Omega-3 Fatty Acid Ethyl Esters (Lotriga) Granular Capsules Special Drug Use Surveillance (Long-term Use Survey)
Conditions: Hyperlipidemia
Sponsor: Takeda

 
 
Title: Lotriga Granular Capsules Special Drug Use Surveillance [Long-term use survey] 
 
NCT Number: NCT02153073 
Protocol Approve Date: 02-Apr-2018 
 
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. 

 
 
 
 
 
Special Drug Use Surveillance Protocol 
Lotriga Granular Capsules Special Drug Use 
Surveillance 
[Long-term use survey] 
 
 
 
 
 
 
 
Version No. 
7th Version 
Date Prepared 
April 2, 2018 
Study Sponsor 
Takeda Pharmaceutical Company Limited 
 

 
Table of Contents 
1.0 
Background .................................................................................................................................................... 1 
2.0 
Objective ........................................................................................................................................................ 1 
3.0 
Target Sample Size and Rationale for Sample Size Setting ........................................................................... 1 
3.1 
Target Sample Size ..................................................................................................................................... 1 
3.2 
Rationale for Sample Size Setting .............................................................................................................. 1 
4.0 
Study Population ............................................................................................................................................ 1 
5.0 
Dosage and Administration for Study Population .......................................................................................... 2 
6.0 
Number of Study Sites by Clinical Department ............................................................................................. 2 
7.0 
Study Method ................................................................................................................................................. 2 
7.1 
Observation Period ..................................................................................................................................... 2 
7.2 
Request and Contract to Study Sites .......................................................................................................... 2 
7.3 
Patient Enrollment Method ........................................................................................................................ 2 
7.4 
Data Entry and Electronic Signature to Electronic Case Report Form (eCRF) .......................................... 2 
7.5 
Action Taken at Onset of Serious Adverse Event ....................................................................................... 3 
8.0 
Expected Duration of Study ........................................................................................................................... 3 
9.0 
Survey Items ................................................................................................................................................... 3 
9.1 
Patient Enrollment ...................................................................................................................................... 3 
9.2 
Patient Demographics................................................................................................................................. 3 
9.3 
Treatment Information ................................................................................................................................ 3 
9.4 
Testing/Observation Items .......................................................................................................................... 4 
9.5 
Other Observation Items ............................................................................................................................ 4 
9.6 
Adverse Events (AEs) ................................................................................................................................ 4 
10.0 
Analysis Items and Method ............................................................................................................................ 7 
10.1 
Patient Disposition Items............................................................................................................................ 7 
10.2 
Patient Demographics................................................................................................................................. 7 
10.3 
Treatment Details ....................................................................................................................................... 7 
10.4 
Safety Items ................................................................................................................................................ 7 
 
Onset Status of Adverse Events .......................................................................................................... 7 
10.4.1
 
Factors Likely to Affect Safety ........................................................................................................... 7 
10.4.2
10.5 
Efficacy Items............................................................................................................................................. 8 
 
Changes in Lipid Parameters: TG, TC, LDL-C, HDL-C, Non-HDL-C, etc. ...................................... 8 
10.5.1
 
Factors Likely to Affect Efficacy ....................................................................................................... 8 
10.5.2
11.0 
Organizational Structure for Conducting the Study ....................................................................................... 8 
12.0 
Service Contractor’s Name and Address and Scope of Contract Work .......................................................... 8 
13.0 
Other Necessary Items ................................................................................................................................... 9 
13.1 
Protocol Revision ....................................................................................................................................... 9 
13.2 
Action Taken in Case of Problem or Question ........................................................................................... 9 
 
Appendix Study Schedule.......................................................................................................................................10 

 
1 
1.0 
Background 
Lotriga Granular Capsules (the “Drug”) is an oral capsule formulation containing the active 
ingredient omega-3 fatty acid ethyl esters (principally EPA-E and DHA-E). The Drug differs 
from general marine oil products, such as supplements, in containing a high concentration of 
omega-3 fatty acid ethyl esters. Since first approved in Norway in September 1994, the Drug 
has been in extensive use overseas, sold in more than 60 countries. In the clinical study of the 
Drug conducted in Japan in patients with hypertriglyceridemia, adverse drug reactions (ADRs) 
including ‘laboratory test abnormal’ were observed in 91 (9.6%) of the 948 patients 
administered at 2 g or 4 g of omega-3 fatty acid ethyl esters, and the major ADR was Diarrhea 
(2.5%). 
Despite the proven track record of extensive use overseas and the fact that the safety of 
long-term use was already evaluated during the clinical study, it is important to evaluate the 
safety of long-term use of the Drug in the general patient population in Japan. 
Special drug use surveillance (hereinafter the "Study") has been therefore designed to evaluate 
the safety and efficacy of long-term use of the Drug in patients with hyperlipidemia in a 
routine clinical setting. 
 
2.0 
Objective 
To evaluate the safety and efficacy of long-term use of the Drug in patients with 
hyperlipidemia in a routine clinical setting. 
 
3.0 
Target Sample Size and Rationale for Sample Size Setting 
3.1 
Target Sample Size 
3,000 patients 
 
3.2 
Rationale for Sample Size Setting 
Bleeding-related events are set as a priority survey item for the Drug. As postmarketing 
surveillance of EPA products in antihyperlipidemic therapy has reported that the incidence of 
bleeding-related ADRs was 0.4% and that the percentage of anticoagulant and antiplatelet 
concomitant use was about 10%, the Study sets a target of 3,000 patients so that anticoagulant 
and antiplatelet concomitant use can be assessed to some degree, in addition to 
bleeding-related ADRs. 
Note that this rationale for the sample size is not based on statistical evidence. 
 
4.0 
Study Population 
Patients with hyperlipidemia will be eligible for this study; however, those who meet the 
following exclusion criteria were excluded from the study. 
Exclusion criteria: 
(1) Patients with hemorrhage (e.g., hemophilia, capillary fragility, gastrointestinal ulcer, 
urinary tract hemorrhage, hemoptysis, or vitreous hemorrhage) 
(2) Patients with a history of hypersensitivity to ingredients in the Drug 

 
2 
 
5.0 
Dosage and Administration for Study Population 
The usual adult dosage is 2 g of omega-3 fatty acid ethyl esters administered orally once daily 
after meals. However, the dosage can be increased up to twice daily (at a dose of 2 g) 
depending on the patient's triglyceride level. 
 
6.0 
Number of Study Sites by Clinical Department 
 About 200 sites (clinical departments not specified) 
 
7.0 
Study Method 
7.1 
Observation Period 
12 months 
 
7.2 
Request and Contract to Study Sites 
The Study will be requested and contracted using a web-based electronic data collection 
system 
. Takeda Pharmaceutical’s staffs (hereinafter "Takeda staffs") will 
adequately explain to investigators about the purpose and description of the Study, 
’s operating procedure, electronic signature, and user ID and password handling for 
request for the Study, based on the Letter of Request for Cooperation in Special Drug Use 
Surveillance, the Implementation Guidance, data input screen images, and the abbreviated 
 Operating Manual. Takeda MRs will then conclude a contract in writing with 
study sites to perform the Study within the specified surveillance period. 
 
7.3 
Patient Enrollment Method 
Patients will be "centrally" enrolled using 
. The investigator will enter into 
 patient enrollment information (see Section 9.1) of patients for whom the Drug has 
been prescribed since the start date of the period of contract with the study site, within 14 days 
after the prescription date of the Drug (the prescription date is defined as "Day 0"; the day 
following the prescription date is defined as "Day 1"). 
 
7.4 
Data Entry and Electronic Signature to Electronic Case Report Form (eCRF) 
The investigator will enter patient data including demographics and treatment into 
 
and electronically sign the eCRF in 12 months after the start of treatment with the Drug 
(baseline). 
If a patient discontinues the treatment with the Drug for some reason during the observation 
period, the investigator will be expected to enter their information including demographics and 
treatment into 
 and electronically sign the eCRF within one month after the 
completion of necessary observations. However, if the patient discontinues the treatment with 
the Drug due to the occurrence of an adverse event (AE), the investigator should continue to 
observe them after discontinuation, as long as possible until the AE is resolved or resolving. 
The investigator should then enter the result of the observation into 
 and 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

 
3 
electronically sign the eCRF. 
After review of the information, Takeda Pharmaceutical may request for re-survey, if deemed 
necessary, via 
 The investigator will, upon checking, perform the details of the 
requested re-survey and enter the result of the re-survey into 
 and electronically 
sign the eCRF. 
 
7.5 
Action Taken at Onset of Serious Adverse Event 
The investigator will immediately contact the Takeda staff if a serious AE occurs during the 
observation period. The investigator will also separately provide detailed information thereof 
upon request, if any, from the Takeda staff. 
 
8.0 
Expected Duration of Study 
Surveillance period: May 2013 to May 31, 2017 
Patient enrollment period: May 2013 to May 31, 2015* 
 
*Enrollment may be closed before the end of the enrollment period if the total number of 
patients enrolled in the Study reaches the target sample size. 
 
9.0 
Survey Items 
The investigator will enter the information of the following items into 
. The 
schedule for the Study is provided in the Appendix. 
9.1 
Patient Enrollment 
1) Survey items 
Prescription date of the Date, patient ID number, patient initials, sex, birth date, 
determination with inclusion criteria, and determination with exclusion criteria 
2) Survey timing 
The time of patient enrollment 
 
9.2 
Patient Demographics 
1) Survey items 
Height, weight, time of hyperlipidemia diagnosis, treatment category, menopausal status 
(only for female), complications (presence or absence and details), medical history 
(presence or absence and details), hypersensitivity disposition (presence or absence and 
details), drinking history, smoking history, presence or absence of surgery within one 
month before baseline, and presence or absence of healthier lifestyle education (diet and 
exercise therapies) 
2) Survey time 
Baseline 
 
9.3 
Treatment Information 
1) Survey items 
CCI
CCI
CCI

 
4 
Administration of the Drug (daily dose, treatment duration, and status of completion of 
treatment with the Drug), administration of antihyperlipidemic drugs other than the Drug* 
(presence or absence, drug name, daily dose, and treatment duration), and administration of 
concomitant medications (other than antihyperlipidemic drugs) (presence or absence, drug 
name, and purpose of administration) 
*: Including antihyperlipidemic drugs with which treatment is discontinued within two 
months before baseline. 
2) Survey timing 
Period from baseline to Month 12 (or discontinuation of treatment) 
 
9.4 
Testing/Observation Items 
1) Survey items 
Triglyceride (TG), total cholesterol (TC), LDL cholesterol* (LDL-C), HDL cholesterol 
(HDL-C), VLDL cholesterol (VLDL-C), Apo-AI, Apo-B, Apo-CIII, lipoprotein (a), 
remnant lipoprotein cholesterol (RLP-C), fasting blood glucose (FBG), HbA1c 
*: When tested by direct measurement 
2) Survey timing 
Baseline, Month 3, Month 6, Month 9, and Month 12 (or discontinuation of treatment) test 
timepoints 
 
9.5 
Other Observation Items 
1) Survey items 
Pregnancy status 
If the patient is found to be pregnant during the observation period, the investigator 
will report the Takeda staff. The investigator will, upon request from the Takeda staff, 
use a sheet for pregnant women to provide detailed information (including information 
available up to childbirth, including premature birth or other pregnancy results, if 
possible). 
2) Survey timing 
Period from baseline to Month 12 (or discontinuation of treatment) 
 
9.6 
Adverse Events (AEs) 
1) Survey items 
Presence or absence of AE (see Table 1), AE name, date of onset, seriousness and reason 
for seriousness (see Table 2), action taken to the Drug, date of determination of outcome, 
outcome, and causal relationship to the Drug* (see Table 3) 
If the outcome is not resolved or unknown and the casual relationship is determined as 
unevaluable, follow-up survey should be conducted to some extent possible. 
*If causal relationship to the Drug is determined as not related, reasons that may constitute 
the rationale for determination should be collected if it is unevaluable. 
2) Survey timing 

 
5 
Period from baseline to Month 12 (or discontinuation of treatment) 
3) Priority survey item 
Bleeding-related events occurring after baseline are set as a priority survey item. If 
any bleeding-related event is reported as an AE, laboratory test values related to bleeding 
should be separately collected. 
 
 
 

 
6 
Table 1 Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a medicinal 
product and which does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
The following should be also handled as an AE: 
• A symptoms or other problem occurring in an infant breastfed from a mother taking the medicinal 
product 
• A symptom or other problem occurring in a child administered the medicinal product 
• A symptom or other problem occurring in a patient administered or taking more than the approved 
dose of the medicinal product 
 
Table 2 Seriousness Criteria 
An event is classified as serious if: 
1. resulting in death (death), 
2. being life-threatening (at risk of death), 
3. requiring inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization), 
4. resulting in persistent or significant disability/incapacity (disorder), 
5. being a congenital anomaly/birth defect (birth defect), or 
6. being any other medically serious condition that does not fall under any of 1 to 5 above. Note that 
all those listed in the Takeda Medically Significant AE List are included in this criterion. 
(Examples include bronchospasm, which requires short-term intensive care in emergency room 
settings.) 
 
Takeda Medically Significant AE List 
• Acute respiratory failure/acute respiratory distress 
syndrome (ARDS) 
• Anaphylactic shock 
• Torsade de pointes/ventricular 
fibrillation/ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizure (including spasm and 
epilepsy) 
• Pulmonary fibrosis (including interstitial lung 
disease) 
• Agranulocytosis 
• Neuroleptic malignant syndrome/malignant 
hyperthermia 
• Aplastic anaemia 
• Spontaneous abortion/stillbirth and foetal death 
• Toxic epidermal necrolysis/muco-cutaneo-ocular 
syndrome (Stevens-Johnson syndrome) 
• Confirmed or suspected transmission of infection 
by a medicinal product 
• Hepatic necrosis 
• Confirmed or suspected endotoxin shock 
• Acute hepatic failure 
 
 

 
7 
Table 3 Criteria for Casual Relationship between Adverse Event and the Drug 
Determination 
Criteria 
Related 
There is temporal correlation between the Drug and the event 
(including results from discontinuation of treatment). 
Or the event is an AE considered likely to have been caused by the 
Drug although it is presumed to have been contributed by other 
factors, such as primary disease, complications, concomitant 
medications, or combined treatments. 
Not related 
There is no temporal correlation between the Drug and the event. Or 
the event is adequately considered to have been contributed by other 
factors, such as primary disease, complications, concomitant 
medications, or combined treatments. 
Unevaluable 
There is lack of information necessary for evaluation of the event, 
including temporal correlation (including results from discontinuation 
of treatment), primary disease, complications, concomitant 
medications, and combined treatments. 
 
10.0 
Analysis Items and Method 
10.1 Patient Disposition Items 
Compile information including the number of enrolled patients, number of patients with 
eCRFs collected, numbers of safety- and efficacy-evaluable patients, and the number of 
patients excluded from analysis and reasons for exclusion. 
 
