Frequency count in each analysis set about handling for 
subjects 
(2) Frequency count in each analysis set of adopted subjects. 
 
6.2. Demographics and Other Baseline Characteristics 
6.2.1. Distribution of Demographics  
Analysis Set:  Safety Analysis Set 


 
5 
 
Analysis Variables:   
Age (years old) [Min<= - <65, 65<= - <75, 75<= - <=Max] 
Sex          [Male, Female] 
Height (Observation period) (cm) 
[Min<= - <150, 150<= - <160,  
160<= - <170, 170<= - <=Max] 
Weight (Observation period) (kg) 
[Min<= - <50.0, 50.0<= - <60.0, 
60.0<= - <70.0, 70.0<= - <80.0, 
80.0<= - <=Max] 
BMI (Observation period) (kg/m2) 
[Min<= - <18.5, 18.5<= - <25.0,  
25.0<= - <=Max] 
Duration of Dyslipidemia (year)  
       [Min<5, 5<=Max, Unknown] 
Last Menstrual Period       
[<2 years, 2 years <=, Not Applicable] 
Frequency of Consumption of Fish       
[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] 
TG level (fasting) (Start of Treatment Period) (mg/dL)    
[Min<= - <200, 200<= - <500, 500<= - <=Max] 
TG level (4h postprandial) (Start of Treatment Period) (mg/dL) 
[Min<= - <200, 200<= - <500, 500<= - <=Max] 
Plasma Fatty acid Fraction EPA/AA ratio (Start of Treatment Period) 
[Min<0.3, 0.3<=Max] 
Analysis Methods:  For the above analysis variables, the following analysis is 
performed for each treatment group and all subjects in the 
analysis set. 
(1) Frequency count for discrete variables and summary 
statistics for continuous variables 
 


 
6 
 
6.2.2. Medical History and Concurrent Disease 
Analysis Set:  Safety Analysis Set 
Analysis Variables:  Medical history, Concurrent disease 
Analysis Methods:  For the above analysis variables, the following analysis is 
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) Frequency of medical history by SOC/PT 
(2) Frequency of concurrent disease by SOC/PT 
     The method of accounting for the frequency is as follows. 
     [Number of Subjects] 
Within 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. Prior and Concomitant Medication 
Analysis Set:  Safety Analysis Set 
Analysis Variables:  Prior medication 
Concomitant medication 
Analysis Methods:  For the above analysis variables, the following analysis is 
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) Frequency of prior medication 
(2) Frequency of concomitant medication which was 
completed administration before study drug administration 
(3) Frequency of concomitant medication which was started 
administration before study drug administration and was 
continued administered after start of study drug 
administration 
(4) Frequency of concomitant medication which was started 
administration after start of study drug administration 


 
7 
 
(5) Frequency of concomitant medication which was 
administered study drug administration period. 
 
6.3. Treatment Compliance 
6.3.1. Study Medication Compliance 
Analysis Set:  Safety Analysis Set 
Analysis Variables:  Study medication compliance   
 [Min<= - <50.0%,  
50.0%<= - <=Max]   
Visit:  Treatment Period 4 week and 8 week 
Analysis Methods: For the above analysis variables, the following analysis is 
performed for each treatment group and all subjects in the 
analysis set by visit.  
(1) Frequency Count 
 
6.3.2. Food and Drink Consumption before the Visit 
Analysis Set: Safety Analysis Set 
     Analysis Variables: Did you consume alcohol from 9:00 pm two days before the 
hospital visit to the time of the fasting test, or consume food 
from 9:00 pm on the day before to the time of the fasting test? 
[Yes, No] 
Did you experience excess and extreme change of dietary 
content (Eating/Drinking) on the day before the fasting test. 
[Yes, No] 
Visit: Treatment Period 4 week and 8 week 
Analysis Methods: For the above analysis variables, the following analysis is 
performed for each treatment group and all subjects in the 
analysis set by visit.   
(1) Frequency Count 
 
6.3.3. Study Medication Exposure 
Analysis Set:  All Subjects Administered 
Analysis Variables:  Duration of exposure (days)  
[1<= - <29, 29<= - <57, 57<= - <=Max] 
Analysis Methods: For the above analysis variables, the following analysis is 
performed for each treatment group and all subjects in the 