10.2 Patient Demographics 
Compile patient demographic information including sex, age, hypersensitivity disposition, and 
complications. 
 
10.3 Treatment Details 
Compile information on administration of the Drug and of concomitant medications. 
 
10.4 Safety Items 
Compile the following regarding the safety-evaluable population. AEs, coded using MedDRA, 
will be summarized by preferred term (PT) and by system organ class (SOC). 
 Onset Status of Adverse Events 
10.4.1
Compile the incidence of AEs occurring during the observation period, in terms of, e.g., 
causal relationship with the Drug, type, seriousness. Note that bleeding-related events 
should be separately compiled because such events are set as a priority survey item. 
 
 Factors Likely to Affect Safety 
10.4.2
Compile the incidence of ADRs occurring during the observation period, by stratification 
variables: patient baseline characteristics (sex, age, presence or absence of renal 

 
8 
dysfunction, presence or absence of hepatic dysfunction, etc.) and treatment regimen 
(administration of the Drug, administration of concomitant medications such as 
anticoagulant drugs, antiplatelet drugs). 
 
10.5 Efficacy Items 
Compile the following regarding the efficacy-evaluable population. 
 Changes in Lipid Parameters: TG, TC, LDL-C, HDL-C, Non-HDL-C, etc. 
10.5.1
Tabulate observed values and changes (observed value at each observational timepoint after 
baseline minus observed value at baseline) at each observational timepoint for TG, TC, 
LDL-C (by converted value calculated by direct measurement, Friedewald formula*), 
HDL-C, Non-HDL-C (converted value**), VLDL cholesterol, Apo-AI, Apo-B, Apo-CIII, 
lipoprotein (a), and RLP-C. 
*: LDL-C = TC-HDL-C - TG / 5 
**: Non-HDL-C = TC-HDL-C 
Note that LDL-C, Non-HDL-C, TC/LDL-C ratio, LDL-C/HDL-C ratio, and LDL-C/Apo-B 
ratio should be calculated from test results. 
 
 Factors Likely to Affect Efficacy 
10.5.2
Compile TG values by stratification variables: patient baseline characteristics (sex and age) 
and treatment regimen (administration of the Drug, administration of concomitant 
medications, etc.). 
 
11.0 
Organizational Structure for Conducting the Study 
Study Chair 
Takeda Pharmaceutical Co., Ltd. 
Post Marketing Surveillance Manager 
 
12.0 
Service Contractor’s Name and Address and Scope of Contract Work 
(1) 
Scope of work: Data management 
 
(2) 
Scope of work: Data management and statistical analysis 
 
(3) 
Scope of work: Storage of relevant records, PDF preparation of adverse events and other 
relevant information, and support services related to provision of information 
 
PPD
PPD
PPD

9 
(4) 
Scope of work: Formulation of 
 and its technical operations 
 
(5) 
Scope of work: Medical writing 
  
13.0 
Other Necessary Items 
13.1 Protocol Revision 
During the surveillance period, keep track of, e.g., the progress of the Study, the onset of 
unexpected ADRs or serious ADRs based on the precautions, presence or absence of increased 
incidence of specified ADRs, the appropriateness of survey items. If needed, review and revise 
this protocol. If partial change approval is obtained for dosage and administration or 
indications during the surveillance period, examine whether to revise this protocol if necessary 
and revise it if necessary. 
 
13.2 Action Taken in Case of Problem or Question 
If any problem is found in the safety or efficacy of the Drug, carefully review the data and 
examine what needs to be done. 
PPD
PPD
CCI

 
10 
Appendix Study Schedule 
Survey and Data Entry Timing 
 
Survey Item 
Observation Period 
Patient 
enrollme
nt
Baseline 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
Discon- 
tinuation 
Patient Enrollment 
Prescription date of the Drug 
○ 
 
 
 
 
 
 
Patient ID number 
○ 
Patient initials 
○ 
Sex 
○ 
Birth date 
○ 
Inclusion criteria/exclusion criteria 
○ 
Patient demographics 
Height, Weight 
○ 
 
 
 
Time of hyperlipidemia diagnosis 
○ 
 
 
 
Treatment category 
○ 
 
 
 
Menopausal status (only for female) 
○ 
 
 
 
Complications 
○  
 
 
 
Medical history 
○ 
 
 
 
Hypersensitivity disposition 
 
○ 
 
 
 
Drinking history, smoking history 
 
○ 
 
 
 
Presence or absence of surgery before 
baseline 
 
○  
 
 
 
Presence or absence of healthier 
lifestyle education (diet and exercise 
therapies) 
 
○ 
 
 
 
 
 
Treatment 
Information 
Administration of the Drug 
○ 
○ 
Administration of other 
antihyperlipidemic drugs 
○ 
○ 
Administration of concomitant 
medications (other than 
antihyperlipidemic drug) 
 
○ 
○ 
Testing /Observation Items 
TG 
○ 
○ 
○ 
○ 
○ 
○ 
TC 
○ 
○ 
○ 
○ 
○ 
○ 
LDL-C (direct measurement) 
○ 
○ 
○ 
○ 
○ 
○ 
HDL-C 
○  
○  
○  
○  
○  
○  
VLDL-C 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-AI 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-B 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-CIII 
○ 
○ 
○ 
○ 
○ 
○ 
Lipoprotein (a) 
○ 
○ 
○ 
○ 
○ 
○ 
RLP-C 
○  
○  
○  
○  
○  
○  
FBG 
○  
○  
○  
○  
○  
○  
HbA1c 
○  
○  
○  
○  
○  
○  
Pregnancy status (only for female) 
○ 
○ 
AE 
○ 
○ 
○: Surveyed, tested, or observed     ○:     Surveyed, tested, or observed throughout the period 

 
 
 
 
 
Special Drug Use Surveillance Protocol 
Lotriga Granular Capsules Special Drug Use 
Surveillance 
[Long-term use survey] 
 
 
 
 
 
 
 
Version No. 
6th Version 
Date Prepared 
June 2, 2017 
Study Sponsor 
Takeda Pharmaceutical Company Limited 
 

 
Table of Contents 
1.0 
Background .................................................................................................................................................... 1 
2.0 
Objective ........................................................................................................................................................ 1 
3.0 
Target Sample Size and Rationale for Sample Size Setting ........................................................................... 1 
3.1 
Target Sample Size ..................................................................................................................................... 1 
3.2 
Rationale for Sample Size Setting .............................................................................................................. 1 
4.0 
Study Population ............................................................................................................................................ 1 
5.0 
Dosage and Administration for Study Population .......................................................................................... 2 
6.0 
Number of Study Sites by Clinical Department ............................................................................................. 2 
7.0 
Study Method ................................................................................................................................................. 2 
7.1 
Observation Period ..................................................................................................................................... 2 
7.2 
Request and Contract to Study Sites .......................................................................................................... 2 
7.3 
Patient Enrollment Method ........................................................................................................................ 2 
7.4 
Data Entry and Electronic Signature to Electronic Case Report Form (eCRF) .......................................... 2 
7.5 
Action Taken at Onset of Serious Adverse Event ....................................................................................... 3 
8.0 
Expected Duration of Study ........................................................................................................................... 3 
9.0 
Survey Items ................................................................................................................................................... 3 
9.1 
Patient Enrollment ...................................................................................................................................... 3 
9.2 
Patient Demographics................................................................................................................................. 3 
9.3 
Treatment Information ................................................................................................................................ 3 
9.4 
Testing/Observation Items .......................................................................................................................... 4 
9.5 
Other Observation Items ............................................................................................................................ 4 
9.6 
Adverse Events (AEs) ................................................................................................................................ 4 
10.0 
Analysis Items and Method ............................................................................................................................ 7 
10.1 
Patient Disposition Items............................................................................................................................ 7 
10.2 
Patient Demographics................................................................................................................................. 7 
10.3 
Treatment Details ....................................................................................................................................... 7 
10.4 
Safety Items ................................................................................................................................................ 7 
 
Onset Status of Adverse Events .......................................................................................................... 7 
10.4.1
 
Factors Likely to Affect Safety ........................................................................................................... 7 
10.4.2
10.5 
Efficacy Items............................................................................................................................................. 8 
 
Changes in Lipid Parameters: TG, TC, LDL-C, HDL-C, Non-HDL-C, etc. ...................................... 8 
10.5.1
 
Factors Likely to Affect Efficacy ....................................................................................................... 8 
10.5.2
11.0 
Organizational Structure for Conducting the Study ....................................................................................... 8 
12.0 
Service Contractor’s Name and Address and Scope of Contract Work .......................................................... 8 
13.0 
Other Necessary Items ................................................................................................................................... 9 
13.1 
Protocol Revision ....................................................................................................................................... 9 
13.2 
Action Taken in Case of Problem or Question ........................................................................................... 9 
 
Appendix Study Schedule.......................................................................................................................................10 

 
1 
1.0 
Background 
Lotriga Granular Capsules (the “Drug”) is an oral capsule formulation containing the active 
ingredient omega-3 fatty acid ethyl esters (principally EPA-E and DHA-E). The Drug differs 
from general marine oil products, such as supplements, in containing a high concentration of 
omega-3 fatty acid ethyl esters. Since first approved in Norway in September 1994, the Drug 
has been in extensive use overseas, sold in more than 60 countries. In the clinical study of the 
Drug conducted in Japan in patients with hypertriglyceridemia, adverse drug reactions (ADRs) 
including ‘laboratory test abnormal’ were observed in 91 (9.6%) of the 948 patients 
administered at 2 g or 4 g of omega-3 fatty acid ethyl esters, and the major ADR was Diarrhea 
(2.5%). 
Despite the proven track record of extensive use overseas and the fact that the safety of 
long-term use was already evaluated during the clinical study, it is important to evaluate the 
safety of long-term use of the Drug in the general patient population in Japan. 
Special drug use surveillance (hereinafter the "Study") has been therefore designed to evaluate 
the safety and efficacy of long-term use of the Drug in patients with hyperlipidemia in a 
routine clinical setting. 
 
2.0 
Objective 
To evaluate the safety and efficacy of long-term use of the Drug in patients with 
hyperlipidemia in a routine clinical setting. 
 
3.0 
Target Sample Size and Rationale for Sample Size Setting 
3.1 
Target Sample Size 
3,000 patients 
 
3.2 
Rationale for Sample Size Setting 
Bleeding-related events are set as a priority survey item for the Drug. As postmarketing 
surveillance of EPA products in antihyperlipidemic therapy has reported that the incidence of 
bleeding-related ADRs was 0.4% and that the percentage of anticoagulant and antiplatelet 
concomitant use was about 10%, the Study sets a target of 3,000 patients so that anticoagulant 
and antiplatelet concomitant use can be assessed to some degree, in addition to 
bleeding-related ADRs. 
Note that this rationale for the sample size is not based on statistical evidence. 
 
4.0 
Study Population 
Patients with hyperlipidemia will be eligible for this study; however, those who meet the 
following exclusion criteria were excluded from the study. 
Exclusion criteria: 
(1) Patients with hemorrhage (e.g., hemophilia, capillary fragility, gastrointestinal ulcer, 
urinary tract hemorrhage, hemoptysis, or vitreous hemorrhage) 
(2) Patients with a history of hypersensitivity to ingredients in the Drug 

 
2 
 
5.0 
Dosage and Administration for Study Population 
The usual adult dosage is 2 g of omega-3 fatty acid ethyl esters administered orally once daily 
after meals. However, the dosage can be increased up to twice daily (at a dose of 2 g) 
depending on the patient's triglyceride level. 
 
6.0 
Number of Study Sites by Clinical Department 
 About 200 sites (clinical departments not specified) 
 
7.0 
Study Method 
7.1 
Observation Period 
12 months 
 
7.2 
Request and Contract to Study Sites 
The Study will be requested and contracted using a web-based electronic data collection 
system 
. Takeda Pharmaceutical’s staffs (hereinafter "Takeda staffs") will 
adequately explain to investigators about the purpose and description of the Study, 
’s operating procedure, electronic signature, and user ID and password handling for 
request for the Study, based on the Letter of Request for Cooperation in Special Drug Use 
Surveillance, the Implementation Guidance, data input screen images, and the abbreviated 
 Operating Manual. Takeda MRs will then conclude a contract in writing with 
study sites to perform the Study within the specified surveillance period. 
 
7.3 
Patient Enrollment Method 
Patients will be "centrally" enrolled using 
. The investigator will enter into 
 patient enrollment information (see Section 9.1) of patients for whom the Drug has 
been prescribed since the start date of the period of contract with the study site, within 14 days 
after the prescription date of the Drug (the prescription date is defined as "Day 0"; the day 
following the prescription date is defined as "Day 1"). 
 
7.4 
Data Entry and Electronic Signature to Electronic Case Report Form (eCRF) 
The investigator will enter patient data including demographics and treatment into 
 
and electronically sign the eCRF in 12 months after the start of treatment with the Drug 
(baseline). 
If a patient discontinues the treatment with the Drug for some reason during the observation 
period, the investigator will be expected to enter their information including demographics and 
treatment into 
 and electronically sign the eCRF within one month after the 
completion of necessary observations. However, if the patient discontinues the treatment with 
the Drug due to the occurrence of an adverse event (AE), the investigator should continue to 
observe them after discontinuation, as long as possible until the AE is resolved or resolving. 
The investigator should then enter the result of the observation into 
 and 
CCI
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3 
electronically sign the eCRF. 
After review of the information, Takeda Pharmaceutical may request for re-survey, if deemed 
necessary, via 
. The investigator will, upon checking, perform the details of the 
requested re-survey and enter the result of the re-survey into 
 and electronically 
sign the eCRF. 
 
7.5 
Action Taken at Onset of Serious Adverse Event 
The investigator will immediately contact the Takeda staff if a serious AE occurs during the 
observation period. The investigator will also separately provide detailed information thereof 
upon request, if any, from the Takeda staff. 
 
8.0 
Expected Duration of Study 
Surveillance period: May 2013 to May 31, 2017 
Patient enrollment period: May 2013 to May 31, 2015* 
 
*Enrollment may be closed before the end of the enrollment period if the total number of 
patients enrolled in the Study reaches the target sample size. 
 
9.0 
Survey Items 
The investigator will enter the information of the following items into 
. The 
schedule for the Study is provided in the Appendix. 
9.1 
Patient Enrollment 
1) Survey items 
Prescription date of the Date, patient ID number, patient initials, sex, birth date, 
determination with inclusion criteria, and determination with exclusion criteria 
2) Survey timing 
The time of patient enrollment 
 
9.2 
Patient Demographics 
1) Survey items 
Height, weight, time of hyperlipidemia diagnosis, treatment category, menopausal status 
(only for female), complications (presence or absence and details), medical history 
(presence or absence and details), hypersensitivity disposition (presence or absence and 
details), drinking history, smoking history, presence or absence of surgery within one 
month before baseline, and presence or absence of healthier lifestyle education (diet and 
exercise therapies) 
2) Survey time 
Baseline 
 
9.3 
Treatment Information 
1) Survey items 
CCI
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4 
Administration of the Drug (daily dose, treatment duration, and status of completion of 
treatment with the Drug), administration of antihyperlipidemic drugs other than the Drug* 
(presence or absence, drug name, daily dose, and treatment duration), and administration of 
concomitant medications (other than antihyperlipidemic drugs) (presence or absence, drug 
name, and purpose of administration) 
*: Including antihyperlipidemic drugs with which treatment is discontinued within two 
months before baseline. 
2) Survey timing 
Period from baseline to Month 12 (or discontinuation of treatment) 
 
9.4 
Testing/Observation Items 
1) Survey items 
Triglyceride (TG), total cholesterol (TC), LDL cholesterol* (LDL-C), HDL cholesterol 
(HDL-C), VLDL cholesterol (VLDL-C), Apo-AI, Apo-B, Apo-CIII, lipoprotein (a), 
remnant lipoprotein cholesterol (RLP-C), fasting blood glucose (FBG), HbA1c 
*: When tested by direct measurement 
2) Survey timing 
Baseline, Month 3, Month 6, Month 9, and Month 12 (or discontinuation of treatment) test 
timepoints 
 
9.5 
Other Observation Items 
1) Survey items 
Pregnancy status 
If the patient is found to be pregnant during the observation period, the investigator 
will report the Takeda staff. The investigator will, upon request from the Takeda staff, 
use a sheet for pregnant women to provide detailed information (including information 
available up to childbirth, including premature birth or other pregnancy results, if 
possible). 
2) Survey timing 
Period from baseline to Month 12 (or discontinuation of treatment) 
 
9.6 
Adverse Events (AEs) 
1) Survey items 
Presence or absence of AE (see Table 1), AE name, date of onset, seriousness and reason 
for seriousness (see Table 2), action taken to the Drug, date of determination of outcome, 
outcome, and causal relationship to the Drug* (see Table 3) 
If the outcome is not resolved or unknown and the casual relationship is determined as 
unevaluable, follow-up survey should be conducted to some extent possible. 
*If causal relationship to the Drug is determined as not related, reasons that may constitute 
the rationale for determination should be collected if it is unevaluable. 
2) Survey timing 

 
5 
Period from baseline to Month 12 (or discontinuation of treatment) 
3) Priority survey item 
Bleeding-related events occurring after baseline are set as a priority survey item. If 
any bleeding-related event is reported as an AE, laboratory test values related to bleeding 
should be separately collected. 
 
 
 

 
6 
Table 1 Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a medicinal 
product and which does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
The following should be also handled as an AE: 
• A symptoms or other problem occurring in an infant breastfed from a mother taking the medicinal 
product 
• A symptom or other problem occurring in a child administered the medicinal product 
• A symptom or other problem occurring in a patient administered or taking more than the approved 
dose of the medicinal product 
 
Table 2 Seriousness Criteria 
An event is classified as serious if: 
1. resulting in death (death), 
2. being life-threatening (at risk of death), 
3. requiring inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization), 
4. resulting in persistent or significant disability/incapacity (disorder), 
5. being a congenital anomaly/birth defect (birth defect), or 
6. being any other medically serious condition that does not fall under any of 1 to 5 above. Note that 
all those listed in the Takeda Medically Significant AE List are included in this criterion. 
(Examples include bronchospasm, which requires short-term intensive care in emergency room 
settings.) 
 
Takeda Medically Significant AE List 
• Acute respiratory failure/acute respiratory distress 
syndrome (ARDS) 
• Anaphylactic shock 
• Torsade de pointes/ventricular 
fibrillation/ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizure (including spasm and 
epilepsy) 
• Pulmonary fibrosis (including interstitial lung 
disease) 
• Agranulocytosis 
• Neuroleptic malignant syndrome/malignant 
hyperthermia 
• Aplastic anaemia 
• Spontaneous abortion/stillbirth and foetal death 
• Toxic epidermal necrolysis/muco-cutaneo-ocular 
syndrome (Stevens-Johnson syndrome) 
• Confirmed or suspected transmission of infection 
by a medicinal product 
• Hepatic necrosis 
• Confirmed or suspected endotoxin shock 
• Acute hepatic failure 
 
 

 
7 
Table 3 Criteria for Casual Relationship between Adverse Event and the Drug 
Determination 
Criteria 
Related 
There is temporal correlation between the Drug and the event 
(including results from discontinuation of treatment). 
Or the event is an AE considered likely to have been caused by the 
Drug although it is presumed to have been contributed by other 
factors, such as primary disease, complications, concomitant 
medications, or combined treatments. 
Not related 
There is no temporal correlation between the Drug and the event. Or 
the event is adequately considered to have been contributed by other 
factors, such as primary disease, complications, concomitant 
medications, or combined treatments. 
Unevaluable 
There is lack of information necessary for evaluation of the event, 
including temporal correlation (including results from discontinuation 
of treatment), primary disease, complications, concomitant 
medications, and combined treatments. 
 
10.0 
Analysis Items and Method 
10.1 Patient Disposition Items 
Compile information including the number of enrolled patients, number of patients with 
eCRFs collected, numbers of safety- and efficacy-evaluable patients, and the number of 
patients excluded from analysis and reasons for exclusion. 
 
10.2 Patient Demographics 
Compile patient demographic information including sex, age, hypersensitivity disposition, and 
complications. 
 
10.3 Treatment Details 
Compile information on administration of the Drug and of concomitant medications. 
 
10.4 Safety Items 
Compile the following regarding the safety-evaluable population. AEs, coded using MedDRA, 
will be summarized by preferred term (PT) and by system organ class (SOC). 
 Onset Status of Adverse Events 
10.4.1
Compile the incidence of AEs occurring during the observation period, in terms of, e.g., 
causal relationship with the Drug, type, seriousness. Note that bleeding-related events 
should be separately compiled because such events are set as a priority survey item. 
 
 Factors Likely to Affect Safety 
10.4.2
Compile the incidence of ADRs occurring during the observation period, by stratification 
variables: patient baseline characteristics (sex, age, presence or absence of renal 

 
8 
dysfunction, presence or absence of hepatic dysfunction, etc.) and treatment regimen 
(administration of the Drug, administration of concomitant medications such as 
anticoagulant drugs, antiplatelet drugs). 
 
10.5 Efficacy Items 
Compile the following regarding the efficacy-evaluable population. 
 Changes in Lipid Parameters: TG, TC, LDL-C, HDL-C, Non-HDL-C, etc. 
10.5.1
Tabulate observed values and changes (observed value at each observational timepoint after 
baseline minus observed value at baseline) at each observational timepoint for TG, TC, 
LDL-C (by converted value calculated by direct measurement, Friedewald formula*), 
HDL-C, Non-HDL-C (converted value**), VLDL cholesterol, Apo-AI, Apo-B, Apo-CIII, 
lipoprotein (a), and RLP-C. 
*: LDL-C = TC-HDL-C - TG / 5 
**: Non-HDL-C = TC-HDL-C 
Note that LDL-C, Non-HDL-C, TC/LDL-C ratio, LDL-C/HDL-C ratio, and LDL-C/Apo-B 
ratio should be calculated from test results. 
 
 Factors Likely to Affect Efficacy 
10.5.2
Compile TG values by stratification variables: patient baseline characteristics (sex and age) 
and treatment regimen (administration of the Drug, administration of concomitant 
medications, etc.). 
 
11.0 
Organizational Structure for Conducting the Study 
Study Chair 
Takeda Pharmaceutical Co., Ltd. 
Post Marketing Surveillance Manager 
 
12.0 
Service Contractor’s Name and Address and Scope of Contract Work 
(1) 
Scope of work: Data management 
 
(2) 
Scope of work: Data management and statistical analysis 
 
(3) 
Scope of work: Storage of relevant records, PDF preparation of adverse events and other 
relevant information, and support services related to provision of information 
 
PPD
PPD
PPD

9 
(4) 
Scope of work: Formulation of 
and its technical operations 
  
13.0 
Other Necessary Items 
13.1 Protocol Revision 
During the surveillance period, keep track of, e.g., the progress of the Study, the onset of 
unexpected ADRs or serious ADRs based on the precautions, presence or absence of increased 
incidence of specified ADRs, the appropriateness of survey items. If needed, review and revise 
this protocol. If partial change approval is obtained for dosage and administration or 
indications during the surveillance period, examine whether to revise this protocol if necessary 
and revise it if necessary. 
 
13.2 Action Taken in Case of Problem or Question 
If any problem is found in the safety or efficacy of the Drug, carefully review the data and 
examine what needs to be done. 
PPD
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10 
Appendix Study Schedule 
Survey and Data Entry Timing 
 
Survey Item 
Observation Period 
Patient 
enrollme
nt
Baseline 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
Discon- 
tinuation 
Patient Enrollment 
Prescription date of the Drug 
○ 
 
 
 
 
 
 
Patient ID number 
○ 
Patient initials 
○ 
Sex 
○ 
Birth date 
○ 
Inclusion criteria/exclusion criteria 
○ 
Patient demographics 
Height, Weight 
○ 
 
 
 
Time of hyperlipidemia diagnosis 
○ 
 
 
 
Treatment category 
○ 
 
 
 
Menopausal status (only for female) 
○ 
 
 
 
Complications 
○  
 
 
 
Medical history 
○ 
 
 
 
Hypersensitivity disposition 
 
○ 
 
 
 
Drinking history, smoking history 
 
○ 
 
 
 
Presence or absence of surgery before 
baseline 
 
○  
 
 
 
Presence or absence of healthier 
lifestyle education (diet and exercise 
therapies) 
 
○ 
 
 
 
 
 
Treatment 
Information 
Administration of the Drug 
○ 
○ 
Administration of other 
antihyperlipidemic drugs 
○ 
○ 
Administration of concomitant 
medications (other than 
antihyperlipidemic drug) 
 
○ 
○ 
Testing /Observation Items 
TG 
○ 
○ 
○ 
○ 
○ 
○ 
TC 
○ 
○ 
○ 
○ 
○ 
○ 
LDL-C (direct measurement) 
○ 
○ 
○ 
○ 
○ 
○ 
HDL-C 
○  
○  
○  
○  
○  
○  
VLDL-C 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-AI 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-B 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-CIII 
○ 
○ 
○ 
○ 
○ 
○ 
Lipoprotein (a) 
○ 
○ 
○ 
○ 
○ 
○ 
RLP-C 
○  
○  
○  
○  
○  
○  
FBG 
○  
○  
○  
○  
○  
○  
HbA1c 
○  
○  
○  
○  
○  
○  
Pregnancy status (only for female) 
○ 
○ 
AE 
○ 
○ 
○: Surveyed, tested, or observed     ○:     Surveyed, tested, or observed throughout the period 

 
 
 
 
 
Special Drug Use Surveillance Protocol 
Lotriga Granular Capsules Special Drug Use 
Surveillance 
[Long-term use survey] 
 
 
 
 
 
 
 
Version No. 
5th Version 
Date Prepared 
March 2, 2017 
Study Sponsor 
Takeda Pharmaceutical Company Limited 
 

Table of Contents 
1.0 
Background .................................................................................................................................................... 1 
2.0 
Objective ........................................................................................................................................................ 1 
3.0 
Target Sample Size and Rationale for Sample Size Setting ........................................................................... 1 
3.1 
Target Sample Size ..................................................................................................................................... 1 
3.2 
Rationale for Sample Size Setting .............................................................................................................. 1 
4.0 
Study Population ............................................................................................................................................ 1 
5.0 
Dosage and Administration for Study Population .......................................................................................... 2 
6.0 
Number of Study Sites by Clinical Department ............................................................................................. 2 
7.0 
Study Method ................................................................................................................................................. 2 
7.1 
Observation Period ..................................................................................................................................... 2 
7.2 
Request and Contract to Study Sites .......................................................................................................... 2 
7.3 
Patient Enrollment Method ........................................................................................................................ 2 
7.4 
Data Entry and Electronic Signature to Electronic Case Report Form (eCRF) .......................................... 2 
7.5 
Action Taken at Onset of Serious Adverse Event ....................................................................................... 3 
8.0 
Expected Duration of Study ........................................................................................................................... 3 
9.0 
Survey Items ................................................................................................................................................... 3 
9.1 
Patient Enrollment ...................................................................................................................................... 3 
9.2 
Patient Demographics................................................................................................................................. 3 
9.3 
Treatment Information ................................................................................................................................ 3 
9.4 
Testing/Observation Items .......................................................................................................................... 4 
9.5 
Other Observation Items ............................................................................................................................ 4 
9.6 
Adverse Events (AEs) ................................................................................................................................ 4 
10.0 
Analysis Items and Method ............................................................................................................................ 7 
10.1 
Patient Disposition Items............................................................................................................................ 7 
10.2 
Patient Demographics................................................................................................................................. 7 
10.3 
Treatment Details ....................................................................................................................................... 7 
10.4 
Safety Items ................................................................................................................................................ 7 
 
Onset Status of Adverse Events .......................................................................................................... 7 
10.4.1
 
Factors Likely to Affect Safety ........................................................................................................... 7 
10.4.2
10.5 
Efficacy Items............................................................................................................................................. 8 
 
Changes in Lipid Parameters: TG, TC, LDL-C, HDL-C, Non-HDL-C, etc. ...................................... 8 
10.5.1
 
Factors Likely to Affect Efficacy ....................................................................................................... 8 
10.5.2
11.0 
Organizational Structure for Conducting the Study ....................................................................................... 8 
12.0 
Service Contractor’s Name and Address and Scope of Contract Work .......................................................... 8 
13.0 
Other Necessary Items ................................................................................................................................... 8 
13.1 
Protocol Revision ....................................................................................................................................... 8 
13.2 
Action Taken in Case of Problem or Question ........................................................................................... 9 
Appendix Study Schedule.......................................................................................................................................10 

 
1 
1.0 
Background 
Lotriga Granular Capsules (the “Drug”) is an oral capsule formulation containing the active 
ingredient omega-3 fatty acid ethyl esters (principally EPA-E and DHA-E). The Drug differs 
from general marine oil products, such as supplements, in containing a high concentration of 
omega-3 fatty acid ethyl esters. Since first approved in Norway in September 1994, the Drug 
has been in extensive use overseas, sold in more than 60 countries. In the clinical study of the 
Drug conducted in Japan in patients with hypertriglyceridemia, adverse drug reactions (ADRs) 
including ‘laboratory test abnormal’ were observed in 91 (9.6%) of the 948 patients 
administered at 2 g or 4 g of omega-3 fatty acid ethyl esters, and the major ADR was Diarrhea 
(2.5%). 
Despite the proven track record of extensive use overseas and the fact that the safety of 
long-term use was already evaluated during the clinical study, it is important to evaluate the 
safety of long-term use of the Drug in the general patient population in Japan. 
Special drug use surveillance (hereinafter the "Study") has been therefore designed to evaluate 
the safety and efficacy of long-term use of the Drug in patients with hyperlipidemia in a 
routine clinical setting. 
 