 
8 
 
analysis set. 
(1) Frequency count for discrete 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: %FMD (fasting)  
Visit: Start of Treatment Period, Treatment Period 4 week and 8 week 
Stratification Factor: Fasting TG at Observation Period  
[150<= - <200, 200<= - <500] 
Analysis Methods: For the above analysis variables, the following analysis is 
performed. 
(1) Summary statistics by treatment group and a two-sided 
95% confidence interval for the mean will be calculated at 
each visit during the treatment period, and a diagram 
illustrating the change in the mean ± SD will be prepared.  
(2) The change for each treatment group (Treatment Period 4 
week/8 week – Start of Treatment Period) will be 
calculated at each visit during the treatment period and the 
same analysis as in (1) will be performed. 
(3) Summary statistics using stratification factor and 
two-sided 95% confidence interval (CI) of mean value by 
visit will be calculated by treatment group.  
(4) Using stratification factor, the change for each treatment 
group (Treatment Period 4 week/8 week – Start of 
Treatment Period) will be calculated at each visit during 
the treatment period and the same analysis as in (3) will be 
performed. 
(5) Analyses same as (1) - (4) are performed, excluding 
subjects with missing of %FMD (fasting) data at any visit 
as sensibility analysis. 
 
7.2. Secondary Endpoints and the Analytical Methods 
Analysis Set: Full Analysis Set 


 
9 
 
Analysis Variables: %FMD (4h postprandial)  
        TG level (fasting)  
           TG level (4h postprandial)  
        Plasma fatty acid fraction 
Visit: Start of Treatment Period, Treatment Period 4 week and 8 week 
* Treatment period 4 is excluded about %FMD (4h postprandial)  
Stratification Factor: Fasting TG at Observation Period  
[150<= - <200, 200<= - <500] 
Analysis Methods: For the above analysis variables, the same analyses describes in 
7.1 (1) - (4) are performed by visit. 
 
7.3. Analysis of other endpoints 
7.3.1. Efficacy Endpoints 
Analysis Set: Full Analysis Set 
Analysis Variables: Total cholesterol (fasting and 4h postprandial)  
           LDL-C(fasting and 4h postprandial)  
                HDL-C(fasting and 4h postprandial)  
                Remnant-like particle (RLP) cholesterol  
(fasting and 4h postprandial)  
                Apoprotein B-48 (fasting and 4h postprandial)  
                C-reactive protein (CRP) (fasting)  
                8-epi-PGF2α quantitative (urinary) (fasting)  
Visit: Start of Treatment Period, Treatment Period 4 week and 8 week 
Analysis Methods: For the above analysis variables, the same analyses describes in 
7.1 (1) and (2) are performed by visit.  
 
8. 
SAFETY EVALUATION 
8.1. Frequency of Adverse Event Occurrence 
8.1.1. Brief Summary of Adverse Events 
Analysis Set: Safety Analysis Set 
Analysis Variables: Adverse Event 
Category Classification:  
Causal Relationship with the Study Drug [Related, Unrelated] 
              Severity 
 
 
  
  
  
  
[Mild, 
Moderate, 
Severe]       
Time of Onset                 [1<= - <29,  
29<= - <57, 


 
10 
 
           57<= - <=Max]  
Analysis Methods: For the above analysis variables, the following analysis is 
performed for each treatment group. 
(1) Tabulation of frequencies of all adverse events 
(2) Tabulation of frequency of adverse events with a causal 
relationship to the study drug 
(3) Tabulation of frequency of all adverse events by severity 
(4) Tabulation of frequency of adverse events with a causal 
relationship to the study drug by severity 
(5) Tabulation of frequency of adverse events leading to study 
drug discontinuation 
(6) Tabulation of frequency of serious adverse events 
(7) Tabulation of frequency of Non-serious adverse events 
(8) Tabulation of frequency of serious adverse events with a 
causal relationship to the study drug 
(9) Tabulation of frequency of serious adverse events leading 
to study drug discontinuation 
(10) Tabulation of frequency of adverse events leading to death 
(11) Tabulation of frequency of all adverse events by time of 
onset 
Incidence rates will be calculated as following on each analysis. 
   [Frequency 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 of Onset 
Subjects with one or more adverse events within a level of MedDRA term 
is counted only once in that category of time of onset. The denominator 
when calculating the incidence of adverse events is the number of 
subjects “whose study drug administration has been continued at that time 
point and later” or “who experienced an onset of adverse events at that 
time point or later” in safety analysis set and numerator is the number of 
subjects “experienced an onset of adverse events at that time point”. 
・Analyses Other Than the Above 


 
11 
 
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. 
 