2.0 
Objective 
To evaluate the safety and efficacy of long-term use of the Drug in patients with 
hyperlipidemia in a routine clinical setting. 
 
3.0 
Target Sample Size and Rationale for Sample Size Setting 
3.1 
Target Sample Size 
3,000 patients 
 
3.2 
Rationale for Sample Size Setting 
Bleeding-related events are set as a priority survey item for the Drug. As postmarketing 
surveillance of EPA products in antihyperlipidemic therapy has reported that the incidence of 
bleeding-related ADRs was 0.4% and that the percentage of anticoagulant and antiplatelet 
concomitant use was about 10%, the Study sets a target of 3,000 patients so that anticoagulant 
and antiplatelet concomitant use can be assessed to some degree, in addition to 
bleeding-related ADRs. 
Note that this rationale for the sample size is not based on statistical evidence. 
 
4.0 
Study Population 
Patients with hyperlipidemia will be eligible for this study; however, those who meet the 
following exclusion criteria were excluded from the study. 
Exclusion criteria: 
(1) Patients with hemorrhage (e.g., hemophilia, capillary fragility, gastrointestinal ulcer, 
urinary tract hemorrhage, hemoptysis, or vitreous hemorrhage) 
(2) Patients with a history of hypersensitivity to ingredients in the Drug 

 
2 
 
5.0 
Dosage and Administration for Study Population 
The usual adult dosage is 2 g of omega-3 fatty acid ethyl esters administered orally once daily 
after meals. However, the dosage can be increased up to twice daily (at a dose of 2 g) 
depending on the patient's triglyceride level. 
 
6.0 
Number of Study Sites by Clinical Department 
 About 200 sites (clinical departments not specified) 
 
7.0 
Study Method 
7.1 
Observation Period 
12 months 
 
7.2 
Request and Contract to Study Sites 
The Study will be requested and contracted using a web-based electronic data collection 
system (
). Takeda Pharmaceutical’s staffs (hereinafter "Takeda staffs") will 
adequately explain to investigators about the purpose and description of the Study, 
’s operating procedure, electronic signature, and user ID and password handling for 
request for the Study, based on the Letter of Request for Cooperation in Special Drug Use 
Surveillance, the Implementation Guidance, data input screen images, and the abbreviated 
 Operating Manual. Takeda MRs will then conclude a contract in writing with 
study sites to perform the Study within the specified surveillance period. 
 
7.3 
Patient Enrollment Method 
Patients will be "centrally" enrolled using 
. The investigator will enter into 
 patient enrollment information (see Section 9.1) of patients for whom the Drug has 
been prescribed since the start date of the period of contract with the study site, within 14 days 
after the prescription date of the Drug (the prescription date is defined as "Day 0"; the day 
following the prescription date is defined as "Day 1"). 
 
7.4 
Data Entry and Electronic Signature to Electronic Case Report Form (eCRF) 
The investigator will enter patient data including demographics and treatment into 
 
and electronically sign the eCRF in 12 months after the start of treatment with the Drug 
(baseline). 
If a patient discontinues the treatment with the Drug for some reason during the observation 
period, the investigator will be expected to enter their information including demographics and 
treatment into 
 and electronically sign the eCRF within one month after the 
completion of necessary observations. However, if the patient discontinues the treatment with 
the Drug due to the occurrence of an adverse event (AE), the investigator should continue to 
observe them after discontinuation, as long as possible until the AE is resolved or resolving. 
The investigator should then enter the result of the observation into 
 and 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

 
3 
electronically sign the eCRF. 
After review of the information, Takeda Pharmaceutical may request for re-survey, if deemed 
necessary, via 
. The investigator will, upon checking, perform the details of the 
requested re-survey and enter the result of the re-survey into 
 and electronically 
sign the eCRF. 
 
7.5 
Action Taken at Onset of Serious Adverse Event 
The investigator will immediately contact the Takeda staff if a serious AE occurs during the 
observation period. The investigator will also separately provide detailed information thereof 
upon request, if any, from the Takeda staff. 
 
8.0 
Expected Duration of Study 
Surveillance period: May 2013 to May 31, 2017 
Patient enrollment period: May 2013 to May 31, 2015* 
 
*Enrollment may be closed before the end of the enrollment period if the total number of 
patients enrolled in the Study reaches the target sample size. 
 
9.0 
Survey Items 
The investigator will enter the information of the following items into 
. The 
schedule for the Study is provided in the Appendix. 
9.1 
Patient Enrollment 
1) Survey items 
Prescription date of the Date, patient ID number, patient initials, sex, birth date, 
determination with inclusion criteria, and determination with exclusion criteria 
2) Survey timing 
The time of patient enrollment 
 
9.2 
Patient Demographics 
1) Survey items 
Height, weight, time of hyperlipidemia diagnosis, treatment category, menopausal status 
(only for female), complications (presence or absence and details), medical history 
(presence or absence and details), hypersensitivity disposition (presence or absence and 
details), drinking history, smoking history, presence or absence of surgery within one 
month before baseline, and presence or absence of healthier lifestyle education (diet and 
exercise therapies) 
2) Survey time 
Baseline 
 
9.3 
Treatment Information 
1) Survey items 
CCI
CCI
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4 
Administration of the Drug (daily dose, treatment duration, and status of completion of 
treatment with the Drug), administration of antihyperlipidemic drugs other than the Drug* 
(presence or absence, drug name, daily dose, and treatment duration), and administration of 
concomitant medications (other than antihyperlipidemic drugs) (presence or absence, drug 
name, and purpose of administration) 
*: Including antihyperlipidemic drugs with which treatment is discontinued within two 
months before baseline. 
2) Survey timing 
Period from baseline to Month 12 (or discontinuation of treatment) 
 
9.4 
Testing/Observation Items 
1) Survey items 
Triglyceride (TG), total cholesterol (TC), LDL cholesterol* (LDL-C), HDL cholesterol 
(HDL-C), VLDL cholesterol (VLDL-C), Apo-AI, Apo-B, Apo-CIII, lipoprotein (a), 
remnant lipoprotein cholesterol (RLP-C), fasting blood glucose (FBG), HbA1c 
*: When tested by direct measurement 
2) Survey timing 
Baseline, Month 3, Month 6, Month 9, and Month 12 (or discontinuation of treatment) test 
timepoints 
 
9.5 
Other Observation Items 
1) Survey items 
Pregnancy status 
If the patient is found to be pregnant during the observation period, the investigator 
will report the Takeda staff. The investigator will, upon request from the Takeda staff, 
use a sheet for pregnant women to provide detailed information (including information 
available up to childbirth, including premature birth or other pregnancy results, if 
possible). 
2) Survey timing 
Period from baseline to Month 12 (or discontinuation of treatment) 
 
9.6 
Adverse Events (AEs) 
1) Survey items 
Presence or absence of AE (see Table 1), AE name, date of onset, seriousness and reason 
for seriousness (see Table 2), action taken to the Drug, date of determination of outcome, 
outcome, and causal relationship to the Drug* (see Table 3) 
If the outcome is not resolved or unknown and the casual relationship is determined as 
unevaluable, follow-up survey should be conducted to some extent possible. 
*If causal relationship to the Drug is determined as not related, reasons that may constitute 
the rationale for determination should be collected if it is unevaluable. 
2) Survey timing 

 
5 
Period from baseline to Month 12 (or discontinuation of treatment) 
3) Priority survey item 
Bleeding-related events occurring after baseline are set as a priority survey item. If 
any bleeding-related event is reported as an AE, laboratory test values related to bleeding 
should be separately collected. 
 
 
 

 
6 
Table 1 Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a medicinal 
product and which does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
The following should be also handled as an AE: 
• A symptoms or other problem occurring in an infant breastfed from a mother taking the medicinal 
product 
• A symptom or other problem occurring in a child administered the medicinal product 
• A symptom or other problem occurring in a patient administered or taking more than the approved 
dose of the medicinal product 
 
Table 2 Seriousness Criteria 
An event is classified as serious if: 
1. resulting in death (death), 
2. being life-threatening (at risk of death), 
3. requiring inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization), 
4. resulting in persistent or significant disability/incapacity (disorder), 
5. being a congenital anomaly/birth defect (birth defect), or 
6. being any other medically serious condition that does not fall under any of 1 to 5 above. Note that 
all those listed in the Takeda Medically Significant AE List are included in this criterion. 
(Examples include bronchospasm, which requires short-term intensive care in emergency room 
settings.) 
 
Takeda Medically Significant AE List 
• Acute respiratory failure/acute respiratory distress 
syndrome (ARDS) 
• Anaphylactic shock 
• Torsade de pointes/ventricular 
fibrillation/ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizure (including spasm and 
epilepsy) 
• Pulmonary fibrosis (including interstitial lung 
disease) 
• Agranulocytosis 
• Neuroleptic malignant syndrome/malignant 
hyperthermia 
• Aplastic anaemia 
• Spontaneous abortion/stillbirth and foetal death 
• Toxic epidermal necrolysis/muco-cutaneo-ocular 
syndrome (Stevens-Johnson syndrome) 
• Confirmed or suspected transmission of infection 
by a medicinal product 
• Hepatic necrosis 
• Confirmed or suspected endotoxin shock 
• Acute hepatic failure 
 
 

 
7 
Table 3 Criteria for Casual Relationship between Adverse Event and the Drug 
Determination 
Criteria 
Related 
There is temporal correlation between the Drug and the event 
(including results from discontinuation of treatment). 
Or the event is an AE considered likely to have been caused by the 
Drug although it is presumed to have been contributed by other 
factors, such as primary disease, complications, concomitant 
medications, or combined treatments. 
Not related 
There is no temporal correlation between the Drug and the event. Or 
the event is adequately considered to have been contributed by other 
factors, such as primary disease, complications, concomitant 
medications, or combined treatments. 
Unevaluable 
There is lack of information necessary for evaluation of the event, 
including temporal correlation (including results from discontinuation 
of treatment), primary disease, complications, concomitant 
medications, and combined treatments. 
 
10.0 
Analysis Items and Method 
10.1 Patient Disposition Items 
Compile information including the number of enrolled patients, number of patients with 
eCRFs collected, numbers of safety- and efficacy-evaluable patients, and the number of 
patients excluded from analysis and reasons for exclusion. 
 
10.2 Patient Demographics 
Compile patient demographic information including sex, age, hypersensitivity disposition, and 
complications. 
 
10.3 Treatment Details 
Compile information on administration of the Drug and of concomitant medications. 
 
10.4 Safety Items 
Compile the following regarding the safety-evaluable population. AEs, coded using MedDRA, 
will be summarized by preferred term (PT) and by system organ class (SOC). 
 Onset Status of Adverse Events 
10.4.1
Compile the incidence of AEs occurring during the observation period, in terms of, e.g., 
causal relationship with the Drug, type, seriousness. Note that bleeding-related events 
should be separately compiled because such events are set as a priority survey item. 
 
 Factors Likely to Affect Safety 
10.4.2
Compile the incidence of ADRs occurring during the observation period, by stratification 
variables: patient baseline characteristics (sex, age, presence or absence of renal 

 
8 
dysfunction, presence or absence of hepatic dysfunction, etc.) and treatment regimen 
(administration of the Drug, administration of concomitant medications such as 
anticoagulant drugs, antiplatelet drugs). 
 
10.5 Efficacy Items 
Compile the following regarding the efficacy-evaluable population. 
 Changes in Lipid Parameters: TG, TC, LDL-C, HDL-C, Non-HDL-C, etc. 
10.5.1
Tabulate observed values and changes (observed value at each observational timepoint after 
baseline minus observed value at baseline) at each observational timepoint for TG, TC, 
LDL-C (by converted value calculated by direct measurement, Friedewald formula*), 
HDL-C, Non-HDL-C (converted value**), VLDL cholesterol, Apo-AI, Apo-B, Apo-CIII, 
lipoprotein (a), and RLP-C. 
*: LDL-C = TC-HDL-C - TG / 5 
**: Non-HDL-C = TC-HDL-C 
Note that LDL-C, Non-HDL-C, TC/LDL-C ratio, LDL-C/HDL-C ratio, and LDL-C/Apo-B 
ratio should be calculated from test results. 
 
 Factors Likely to Affect Efficacy 
10.5.2
Compile TG values by stratification variables: patient baseline characteristics (sex and age) 
and treatment regimen (administration of the Drug, administration of concomitant 
medications, etc.). 
 
11.0 
Organizational Structure for Conducting the Study 
Study Chair 
Takeda Pharmaceutical Co., Ltd. 
Post Marketing Surveillance Manager 
 
12.0 
Service Contractor’s Name and Address and Scope of Contract Work 
Contractor: 
 
 
Scope of contract work: Data management and statistical analysis 
 
Contractor: 
 
 
Scope of contract work: Storage of relevant records 
  
13.0 
Other Necessary Items 
13.1 Protocol Revision 
During the surveillance period, keep track of, e.g., the progress of the Study, the onset of 
unexpected ADRs or serious ADRs based on the precautions, presence or absence of increased 
incidence of specified ADRs, the appropriateness of survey items. If needed, review and revise 
PPD
PPD

 
9 
this protocol. If partial change approval is obtained for dosage and administration or 
indications during the surveillance period, examine whether to revise this protocol if necessary 
and revise it if necessary. 
 
13.2 Action Taken in Case of Problem or Question 
If any problem is found in the safety or efficacy of the Drug, carefully review the data and 
examine what needs to be done. 

10 
Appendix Study Schedule 
Survey and Data Entry Timing 
Survey Item 
Observation Period 
Patient 
enrollme
nt
Baseline 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
Discon- 
tinuation 
Patient Enrollment 
Prescription date of the Drug 
○ 
Patient ID number 
○ 
Patient initials 
○ 
Sex 
○ 
Birth date 
○ 
Inclusion criteria/exclusion criteria 
○ 
Patient demographics 
Height, Weight 
○ 
Time of hyperlipidemia diagnosis 
○ 
Treatment category 
○ 
Menopausal status (only for female) 
○ 
Complications 
○ 
Medical history 
○ 
Hypersensitivity disposition 
○ 
Drinking history, smoking history 
○ 
Presence or absence of surgery before 
baseline 
○ 
Presence or absence of healthier 
lifestyle education (diet and exercise 
therapies) 
○ 
Treatment 
Information 
Administration of the Drug 
○ 
○ 
Administration of other 
antihyperlipidemic drugs 
○ 
○ 
Administration of concomitant 
medications (other than 
antihyperlipidemic drug) 
○ 
○ 
Testing /Observation Items 
TG 
○ 
○ 
○ 
○ 
○ 
○ 
TC 
○ 
○ 
○ 
○ 
○ 
○ 
LDL-C (direct measurement) 
○ 
○ 
○ 
○ 
○ 
○ 
HDL-C 
○ 
○ 
○ 
○ 
○ 
○ 
VLDL-C 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-AI 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-B 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-CIII 
○ 
○ 
○ 
○ 
○ 
○ 
Lipoprotein (a) 
○ 
○ 
○ 
○ 
○ 
○ 
RLP-C 
○ 
○ 
○ 
○ 
○ 
○ 
FBG 
○ 
○ 
○ 
○ 
○ 
○ 
HbA1c 
○ 
○ 
○ 
○ 
○ 
○ 
Pregnancy status (only for female) 
○ 
○ 
AE 
○ 
○ 
○: Surveyed, tested, or observed
○:
Surveyed, tested, or observed throughout the period 

 
 
 
 
 
Special Drug Use Surveillance Protocol 
Lotriga Granular Capsules Special Drug Use 
Surveillance 
[Long-term use survey] 
 
 
 
 
 
 
 
Version No. 
4th Version 
Date Prepared 
June 14, 2016 
Study Sponsor 
Takeda Pharmaceutical Company Limited 
 

Table of Contents 
1.0 
Background .................................................................................................................................................... 1 
2.0 
Objective ........................................................................................................................................................ 1 
3.0 
Target Sample Size and Rationale for Sample Size Setting ........................................................................... 1 
3.1 
Target Sample Size ..................................................................................................................................... 1 
3.2 
Rationale for Sample Size Setting .............................................................................................................. 1 
4.0 
Study Population ............................................................................................................................................ 1 
5.0 
Dosage and Administration for Study Population .......................................................................................... 2 
6.0 
Number of Study Sites by Clinical Department ............................................................................................. 2 
7.0 
Study Method ................................................................................................................................................. 2 
7.1 
Observation Period ..................................................................................................................................... 2 
7.2 
Request and Contract to Study Sites .......................................................................................................... 2 
7.3 
Patient Enrollment Method ........................................................................................................................ 2 
7.4 
Data Entry and Electronic Signature to Electronic Case Report Form (eCRF) .......................................... 2 
7.5 
Action Taken at Onset of Serious Adverse Event ....................................................................................... 3 
8.0 
Expected Duration of Study ........................................................................................................................... 3 
9.0 
Survey Items ................................................................................................................................................... 3 
9.1 
Patient Enrollment ...................................................................................................................................... 3 
9.2 
Patient Demographics................................................................................................................................. 3 
9.3 
Treatment Information ................................................................................................................................ 3 
9.4 
Testing/Observation Items .......................................................................................................................... 4 
9.5 
Other Observation Items ............................................................................................................................ 4 
9.6 
Adverse Events (AEs) ................................................................................................................................ 4 
10.0 
Analysis Items and Method ............................................................................................................................ 7 
10.1 
Patient Disposition Items............................................................................................................................ 7 
10.2 
Patient Demographics................................................................................................................................. 7 
10.3 
Treatment Details ....................................................................................................................................... 7 
10.4 
Safety Items ................................................................................................................................................ 7 
 
Onset Status of Adverse Events .......................................................................................................... 7 
10.4.1
 
Factors Likely to Affect Safety ........................................................................................................... 7 
10.4.2
10.5 
Efficacy Items............................................................................................................................................. 8 
 
Changes in Lipid Parameters: TG, TC, LDL-C, HDL-C, Non-HDL-C, etc. ...................................... 8 
10.5.1
 
Factors Likely to Affect Efficacy ....................................................................................................... 8 
10.5.2
11.0 
Organizational Structure for Conducting the Study ....................................................................................... 8 
12.0 
Service Contractor’s Name and Address and Scope of Contract Work .......................................................... 8 
13.0 
Other Necessary Items ................................................................................................................................... 8 
13.1 
Protocol Revision ....................................................................................................................................... 8 
13.2 
Action Taken in Case of Problem or Question ........................................................................................... 9 
Appendix Study Schedule.......................................................................................................................................10 

 
1 
1.0 
Background 
Lotriga Granular Capsules (the “Drug”) is an oral capsule formulation containing the active 
ingredient omega-3 fatty acid ethyl esters (principally EPA-E and DHA-E). The Drug differs 
from general marine oil products, such as supplements, in containing a high concentration of 
omega-3 fatty acid ethyl esters. Since first approved in Norway in September 1994, the Drug 
has been in extensive use overseas, sold in more than 60 countries. In the clinical study of the 
Drug conducted in Japan in patients with hypertriglyceridemia, adverse drug reactions (ADRs) 
including ‘laboratory test abnormal’ were observed in 91 (9.6%) of the 948 patients 
administered at 2 g or 4 g of omega-3 fatty acid ethyl esters, and the major ADR was Diarrhea 
(2.5%). 
Despite the proven track record of extensive use overseas and the fact that the safety of 
long-term use was already evaluated during the clinical study, it is important to evaluate the 
safety of long-term use of the Drug in the general patient population in Japan. 
Special drug use surveillance (hereinafter the "Study") has been therefore designed to evaluate 
the safety and efficacy of long-term use of the Drug in patients with hyperlipidemia in a 
routine clinical setting. 
 
2.0 
Objective 
To evaluate the safety and efficacy of long-term use of the Drug in patients with 
hyperlipidemia in a routine clinical setting. 
 
3.0 
Target Sample Size and Rationale for Sample Size Setting 
3.1 
Target Sample Size 
3,000 patients 
 
3.2 
Rationale for Sample Size Setting 
Bleeding-related events are set as a priority survey item for the Drug. As postmarketing 
surveillance of EPA products in antihyperlipidemic therapy has reported that the incidence of 
bleeding-related ADRs was 0.4% and that the percentage of anticoagulant and antiplatelet 
concomitant use was about 10%, the Study sets a target of 3,000 patients so that anticoagulant 
and antiplatelet concomitant use can be assessed to some degree, in addition to 
bleeding-related ADRs. 
Note that this rationale for the sample size is not based on statistical evidence. 
 
4.0 
Study Population 
Patients with hyperlipidemia will be eligible for this study; however, those who meet the 
following exclusion criteria were excluded from the study. 
Exclusion criteria: 
(1) Patients with hemorrhage (e.g., hemophilia, capillary fragility, gastrointestinal ulcer, 
urinary tract hemorrhage, hemoptysis, or vitreous hemorrhage) 
(2) Patients with a history of hypersensitivity to ingredients in the Drug 

 
2 
 
5.0 
Dosage and Administration for Study Population 
The usual adult dosage is 2 g of omega-3 fatty acid ethyl esters administered orally once daily 
after meals. However, the dosage can be increased up to twice daily (at a dose of 2 g) 
depending on the patient's triglyceride level. 
 
6.0 
Number of Study Sites by Clinical Department 
 About 200 sites (clinical departments not specified) 
 
7.0 
Study Method 
7.1 
Observation Period 
12 months 
 
7.2 
Request and Contract to Study Sites 
The Study will be requested and contracted using a web-based electronic data collection 
system (
. Takeda Pharmaceutical’s staffs (hereinafter "Takeda staffs") will 
adequately explain to investigators about the purpose and description of the Study, 
’s operating procedure, electronic signature, and user ID and password handling for 
request for the Study, based on the Letter of Request for Cooperation in Special Drug Use 
Surveillance, the Implementation Guidance, data input screen images, and the abbreviated 
 Operating Manual. Takeda MRs will then conclude a contract in writing with 
study sites to perform the Study within the specified surveillance period. 
 
7.3 
Patient Enrollment Method 
Patients will be "centrally" enrolled using 
. The investigator will enter into 
patient enrollment information (see Section 9.1) of patients for whom the Drug has 
been prescribed since the start date of the period of contract with the study site, within 14 days 
after the prescription date of the Drug (the prescription date is defined as "Day 0"; the day 
following the prescription date is defined as "Day 1"). 
 
7.4 
Data Entry and Electronic Signature to Electronic Case Report Form (eCRF) 
The investigator will enter patient data including demographics and treatment into 
 
and electronically sign the eCRF in 12 months after the start of treatment with the Drug 
(baseline). 
If a patient discontinues the treatment with the Drug for some reason during the observation 
period, the investigator will be expected to enter their information including demographics and 
treatment into 
 and electronically sign the eCRF within one month after the 
completion of necessary observations. However, if the patient discontinues the treatment with 
the Drug due to the occurrence of an adverse event (AE), the investigator should continue to 
observe them after discontinuation, as long as possible until the AE is resolved or resolving. 
The investigator should then enter the result of the observation into 
 and 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

 
3 
electronically sign the eCRF. 
After review of the information, Takeda Pharmaceutical may request for re-survey, if deemed 
necessary, via 
. The investigator will, upon checking, perform the details of the 
requested re-survey and enter the result of the re-survey into 
 and electronically 
sign the eCRF. 
 
7.5 
Action Taken at Onset of Serious Adverse Event 
The investigator will immediately contact the Takeda staff if a serious AE occurs during the 
observation period. The investigator will also separately provide detailed information thereof 
upon request, if any, from the Takeda staff. 
 
8.0 
Expected Duration of Study 
Surveillance period: May 2013 to March 31, 2017 
Patient enrollment period: May 2013 to May 31, 2015* 
 
*Enrollment may be closed before the end of the enrollment period if the total number of 
patients enrolled in the Study reaches the target sample size. 
 
9.0 
Survey Items 
The investigator will enter the information of the following items into 
. The 
schedule for the Study is provided in the Appendix. 
9.1 
Patient Enrollment 
1) Survey items 
Prescription date of the Date, patient ID number, patient initials, sex, birth date, 
determination with inclusion criteria, and determination with exclusion criteria 
2) Survey timing 
The time of patient enrollment 
 
9.2 
Patient Demographics 
1) Survey items 
Height, weight, time of hyperlipidemia diagnosis, treatment category, menopausal status 
(only for female), complications (presence or absence and details), medical history 
(presence or absence and details), hypersensitivity disposition (presence or absence and 
details), drinking history, smoking history, presence or absence of surgery within one 
month before baseline, and presence or absence of healthier lifestyle education (diet and 
exercise therapies) 
2) Survey time 
Baseline 
 
9.3 
Treatment Information 
1) Survey items 
CCI
CCI
CCI

 
4 
Administration of the Drug (daily dose, treatment duration, and status of completion of 
treatment with the Drug), administration of antihyperlipidemic drugs other than the Drug* 
(presence or absence, drug name, daily dose, and treatment duration), and administration of 
concomitant medications (other than antihyperlipidemic drugs) (presence or absence, drug 
name, and purpose of administration) 
*: Including antihyperlipidemic drugs with which treatment is discontinued within two 
months before baseline. 
2) Survey timing 
Period from baseline to Month 12 (or discontinuation of treatment) 
 
9.4 
Testing/Observation Items 
1) Survey items 
Triglyceride (TG), total cholesterol (TC), LDL cholesterol* (LDL-C), HDL cholesterol 
(HDL-C), VLDL cholesterol (VLDL-C), Apo-AI, Apo-B, Apo-CIII, lipoprotein (a), 
remnant lipoprotein cholesterol (RLP-C), fasting blood glucose (FBG), HbA1c 
*: When tested by direct measurement 
2) Survey timing 
Baseline, Month 3, Month 6, Month 9, and Month 12 (or discontinuation of treatment) test 
timepoints 
 
9.5 
Other Observation Items 
1) Survey items 
Pregnancy status 
If the patient is found to be pregnant during the observation period, the investigator 
will report the Takeda staff. The investigator will, upon request from the Takeda staff, 
use a sheet for pregnant women to provide detailed information (including information 
available up to childbirth, including premature birth or other pregnancy results, if 
possible). 
2) Survey timing 
Period from baseline to Month 12 (or discontinuation of treatment) 
 
9.6 
Adverse Events (AEs) 
1) Survey items 
Presence or absence of AE (see Table 1), AE name, date of onset, seriousness and reason 
for seriousness (see Table 2), action taken to the Drug, date of determination of outcome, 
outcome, and causal relationship to the Drug* (see Table 3) 
If the outcome is not resolved or unknown and the casual relationship is determined as 
unevaluable, follow-up survey should be conducted to some extent possible. 
*If causal relationship to the Drug is determined as not related, reasons that may constitute 
the rationale for determination should be collected if it is unevaluable. 
2) Survey timing 

 
5 
Period from baseline to Month 12 (or discontinuation of treatment) 
3) Priority survey item 
Bleeding-related events occurring after baseline are set as a priority survey item. If 
any bleeding-related event is reported as an AE, laboratory test values related to bleeding 
should be separately collected. 
 
 
 

 
6 
Table 1 Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a medicinal 
product and which does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
The following should be also handled as an AE: 
• A symptoms or other problem occurring in an infant breastfed from a mother taking the medicinal 
product 
• A symptom or other problem occurring in a child administered the medicinal product 
• A symptom or other problem occurring in a patient administered or taking more than the approved 
dose of the medicinal product 
 
Table 2 Seriousness Criteria 
An event is classified as serious if: 
1. resulting in death (death), 
2. being life-threatening (at risk of death), 
3. requiring inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization), 
4. resulting in persistent or significant disability/incapacity (disorder), 
5. being a congenital anomaly/birth defect (birth defect), or 
6. being any other medically serious condition that does not fall under any of 1 to 5 above. Note that 
all those listed in the Takeda Medically Significant AE List are included in this criterion. 
(Examples include bronchospasm, which requires short-term intensive care in emergency room 
settings.) 
 
Takeda Medically Significant AE List 
• Acute respiratory failure/acute respiratory distress 
syndrome (ARDS) 
• Anaphylactic shock 
• Torsade de pointes/ventricular 
fibrillation/ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizure (including spasm and 
epilepsy) 
• Pulmonary fibrosis (including interstitial lung 
disease) 
• Agranulocytosis 
• Neuroleptic malignant syndrome/malignant 
hyperthermia 
• Aplastic anaemia 
• Spontaneous abortion/stillbirth and foetal death 
• Toxic epidermal necrolysis/muco-cutaneo-ocular 
syndrome (Stevens-Johnson syndrome) 
• Confirmed or suspected transmission of infection 
by a medicinal product 
• Hepatic necrosis 
• Confirmed or suspected endotoxin shock 
• Acute hepatic failure 
 
 

 
7 
Table 3 Criteria for Casual Relationship between Adverse Event and the Drug 
Determination 
Criteria 
Related 
There is temporal correlation between the Drug and the event 
(including results from discontinuation of treatment). 
Or the event is an AE considered likely to have been caused by the 
Drug although it is presumed to have been contributed by other 
factors, such as primary disease, complications, concomitant 
medications, or combined treatments. 
Not related 
There is no temporal correlation between the Drug and the event. Or 
the event is adequately considered to have been contributed by other 
factors, such as primary disease, complications, concomitant 
medications, or combined treatments. 
Unevaluable 
There is lack of information necessary for evaluation of the event, 
including temporal correlation (including results from discontinuation 
of treatment), primary disease, complications, concomitant 
medications, and combined treatments. 
 