8.1.2. Display of Adverse Event 
Analysis Set: Safety Analysis Set 
Analysis Variables: Adverse Event 
Category Classification:  
Causal Relationship with the Study Drug [Related, Unrelated] 
              Severity 
 
 
  
  
  
  
[Mild, 
Moderate, 
Severe]       
Time of Onset                 [1<= - <29,  
29<= - <57, 
           57<= - <=Max]  
Analysis Methods: For the above analysis items, the following analysis is 
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) Tabulation of frequencies of all adverse events (by 
SOC/PT) 
(2) Tabulation of frequency of adverse events with a causal 
relationship to the study drug (by SOC/PT) 
(3) Tabulation of frequency of all adverse events by severity 
(by SOC/PT) 
(4) Tabulation of frequency of adverse events with a causal 
relationship to the study drug by severity (by SOC/PT) 
(5) Tabulation of frequency of adverse events leading to study 
drug discontinuation (by SOC/PT) 
(6) Tabulation of frequency of serious adverse events (by 
SOC/PT) 
(7) Tabulation of frequency of Non-serious adverse events (by 
SOC/PT) 
(8) Tabulation of frequency of serious adverse events with a 
causal relationship to the study drug (by SOC/PT) 


 
12 
 
(9) Tabulation of frequency of serious adverse events leading 
to study drug discontinuation (by SOC/PT) 
(10) Tabulation of frequency of adverse events leading to death 
(by SOC/PT) 
(11) Tabulation of frequency of all adverse events by time of 
onset (by SOC/PT) 
Incidence rates will be calculated as following on each analysis. 
   [Frequency 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 
number of subjects of safety analysis set. 
・Frequency by Time of Onset (by SOC/PT) 
Subjects with one or more adverse events within a level of SOC/PT term 
is counted only once in that category of time of onset. The denominator 
when calculating the incidence of adverse events is the number of 
subjects “whose study drug administration has been continued at that time 
point and later” or “who experienced an onset of adverse events at that 
time point or later” in safety analysis set and numerator is the number of 
subjects “experienced an onset of adverse events at that time point”. 
 
8.2. Other Endpoints and the Analytical Methods 
8.2.1. Vital Sign 
Analysis Set: Safety Analysis Set 
Analysis Variables: Body Weight, Blood Pressure in the Sitting Position 
(Systolic, Diastolic), Pulse in the Sitting Position 
Visit: Start of Treatment Period, Treatment Period 4 week and 8 week 
Analysis Methods: The following analysis is performed for Safety Analysis Set.  


 
13 
 
(1) Summary statistics of measurements by treatment group at 
each visit during the treatment period will be calculated 
and a diagram of the change of individual data will be 
created. 
(2) The change for each treatment group (Treatment Period 4 
week/8 week – Start of Treatment Period) will be 
calculated at each visit during the treatment period and the 
same analysis as in (1) will be performed. 
(3) Regarding evaluation results based on standard values, 
shift tables of start of treatment period and each visit of 
treatment period 4 week and 8 week will be prepared. 
 
8.2.2. Laboratory Test 
Analysis Set: Safety Analysis Set 
Analysis Variables: Fasting Plasma Glucose (FPG) 
Visit: Start of Treatment Period, Treatment Period 4 week and 8 week 
Analysis Methods: The following analysis is performed for Safety Analysis Set.  
(1) Summary statistics of measurements by treatment group at 
each visit during the treatment period will be calculated 
and a diagram of the change of individual data will be 
created. 
(2) The change for each treatment group (Treatment Period 4 
week/8 week – Start of Treatment Period) will be 
calculated at each visit during the treatment period and the 
same analysis as in (1) will be performed.  
(3) Regarding evaluation results based on standard values, 
shift tables of start of treatment period and each visit of 
treatment period 4 week and 8 week will be prepared.  
   