10.0 
Analysis Items and Method 
10.1 Patient Disposition Items 
Compile information including the number of enrolled patients, number of patients with 
eCRFs collected, numbers of safety- and efficacy-evaluable patients, and the number of 
patients excluded from analysis and reasons for exclusion. 
 
10.2 Patient Demographics 
Compile patient demographic information including sex, age, hypersensitivity disposition, and 
complications. 
 
10.3 Treatment Details 
Compile information on administration of the Drug and of concomitant medications. 
 
10.4 Safety Items 
Compile the following regarding the safety-evaluable population. AEs, coded using MedDRA, 
will be summarized by preferred term (PT) and by system organ class (SOC). 
 Onset Status of Adverse Events 
10.4.1
Compile the incidence of AEs occurring during the observation period, in terms of, e.g., 
causal relationship with the Drug, type, seriousness. Note that bleeding-related events 
should be separately compiled because such events are set as a priority survey item. 
 
 Factors Likely to Affect Safety 
10.4.2
Compile the incidence of ADRs occurring during the observation period, by stratification 
variables: patient baseline characteristics (sex, age, presence or absence of renal 

 
8 
dysfunction, presence or absence of hepatic dysfunction, etc.) and treatment regimen 
(administration of the Drug, administration of concomitant medications such as 
anticoagulant drugs, antiplatelet drugs). 
 
10.5 Efficacy Items 
Compile the following regarding the efficacy-evaluable population. 
 Changes in Lipid Parameters: TG, TC, LDL-C, HDL-C, Non-HDL-C, etc. 
10.5.1
Tabulate observed values and changes (observed value at each observational timepoint after 
baseline minus observed value at baseline) at each observational timepoint for TG, TC, 
LDL-C (by converted value calculated by direct measurement, Friedewald formula*), 
HDL-C, Non-HDL-C (converted value**), VLDL cholesterol, Apo-AI, Apo-B, Apo-CIII, 
lipoprotein (a), and RLP-C. 
*: LDL-C = TC-HDL-C - TG / 5 
**: Non-HDL-C = TC-HDL-C 
Note that LDL-C, Non-HDL-C, TC/LDL-C ratio, LDL-C/HDL-C ratio, and LDL-C/Apo-B 
ratio should be calculated from test results. 
 
 Factors Likely to Affect Efficacy 
10.5.2
Compile TG values by stratification variables: patient baseline characteristics (sex and age) 
and treatment regimen (administration of the Drug, administration of concomitant 
medications, etc.). 
 
11.0 
Organizational Structure for Conducting the Study 
Study Chair 
Takeda Pharmaceutical Co., Ltd. 
Post Marketing Surveillance Manager 
 
12.0 
Service Contractor’s Name and Address and Scope of Contract Work 
Contractor: 
 
 
Scope of contract work: Data management and statistical analysis 
 
Contractor:
 
 
Scope of contract work: Storage of relevant records 
  
13.0 
Other Necessary Items 
13.1 Protocol Revision 
During the surveillance period, keep track of, e.g., the progress of the Study, the onset of 
unexpected ADRs or serious ADRs based on the precautions, presence or absence of increased 
incidence of specified ADRs, the appropriateness of survey items. If needed, review and revise 
PPD
PPD

 
9 
this protocol. If partial change approval is obtained for dosage and administration or 
indications during the surveillance period, examine whether to revise this protocol if necessary 
and revise it if necessary. 
 
13.2 Action Taken in Case of Problem or Question 
If any problem is found in the safety or efficacy of the Drug, carefully review the data and 
examine what needs to be done. 

10 
Appendix Study Schedule 
Survey and Data Entry Timing 
Survey Item 
Observation Period 
Patient 
enrollme
nt
Baseline 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
Discon- 
tinuation 
Patient Enrollment 
Prescription date of the Drug 
○ 
Patient ID number 
○ 
Patient initials 
○ 
Sex 
○ 
Birth date 
○ 
Inclusion criteria/exclusion criteria 
○ 
Patient demographics 
Height, Weight 
○ 
Time of hyperlipidemia diagnosis 
○ 
Treatment category 
○ 
Menopausal status (only for female) 
○ 
Complications 
○ 
Medical history 
○ 
Hypersensitivity disposition 
○ 
Drinking history, smoking history 
○ 
Presence or absence of surgery before 
baseline 
○ 
Presence or absence of healthier 
lifestyle education (diet and exercise 
therapies) 
○ 
Treatment 
Information 
Administration of the Drug 
○ 
○ 
Administration of other 
antihyperlipidemic drugs 
○ 
○ 
Administration of concomitant 
medications (other than 
antihyperlipidemic drug) 
○ 
○ 
Testing /Observation Items 
TG 
○ 
○ 
○ 
○ 
○ 
○ 
TC 
○ 
○ 
○ 
○ 
○ 
○ 
LDL-C (direct measurement) 
○ 
○ 
○ 
○ 
○ 
○ 
HDL-C 
○ 
○ 
○ 
○ 
○ 
○ 
VLDL-C 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-AI 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-B 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-CIII 
○ 
○ 
○ 
○ 
○ 
○ 
Lipoprotein (a) 
○ 
○ 
○ 
○ 
○ 
○ 
RLP-C 
○ 
○ 
○ 
○ 
○ 
○ 
FBG 
○ 
○ 
○ 
○ 
○ 
○ 
HbA1c 
○ 
○ 
○ 
○ 
○ 
○ 
Pregnancy status (only for female) 
○ 
○ 
AE 
○ 
○ 
○: Surveyed, tested, or observed
○:
Surveyed, tested, or observed throughout the period 

 
 
 
 
 
Special Drug Use Surveillance Protocol 
Lotriga Granular Capsules Special Drug Use 
Surveillance 
[Long-term use survey] 
 
 
 
 
 
 
 
Version No. 
3rd Version 
Date Prepared 
April 1, 2015 
Study Sponsor 
Takeda Pharmaceutical Company Limited 
 

Table of Contents 
1.0 
Background .................................................................................................................................................... 1 
2.0 
Objective ........................................................................................................................................................ 1 
3.0 
Target Sample Size and Rationale for Sample Size Setting ........................................................................... 1 
3.1 
Target Sample Size ..................................................................................................................................... 1 
3.2 
Rationale for Sample Size Setting .............................................................................................................. 1 
4.0 
Study Population ............................................................................................................................................ 1 
5.0 
Dosage and Administration for Study Population .......................................................................................... 2 
6.0 
Number of Study Sites by Clinical Department ............................................................................................. 2 
7.0 
Study Method ................................................................................................................................................. 2 
7.1 
Observation Period ..................................................................................................................................... 2 
7.2 
Request and Contract to Study Sites .......................................................................................................... 2 
7.3 
Patient Enrollment Method ........................................................................................................................ 2 
7.4 
Data Entry and Electronic Signature to Electronic Case Report Form (eCRF) .......................................... 2 
7.5 
Action Taken at Onset of Serious Adverse Event ....................................................................................... 3 
8.0 
Expected Duration of Study ........................................................................................................................... 3 
9.0 
Survey Items ................................................................................................................................................... 3 
9.1 
Patient Enrollment ...................................................................................................................................... 3 
9.2 
Patient Demographics................................................................................................................................. 3 
9.3 
Treatment Information ................................................................................................................................ 3 
9.4 
Testing/Observation Items .......................................................................................................................... 4 
9.5 
Other Observation Items ............................................................................................................................ 4 
9.6 
Adverse Events (AEs) ................................................................................................................................ 4 
10.0 
Analysis Items and Method ............................................................................................................................ 7 
10.1 
Patient Disposition Items............................................................................................................................ 7 
10.2 
Patient Demographics................................................................................................................................. 7 
10.3 
Treatment Details ....................................................................................................................................... 7 
10.4 
Safety Items ................................................................................................................................................ 7 
 
Onset Status of Adverse Events .......................................................................................................... 7 
10.4.1
 
Factors Likely to Affect Safety ........................................................................................................... 7 
10.4.2
10.5 
Efficacy Items............................................................................................................................................. 8 
 
Changes in Lipid Parameters: TG, TC, LDL-C, HDL-C, Non-HDL-C, etc. ...................................... 8 
10.5.1
 
Factors Likely to Affect Efficacy ....................................................................................................... 8 
10.5.2
11.0 
Organizational Structure for Conducting the Study ....................................................................................... 8 
12.0 
Service Contractor’s Name and Address and Scope of Contract Work .......................................................... 8 
13.0 
Other Necessary Items ................................................................................................................................... 8 
13.1 
Protocol Revision ....................................................................................................................................... 8 
13.2 
Action Taken in Case of Problem or Question ........................................................................................... 9 
Appendix Study Schedule.......................................................................................................................................10 

 
1 
1.0 
Background 
Lotriga Granular Capsules (the “Drug”) is an oral capsule formulation containing the active 
ingredient omega-3 fatty acid ethyl esters (principally EPA-E and DHA-E). The Drug differs 
from general marine oil products, such as supplements, in containing a high concentration of 
omega-3 fatty acid ethyl esters. Since first approved in Norway in September 1994, the Drug 
has been in extensive use overseas, sold in more than 60 countries. In the clinical study of the 
Drug conducted in Japan in patients with hypertriglyceridemia, adverse drug reactions (ADRs) 
including ‘laboratory test abnormal’ were observed in 91 (9.6%) of the 948 patients 
administered at 2 g or 4 g of omega-3 fatty acid ethyl esters, and the major ADR was Diarrhea 
(2.5%). 
Despite the proven track record of extensive use overseas and the fact that the safety of 
long-term use was already evaluated during the clinical study, it is important to evaluate the 
safety of long-term use of the Drug in the general patient population in Japan. 
Special drug use surveillance (hereinafter the "Study") has been therefore designed to evaluate 
the safety and efficacy of long-term use of the Drug in patients with hyperlipidemia in a 
routine clinical setting. 
 
2.0 
Objective 
To evaluate the safety and efficacy of long-term use of the Drug in patients with 
hyperlipidemia in a routine clinical setting. 
 
3.0 
Target Sample Size and Rationale for Sample Size Setting 
3.1 
Target Sample Size 
3,000 patients 
 
3.2 
Rationale for Sample Size Setting 
Bleeding-related events are set as a priority survey item for the Drug. As postmarketing 
surveillance of EPA products in antihyperlipidemic therapy has reported that the incidence of 
bleeding-related ADRs was 0.4% and that the percentage of anticoagulant and antiplatelet 
concomitant use was about 10%, the Study sets a target of 3,000 patients so that anticoagulant 
and antiplatelet concomitant use can be assessed to some degree, in addition to 
bleeding-related ADRs. 
Note that this rationale for the sample size is not based on statistical evidence. 
 
4.0 
Study Population 
Patients with hyperlipidemia will be eligible for this study; however, those who meet the 
following exclusion criteria were excluded from the study. 
Exclusion criteria: 
(1) Patients with hemorrhage (e.g., hemophilia, capillary fragility, gastrointestinal ulcer, 
urinary tract hemorrhage, hemoptysis, or vitreous hemorrhage) 
(2) Patients with a history of hypersensitivity to ingredients in the Drug 

 
2 
 
5.0 
Dosage and Administration for Study Population 
The usual adult dosage is 2 g of omega-3 fatty acid ethyl esters administered orally once daily 
after meals. However, the dosage can be increased up to twice daily (at a dose of 2 g) 
depending on the patient's triglyceride level. 
 
6.0 
Number of Study Sites by Clinical Department 
 About 200 sites (clinical departments not specified) 
 
7.0 
Study Method 
7.1 
Observation Period 
12 months 
 
7.2 
Request and Contract to Study Sites 
The Study will be requested and contracted using a web-based electronic data collection 
system (
). Takeda Pharmaceutical’s staffs (hereinafter "Takeda staffs") will 
adequately explain to investigators about the purpose and description of the Study, 
’s operating procedure, electronic signature, and user ID and password handling for 
request for the Study, based on the Letter of Request for Cooperation in Special Drug Use 
Surveillance, the Implementation Guidance, data input screen images, and the abbreviated 
 Operating Manual. Takeda MRs will then conclude a contract in writing with 
study sites to perform the Study within the specified surveillance period. 
 
7.3 
Patient Enrollment Method 
Patients will be "centrally" enrolled using 
. The investigator will enter into 
 patient enrollment information (see Section 9.1) of patients for whom the Drug has 
been prescribed since the start date of the period of contract with the study site, within 14 days 
after the prescription date of the Drug (the prescription date is defined as "Day 0"; the day 
following the prescription date is defined as "Day 1"). 
 
7.4 
Data Entry and Electronic Signature to Electronic Case Report Form (eCRF) 
The investigator will enter patient data including demographics and treatment into 
 
and electronically sign the eCRF in 12 months after the start of treatment with the Drug 
(baseline). 
If a patient discontinues the treatment with the Drug for some reason during the observation 
period, the investigator will be expected to enter their information including demographics and 
treatment into 
 and electronically sign the eCRF within one month after the 
completion of necessary observations. However, if the patient discontinues the treatment with 
the Drug due to the occurrence of an adverse event (AE), the investigator should continue to 
observe them after discontinuation, as long as possible until the AE is resolved or resolving. 
The investigator should then enter the result of the observation into 
 and 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

 
3 
electronically sign the eCRF. 
After review of the information, Takeda Pharmaceutical may request for re-survey, if deemed 
necessary, via 
. The investigator will, upon checking, perform the details of the 
requested re-survey and enter the result of the re-survey into 
 and electronically 
sign the eCRF. 
 
7.5 
Action Taken at Onset of Serious Adverse Event 
The investigator will immediately contact the Takeda staff if a serious AE occurs during the 
observation period. The investigator will also separately provide detailed information thereof 
upon request, if any, from the Takeda staff. 
 
8.0 
Expected Duration of Study 
Surveillance period: May 2013 to September 30, 2016 
Patient enrollment period: May 2013 to May 31, 2015* 
 
*Enrollment may be closed before the end of the enrollment period if the total number of 
patients enrolled in the Study reaches the target sample size. 
 
9.0 
Survey Items 
The investigator will enter the information of the following items into 
. The 
schedule for the Study is provided in the Appendix. 
9.1 
Patient Enrollment 
1) Survey items 
Prescription date of the Date, patient ID number, patient initials, sex, birth date, 
determination with inclusion criteria, and determination with exclusion criteria 
2) Survey timing 
The time of patient enrollment 
 
9.2 
Patient Demographics 
1) Survey items 
Height, weight, time of hyperlipidemia diagnosis, treatment category, menopausal status 
(only for female), complications (presence or absence and details), medical history 
(presence or absence and details), hypersensitivity disposition (presence or absence and 
details), drinking history, smoking history, presence or absence of surgery within one 
month before baseline, and presence or absence of healthier lifestyle education (diet and 
exercise therapies) 
2) Survey time 
Baseline 
 
9.3 
Treatment Information 
1) Survey items 
CCI
CCI
CCI

 
4 
Administration of the Drug (daily dose, treatment duration, and status of completion of 
treatment with the Drug), administration of antihyperlipidemic drugs other than the Drug* 
(presence or absence, drug name, daily dose, and treatment duration), and administration of 
concomitant medications (other than antihyperlipidemic drugs) (presence or absence, drug 
name, and purpose of administration) 
*: Including antihyperlipidemic drugs with which treatment is discontinued within two 
months before baseline. 
2) Survey timing 
Period from baseline to Month 12 (or discontinuation of treatment) 
 
9.4 
Testing/Observation Items 
1) Survey items 
Triglyceride (TG), total cholesterol (TC), LDL cholesterol* (LDL-C), HDL cholesterol 
(HDL-C), VLDL cholesterol (VLDL-C), Apo-AI, Apo-B, Apo-CIII, lipoprotein (a), 
remnant lipoprotein cholesterol (RLP-C), fasting blood glucose (FBG), HbA1c   *: When 
tested by direct measurement 
2) Survey timing 
Baseline, Month 3, Month 6, Month 9, and Month 12 (or discontinuation of treatment) test 
timepoints 
 
9.5 
Other Observation Items 
1) Survey items 
Pregnancy status 
If the patient is found to be pregnant during the observation period, the investigator 
will report the Takeda staff. The investigator will, upon request from the Takeda staff, 
use a sheet for pregnant women to provide detailed information (including information 
available up to childbirth, including premature birth or other pregnancy results, if 
possible). 
2) Survey timing 
Period from baseline to Month 12 (or discontinuation of treatment) 
 
9.6 
Adverse Events (AEs) 
1) Survey items 
Presence or absence of AE (see Table 1), AE name, date of onset, seriousness and reason 
for seriousness (see Table 2), action taken to the Drug, date of determination of outcome, 
outcome, and causal relationship to the Drug* (see Table 3) 
If the outcome is not resolved or unknown and the casual relationship is determined as 
unevaluable, follow-up survey should be conducted to some extent possible. 
*If causal relationship to the Drug is determined as not related, reasons that may constitute 
the rationale for determination should be collected if it is unevaluable. 
2) Survey timing 

 
5 
Period from baseline to Month 12 (or discontinuation of treatment) 
3) Priority survey item 
Bleeding-related events occurring after baseline are set as a priority survey item. If 
any bleeding-related event is reported as an AE, laboratory test values related to bleeding 
should be separately collected. 
 
 
 

 
6 
Table 1 Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a medicinal 
product and which does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
The following should be also handled as an AE: 
• A symptoms or other problem occurring in an infant breastfed from a mother taking the medicinal 
product 
• A symptom or other problem occurring in a child administered the medicinal product 
• A symptom or other problem occurring in a patient administered or taking more than the approved 
dose of the medicinal product 
 
Table 2 Seriousness Criteria 
An event is classified as serious if: 
1. resulting in death (death), 
2. being life-threatening (at risk of death), 
3. requiring inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization), 
4. resulting in persistent or significant disability/incapacity (disorder), 
5. being a congenital anomaly/birth defect (birth defect), or 
6. being any other medically serious condition that does not fall under any of 1 to 5 above. Note that 
all those listed in the Takeda Medically Significant AE List are included in this criterion. 
(Examples include bronchospasm, which requires short-term intensive care in emergency room 
settings.) 
 
Takeda Medically Significant AE List 
• Acute respiratory failure/acute respiratory distress 
syndrome (ARDS) 
• Anaphylactic shock 
• Torsade de pointes/ventricular 
fibrillation/ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizure (including spasm and 
epilepsy) 
• Pulmonary fibrosis (including interstitial lung 
disease) 
• Agranulocytosis 
• Neuroleptic malignant syndrome/malignant 
hyperthermia 
• Aplastic anaemia 
• Spontaneous abortion/stillbirth and foetal death 
• Toxic epidermal necrolysis/muco-cutaneo-ocular 
syndrome (Stevens-Johnson syndrome) 
• Confirmed or suspected transmission of infection 
by a medicinal product 
• Hepatic necrosis 
• Confirmed or suspected endotoxin shock 
• Acute hepatic failure 
 
 

 
7 
Table 3 Criteria for Casual Relationship between Adverse Event and the Drug 
Determination 
Criteria 
Related 
 
There is temporal correlation between the Drug and the event 
(including results from discontinuation of treatment). 
Or the event is an AE considered likely to have been caused by the 
Drug although it is presumed to have been contributed by other 
factors, such as primary disease, complications, concomitant 
medications, or combined treatments. 
Not related 
 
There is no temporal correlation between the Drug and the event. Or 
the event is adequately considered to have been contributed by other 
factors, such as primary disease, complications, concomitant 
medications, or combined treatments. 
Unevaluable 
There is lack of information necessary for evaluation of the event, 
including temporal correlation (including results from discontinuation 
of treatment), primary disease, complications, concomitant 
medications, and combined treatments. 
 
10.0 
Analysis Items and Method 
10.1 Patient Disposition Items 
Compile information including the number of enrolled patients, number of patients with 
eCRFs collected, numbers of safety- and efficacy-evaluable patients, and the number of 
patients excluded from analysis and reasons for exclusion. 
 
10.2 Patient Demographics 
Compile patient demographic information including sex, age, hypersensitivity disposition, and 
complications. 
 
10.3 Treatment Details 
Compile information on administration of the Drug and of concomitant medications. 
 
10.4 Safety Items 
Compile the following regarding the safety-evaluable population. AEs, coded using MedDRA, 
will be summarized by preferred term (PT) and by system organ class (SOC). 
 Onset Status of Adverse Events 
10.4.1
Compile the incidence of AEs occurring during the observation period, in terms of, e.g., 
causal relationship with the Drug, type, seriousness. Note that bleeding-related events 
should be separately compiled because such events are set as a priority survey item. 
 
 Factors Likely to Affect Safety 
10.4.2
Compile the incidence of ADRs occurring during the observation period, by stratification 
variables: patient baseline characteristics (sex, age, presence or absence of renal 

 
8 
dysfunction, presence or absence of hepatic dysfunction, etc.) and treatment regimen 
(administration of the Drug, administration of concomitant medications such as 
anticoagulant drugs, antiplatelet drugs). 
 
10.5 Efficacy Items 
Compile the following regarding the efficacy-evaluable population. 
 Changes in Lipid Parameters: TG, TC, LDL-C, HDL-C, Non-HDL-C, etc. 
10.5.1
Tabulate observed values and changes (observed value at each observational timepoint after baseline 
minus observed value at baseline) at each observational timepoint for TG, TC, LDL-C (by 
converted value calculated by direct measurement, Friedewald formula*), HDL-C, 
Non-HDL-C (converted value**), VLDL cholesterol, Apo-AI, Apo-B, Apo-CIII, 
lipoprotein (a), and RLP-C. 
*: LDL-C = TC-HDL-C - TG / 5 
**: Non-HDL-C = TC-HDL-C 
Note that LDL-C, Non-HDL-C, TC/LDL-C ratio, LDL-C/HDL-C ratio, and LDL-C/Apo-B 
ratio should be calculated from test results. 
 
 Factors Likely to Affect Efficacy 
10.5.2
Compile TG values by stratification variables: patient baseline characteristics (sex and age) 
and treatment regimen (administration of the Drug, administration of concomitant 
medications, etc.). 
 
11.0 
Organizational Structure for Conducting the Study 
Study Chair 
Takeda Pharmaceutical Co., Ltd. 
Post Marketing Surveillance Manager 
 
12.0 
Service Contractor’s Name and Address and Scope of Contract Work 
Contractor: 
 
 
Scope of contract work: Data management and statistical analysis 
 
Contractor: 
 
 
Scope of contract work: Storage of relevant records 
 
13.0 
Other Necessary Items 
13.1 Protocol Revision 
During the surveillance period, keep track of, e.g., the progress of the Study, the onset of 
unexpected ADRs or serious ADRs based on the precautions, presence or absence of increased 
incidence of specified ADRs, the appropriateness of survey items. If needed, review and revise 
PPD
PPD

 
9 
this protocol. If partial change approval is obtained for dosage and administration or 
indications during the surveillance period, examine whether to revise this protocol if necessary 
and revise it if necessary. 
 
13.2 Action Taken in Case of Problem or Question 
If any problem is found in the safety or efficacy of the Drug, carefully review the data and 
examine what needs to be done. 

10 
Appendix Study Schedule 
Survey and Data Entry Timing 
Survey Item 
Observation Period 
Patient 
enrollme
nt
Baseline 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
Discon- 
tinuation 
Patient Enrollment 
Prescription date of the Drug 
○ 
Patient ID number 
○ 
Patient initials 
○ 
Sex 
○ 
Birth date 
○ 
Inclusion criteria/exclusion criteria 
○ 
Patient demographics 
Height, Weight 
○ 
Time of hyperlipidemia diagnosis 
○ 
Treatment category 
○ 
Menopausal status (only for female) 
○ 
Complications 
○ 
Medical history 
○ 
Hypersensitivity disposition 
○ 
Drinking history, smoking history 
○ 
Presence or absence of surgery before 
baseline 
○ 
Presence or absence of healthier 
lifestyle education (diet and exercise 
therapies) 
○ 
Treatment 
Information 
Administration of the Drug 
○ 
○ 
Administration of other 
antihyperlipidemic drugs 
○ 
○ 
Administration of concomitant 
medications (other than 
antihyperlipidemic drug) 
○ 
○ 
Testing /Observation Items 
TG 
○ 
○ 
○ 
○ 
○ 
○ 
TC 
○ 
○ 
○ 
○ 
○ 
○ 
LDL-C (direct measurement) 
○ 
○ 
○ 
○ 
○ 
○ 
HDL-C 
○ 
○ 
○ 
○ 
○ 
○ 
VLDL-C 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-AI 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-B 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-CIII 
○ 
○ 
○ 
○ 
○ 
○ 
Lipoprotein (a) 
○ 
○ 
○ 
○ 
○ 
○ 
RLP-C 
○ 
○ 
○ 
○ 
○ 
○ 
FBG 
○ 
○ 
○ 
○ 
○ 
○ 
HbA1c 
○ 
○ 
○ 
○ 
○ 
○ 
Pregnancy status (only for female) 
○ 
○ 
AE 
○ 
○ 
○: Surveyed, tested, or observed
○:
Surveyed, tested, or observed throughout the period 

 
 
 
 
 
Special Drug Use Surveillance Protocol 
Lotriga Granular Capsules Special Drug Use 
Surveillance 
[Long-term use survey] 
 
 
 
 
 
 
 
Version No. 
2nd Version 
Date Prepared 
April 3, 2013 
Study Sponsor 
Takeda Pharmaceutical Company Limited 
 

Table of Contents 
1.0 
Background .................................................................................................................................................... 1 
2.0 
Objective ........................................................................................................................................................ 1 
3.0 
Target Sample Size and Rationale for Sample Size Setting ........................................................................... 1 
3.1 
Target Sample Size ..................................................................................................................................... 1 
3.2 
Rationale for Sample Size Setting .............................................................................................................. 1 
4.0 
Study Population ............................................................................................................................................ 1 
5.0 
Dosage and Administration for Study Population .......................................................................................... 2 
6.0 
Number of Study Sites by Clinical Department ............................................................................................. 2 
7.0 
Study Method ................................................................................................................................................. 2 
7.1 
Observation Period ..................................................................................................................................... 2 
7.2 
Request and Contract to Study Sites .......................................................................................................... 2 
7.3 
Patient Enrollment Method ........................................................................................................................ 2 
7.4 
Data Entry and Electronic Signature to Electronic Case Report Form (eCRF) .......................................... 2 
7.5 
Action Taken at Onset of Serious Adverse Event ....................................................................................... 3 
8.0 
Expected Duration of Study ........................................................................................................................... 3 
9.0 
Survey Items ................................................................................................................................................... 3 
9.1 
Patient Enrollment ...................................................................................................................................... 3 
9.2 
Patient Demographics................................................................................................................................. 3 
9.3 
Treatment Information ................................................................................................................................ 3 
9.4 
Testing/Observation Items .......................................................................................................................... 4 
9.5 
Other Observation Items ............................................................................................................................ 4 
9.6 
Adverse Events (AEs) ................................................................................................................................ 4 
10.0 
Analysis Items and Method ............................................................................................................................ 7 
10.1 
Patient Disposition Items............................................................................................................................ 7 
10.2 
Patient Demographics................................................................................................................................. 7 
10.3 
Treatment Details ....................................................................................................................................... 7 
10.4 
Safety Items ................................................................................................................................................ 7 
 
Onset Status of Adverse Events .......................................................................................................... 7 
10.4.1
 
Factors Likely to Affect Safety ........................................................................................................... 7 
10.4.2
10.5 
Efficacy Items............................................................................................................................................. 8 
 
Changes in Lipid Parameters: TG, TC, LDL-C, HDL-C, Non-HDL-C, etc. ...................................... 8 
10.5.1
 
Factors Likely to Affect Efficacy ....................................................................................................... 8 
10.5.2
11.0 
Organizational Structure for Conducting the Study ....................................................................................... 8 
12.0 
Service Contractor’s Name and Address and Scope of Contract Work .......................................................... 8 
13.0 
Other Necessary Items ................................................................................................................................... 8 
13.1 
Protocol Revision ....................................................................................................................................... 8 
13.2 
Action Taken in Case of Problem or Question ........................................................................................... 9 
Appendix Study Schedule.......................................................................................................................................10 

1 
1.0 
Background 
Lotriga Granular Capsules (the “Drug”) is an oral capsule formulation containing the active 
ingredient omega-3 fatty acid ethyl esters (principally EPA-E and DHA-E). The Drug differs 
from general marine oil products, such as supplements, in containing a high concentration of 
omega-3 fatty acid ethyl esters. Since first approved in Norway in September 1994, the Drug 
has been in extensive use overseas, sold in more than 60 countries. In the clinical study of the 
Drug conducted in Japan in patients with hypertriglyceridemia, adverse drug reactions (ADRs) 
including ‘laboratory test abnormal’ were observed in 91 (9.6%) of the 948 patients 
administered at 2 g or 4 g of omega-3 fatty acid ethyl esters, and the major ADR was Diarrhea 
(2.5%). 
Despite the proven track record of extensive use overseas and the fact that the safety of 
long-term use was already evaluated during the clinical study, it is important to evaluate the 
safety of long-term use of the Drug in the general patient population in Japan. 
Special drug use surveillance (hereinafter the "Study") has been therefore designed to evaluate 
the safety and efficacy of long-term use of the Drug in patients with hyperlipidemia in a 
routine clinical setting. 
2.0 
Objective 
To evaluate the safety and efficacy of long-term use of the Drug in patients with 
hyperlipidemia in a routine clinical setting. 
3.0 
Target Sample Size and Rationale for Sample Size Setting 
3.1 
Target Sample Size 
3,000 patients 
3.2 
Rationale for Sample Size Setting 
Bleeding-related events are set as a priority survey item for the Drug. As postmarketing 
surveillance of EPA products in antihyperlipidemic therapy has reported that the incidence of 
bleeding-related ADRs was 0.4% and that the percentage of anticoagulant and antiplatelet 
concomitant use was about 10%, the Study sets a target of 3,000 patients so that anticoagulant 
and antiplatelet concomitant use can be assessed to some degree, in addition to 
bleeding-related ADRs. 
Note that this rationale for the sample size is not based on statistical evidence. 
4.0 
Study Population 
Patients with hyperlipidemia will be eligible for this study; however, those who meet the 
following exclusion criteria were excluded from the study. 
Exclusion criteria: 
(1) Patients with hemorrhage (e.g., hemophilia, capillary fragility, gastrointestinal ulcer, 
urinary tract hemorrhage, hemoptysis, or vitreous hemorrhage) 
(2) Patients with a history of hypersensitivity to ingredients in the Drug 

 
2 
 
5.0 
Dosage and Administration for Study Population 
The usual adult dosage is 2 g of omega-3 fatty acid ethyl esters administered orally once daily 
after meals. However, the dosage can be increased up to twice daily (at a dose of 2 g) 
depending on the patient's triglyceride level. 
 