 
9. 
LISTING 
Following lists will be create for randomized subjects. 
・Demographics 
・Discontinuation 
・Protocol Deviation 
・Subjects Excluded from Analyses 


 
14 
 
・Compliance of Study Drug Administration 
・Adverse Event 
・FMD Test 
・Laboratory Tests (Blood biochemical examination including 4h postprandial)  
・Laboratory Tests (Blood biochemical examination and urine test excluding 4h postprandial)  
 
 
10. CONSIDERATIONS on STATISTICAL ANALYSIS 
10.1. Adjustments for Covariates 
In the analysis for primary endpoint for Full Analysis Set, stratified analysis of %FMD (fasting) 
is performed with Fasting TG value (150 <= - <200, 200 <= - <500) at the start of treatment 
as a layer. Details are described in 7.1 (3) and (4).  
 
10.2. Handling of Dropouts or Missing Data 
For laboratory test, values below quantitation limit are treated as zero. 
 
10.3. Criteria for Interim Analysis and Early Discontinuation 
Interim analysis will not be performed 
 
10.4. Multicenter Studies 
Analyses for consideration of medical institution will not be performed. 
 
10.5. Multiple Comparisons/Multiplicity 
  It does not adjust multiplicity. 
 
10.6. Examination of Subgroups 
  Subgroup analysis will not be performed. 


 
15 
 
 
11. REVISION HISTORY 
Ver. 
Date 
Author 
Revised Content 
Reason for Revision 
1.0 
23 May 2016 
- 
 
2.0 
4 Aug 2016 
[2.TIME WINDOW] 
Add <Exploratory biomarker 
evaluation> 
 
Add 7.3.2. Exploratory evaluation 
item (exploratory biomarker 
evaluation) 
For exploratory evaluation 
item addition 
3.0 
29 Aug 2017 
[Title page] 
Modify affiliation of approver and 
biostatistics manager. 
For organization change and 
company integration 
 
 
 
[2.TIME WINDOW] 
Delete <Exploratory biomarker 
evaluation> 
 
Delete 7.3.2. Exploratory 
evaluation item (exploratory 
biomarker evaluation) 
Analysis of exploratory 
biomarker is performed 
after March in 2018  
 
 
 
[5 OTHER DATA HANDLING] 
Add “Non-serious Adverse Event” 
As required by Clinical 
Trial.gov 
 
 
 
[6.1.3 Subject Disposition] 
Change of Analysis Variables 
(“Exit Status of Stud Drug” → 
“Exit status from the study”  
For mistake correction 
 
 
 
[7.1. Primary Endpoint and the 
Analytical Methods] 
Add analysis of Complete Case 
To 
study 
as 
sensitivity 
analysis 
 
 
 
[8.1.1. Brief Summary of Adverse 
Events] 
[8.1.2. Display of Adverse Event] 
Add “Non-serious Adverse Event” 
As required by Clinical 
Trial.gov 
PPD
PPD
PPD


 
16 
 
 
 
 
[10.2. Handling of Dropouts or 
Missing Data] 
Add handling of values below 
quantitation limit in laboratory 
test 
To clarify the definition of 
handling below quantitation 
limit 
4.0 
14 Nov 2017 
[Title page] 
Modify affiliation of biostatistics 
manager. 
For organization change 
 
 
 
[5. OTHER DATA HANDLING] 
Add < Data Handling for Duration 
of Dyslipidemia (year)>  
To clarify the specification  
 
 
 
[General] 
Correct stratification factor from " 
Fasting TG at the Start of 
Treatment" to "Fasting TG at 
Observation Period" 
Due to the data review, 
stratification 
factor 
was 
found to be " Fasting TG at 
Observation Period " 
 
 
 
[7.2. Secondary Endpoints and the 
Analytical Methods] 
“the same analyses describes in 
7.1 are performed by visit” → 
“the same analyses describes in 
7.1 (1) - (4) are performed by 
visit” 
Analysis for complete case 
is 
performed 
only 
for 
primary endpoint. 
 
 
 
[9. LISTING] 
Add list to be created 
For creation of lists 
 
PPD