6.0 
Number of Study Sites by Clinical Department 
 About 200 sites (clinical departments not specified) 
 
7.0 
Study Method 
7.1 
Observation Period 
12 months 
 
7.2 
Request and Contract to Study Sites 
The Study will be requested and contracted using a web-based electronic data collection 
system (
). Takeda Pharmaceutical’s MRs (hereinafter "Takeda MRs") will 
adequately explain to investigators about the purpose and description of the Study, 
’s operating procedure, electronic signature, and user ID and password handling for 
request for the Study, based on the Letter of Request for Cooperation in Special Drug Use 
Surveillance, the Implementation Guidance, data input screen images, and the abbreviated 
 Operating Manual. Takeda MRs will then conclude a contract in writing with 
study sites to perform the Study within the specified surveillance period. 
 
7.3 
Patient Enrollment Method 
Patients will be "centrally" enrolled using 
. The investigator will enter into 
 patient enrollment information (see Section 9.1) of patients for whom the Drug has 
been prescribed since the start date of the period of contract with the study site, within 14 days 
after the prescription date of the Drug (the prescription date is defined as "Day 0"; the day 
following the prescription date is defined as "Day 1"). 
 
7.4 
Data Entry and Electronic Signature to Electronic Case Report Form (eCRF) 
The investigator will enter patient data including demographics and treatment into 
 
and electronically sign the eCRF in 12 months after the start of treatment with the Drug 
(baseline). 
If a patient discontinues the treatment with the Drug for some reason during the observation 
period, the investigator will be expected to enter their information including demographics and 
treatment into 
 and electronically sign the eCRF within one month after the 
completion of necessary observations. However, if the patient discontinues the treatment with 
the Drug due to the occurrence of an adverse event (AE), the investigator should continue to 
observe them after discontinuation, as long as possible until the AE is resolved or resolving. 
The investigator should then enter the result of the observation into 
 and 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

 
3 
electronically sign the eCRF. 
After review of the information, Takeda Pharmaceutical may request for re-survey, if deemed 
necessary, via 
. The investigator will, upon checking, perform the details of the 
requested re-survey and enter the result of the re-survey into 
 and electronically 
sign the eCRF. 
 
7.5 
Action Taken at Onset of Serious Adverse Event 
The investigator will immediately contact the Takeda MR if a serious AE occurs during the 
observation period. The investigator will also separately provide detailed information thereof 
upon request, if any, from the Takeda MR. 
 
8.0 
Expected Duration of Study 
Surveillance period: May 2013 to September 30, 2016 
Patient enrollment period: May 2013 to May 31, 2015* 
 
*Enrollment may be closed before the end of the enrollment period if the total number of 
patients enrolled in the Study reaches the target sample size. 
 
9.0 
Survey Items 
The investigator will enter the information of the following items into 
. The 
schedule for the Study is provided in the Appendix. 
9.1 
Patient Enrollment 
1) Survey items 
Prescription date of the Date, patient ID number, patient initials, sex, birth date, 
determination with inclusion criteria, and determination with exclusion criteria 
2) Survey timing 
The time of patient enrollment 
 
9.2 
Patient Demographics 
1) Survey items 
Height, weight, time of hyperlipidemia diagnosis, treatment category, menopausal status 
(only for female), complications (presence or absence and details), medical history 
(presence or absence and details), hypersensitivity disposition (presence or absence and 
details), drinking history, smoking history, presence or absence of surgery within one 
month before baseline, and presence or absence of healthier lifestyle education (diet and 
exercise therapies) 
2) Survey time 
Baseline 
 
9.3 
Treatment Information 
1) Survey items 
CCI
CCI
CCI

 
4 
Administration of the Drug (daily dose, treatment duration, and status of completion of 
treatment with the Drug), administration of antihyperlipidemic drugs other than the Drug* 
(presence or absence, drug name, daily dose, and treatment duration), and administration of 
concomitant medications (other than antihyperlipidemic drugs) (presence or absence, drug 
name, and purpose of administration) 
*: Including antihyperlipidemic drugs with which treatment is discontinued within two 
months before baseline. 
2) Survey timing 
Period from baseline to Month 12 (or discontinuation of treatment) 
 
9.4 
Testing/Observation Items 
1) Survey items 
Triglyceride (TG), total cholesterol (TC), LDL cholesterol* (LDL-C), HDL cholesterol 
(HDL-C), VLDL cholesterol (VLDL-C), Apo-AI, Apo-B, Apo-CIII, lipoprotein (a), 
remnant lipoprotein cholesterol (RLP-C), fasting blood glucose (FBG), HbA1c   *: When 
tested by direct measurement 
2) Survey timing 
Baseline, Month 3, Month 6, Month 9, and Month 12 (or discontinuation of treatment) test 
timepoints 
 
9.5 
Other Observation Items 
1) Survey items 
Pregnancy status 
If the patient is found to be pregnant during the observation period, the investigator 
will report the Takeda MR. The investigator will, upon request from the Takeda MR, use 
a sheet for pregnant women to provide detailed information (including information 
available up to childbirth, including premature birth or other pregnancy results, if 
possible). 
2) Survey timing 
Period from baseline to Month 12 (or discontinuation of treatment) 
 
9.6 
Adverse Events (AEs) 
1) Survey items 
Presence or absence of AE (see Table 1), AE name, date of onset, seriousness and reason 
for seriousness (see Table 2), action taken to the Drug, date of determination of outcome, 
outcome, and causal relationship to the Drug* (see Table 3) 
If the outcome is not resolved or unknown and the casual relationship is determined as 
unevaluable, follow-up survey should be conducted to some extent possible. 
*If causal relationship to the Drug is determined as not related, reasons that may constitute 
the rationale for determination should be collected if it is unevaluable. 
2) Survey timing 

 
5 
Period from baseline to Month 12 (or discontinuation of treatment) 
3) Priority survey item 
Bleeding-related events occurring after baseline are set as a priority survey item. If 
any bleeding-related event is reported as an AE, laboratory test values related to bleeding 
should be separately collected. 
 
 
 

 
6 
Table 1 Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a medicinal 
product and which does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
The following should be also handled as an AE: 
• A symptoms or other problem occurring in an infant breastfed from a mother taking the medicinal 
product 
• A symptom or other problem occurring in a child administered the medicinal product 
• A symptom or other problem occurring in a patient administered or taking more than the approved 
dose of the medicinal product 
 
Table 2 Seriousness Criteria 
An event is classified as serious if: 
1. resulting in death (death), 
2. being life-threatening (at risk of death), 
3. requiring inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization), 
4. resulting in persistent or significant disability/incapacity (disorder), 
5. being a congenital anomaly/birth defect (birth defect), or 
6. being any other medically serious condition that does not fall under any of 1 to 5 above. Note that 
all those listed in the Takeda Medically Significant AE List are included in this criterion. 
(Examples include bronchospasm, which requires short-term intensive care in emergency room 
settings.) 
 
Takeda Medically Significant AE List 
• Acute respiratory failure/acute respiratory distress 
syndrome (ARDS) 
• Anaphylactic shock 
• Torsade de pointes/ventricular 
fibrillation/ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizure (including spasm and 
epilepsy) 
• Pulmonary fibrosis (including interstitial lung 
disease) 
• Agranulocytosis 
• Neuroleptic malignant syndrome/malignant 
hyperthermia 
• Aplastic anaemia 
• Spontaneous abortion/stillbirth and foetal death 
• Toxic epidermal necrolysis/muco-cutaneo-ocular 
syndrome (Stevens-Johnson syndrome) 
• Confirmed or suspected transmission of infection 
by a medicinal product 
• Hepatic necrosis 
• Confirmed or suspected endotoxin shock 
• Acute hepatic failure 
 
 

 
7 
Table 3 Criteria for Casual Relationship between Adverse Event and the Drug 
Determination 
Criteria 
Related 
 
There is temporal correlation between the Drug and the event 
(including results from discontinuation of treatment). 
Or the event is an AE considered likely to have been caused by the 
Drug although it is presumed to have been contributed by other 
factors, such as primary disease, complications, concomitant 
medications, or combined treatments. 
Not related 
 
There is no temporal correlation between the Drug and the event. Or 
the event is adequately considered to have been contributed by other 
factors, such as primary disease, complications, concomitant 
medications, or combined treatments. 
Unevaluable 
There is lack of information necessary for evaluation of the event, 
including temporal correlation (including results from discontinuation 
of treatment), primary disease, complications, concomitant 
medications, and combined treatments. 
 
10.0 
Analysis Items and Method 
10.1 Patient Disposition Items 
Compile information including the number of enrolled patients, number of patients with 
eCRFs collected, numbers of safety- and efficacy-evaluable patients, and the number of 
patients excluded from analysis and reasons for exclusion. 
 
10.2 Patient Demographics 
Compile patient demographic information including sex, age, hypersensitivity disposition, and 
complications. 
 
10.3 Treatment Details 
Compile information on administration of the Drug and of concomitant medications. 
 
10.4 Safety Items 
Compile the following regarding the safety-evaluable population. AEs, coded using MedDRA, 
will be summarized by preferred term (PT) and by system organ class (SOC). 
 Onset Status of Adverse Events 
10.4.1
Compile the incidence of AEs occurring during the observation period, in terms of, e.g., 
causal relationship with the Drug, type, seriousness. Note that bleeding-related events 
should be separately compiled because such events are set as a priority survey item. 
 
 Factors Likely to Affect Safety 
10.4.2
Compile the incidence of ADRs occurring during the observation period, by stratification 
variables: patient baseline characteristics (sex, age, presence or absence of renal 

 
8 
dysfunction, presence or absence of hepatic dysfunction, etc.) and treatment regimen 
(administration of the Drug, administration of concomitant medications such as 
anticoagulant drugs, antiplatelet drugs). 
 
10.5 Efficacy Items 
Compile the following regarding the efficacy-evaluable population. 
 Changes in Lipid Parameters: TG, TC, LDL-C, HDL-C, Non-HDL-C, etc. 
10.5.1
Tabulate observed values and changes (observed value at each observational timepoint after baseline 
minus observed value at baseline) at each observational timepoint for TG, TC, LDL-C (by 
converted value calculated by direct measurement, Friedewald formula*), HDL-C, 
Non-HDL-C (converted value**), VLDL cholesterol, Apo-AI, Apo-B, Apo-CIII, 
lipoprotein (a), and RLP-C. 
*: LDL-C = TC-HDL-C - TG / 5 
**: Non-HDL-C = TC-HDL-C 
Note that LDL-C, Non-HDL-C, TC/LDL-C ratio, LDL-C/HDL-C ratio, and LDL-C/Apo-B 
ratio should be calculated from test results. 
 
 Factors Likely to Affect Efficacy 
10.5.2
Compile TG values by stratification variables: patient baseline characteristics (sex and age) 
and treatment regimen (administration of the Drug, administration of concomitant 
medications, etc.). 
 
11.0 
Organizational Structure for Conducting the Study 
Study Chair 
Pharmacovigilance 
Department, 
Pharmaceutical 
Development 
Division, 
Takeda 
Pharmaceutical Co., Ltd. 
 
 
12.0 
Service Contractor’s Name and Address and Scope of Contract Work 
Contractor: 
 
 
Scope of contract work: Data management and statistical analysis 
 
13.0 
Other Necessary Items 
13.1 Protocol Revision 
During the surveillance period, keep track of, e.g., the progress of the Study, the onset of 
unexpected ADRs or serious ADRs based on the precautions, presence or absence of increased 
incidence of specified ADRs, the appropriateness of survey items. If needed, review and revise 
this protocol. If partial change approval is obtained for dosage and administration or 
indications during the surveillance period, examine whether to revise this protocol if necessary 
and revise it if necessary. 
PPD
PPD

 
9 
 
13.2 Action Taken in Case of Problem or Question 
If any problem is found in the safety or efficacy of the Drug, carefully review the data and 
examine what needs to be done. 

10 
Appendix Study Schedule 
Survey and Data Entry Timing 
Survey Item 
Observation Period 
Patient 
enrollme
nt
Baseline 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
Discon- 
tinuation 
Patient Enrollment 
Prescription date of the Drug 
○ 
Patient ID number 
○ 
Patient initials 
○ 
Sex 
○ 
Birth date 
○ 
Inclusion criteria/exclusion criteria 
○ 
Patient demographics 
Height, Weight 
○ 
Time of hyperlipidemia diagnosis 
○ 
Treatment category 
○ 
Menopausal status (only for female) 
○ 
Complications 
○ 
Medical history 
○ 
Hypersensitivity disposition 
○ 
Drinking history, smoking history 
○ 
Presence or absence of surgery before 
baseline 
○ 
Presence or absence of healthier 
lifestyle education (diet and exercise 
therapies) 
○ 
Treatment 
Information 
Administration of the Drug 
○ 
○ 
Administration of other 
antihyperlipidemic drugs 
○ 
○ 
Administration of concomitant 
medications (other than 
antihyperlipidemic drug) 
○ 
○ 
Testing /Observation Items 
TG 
○ 
○ 
○ 
○ 
○ 
○ 
TC 
○ 
○ 
○ 
○ 
○ 
○ 
LDL-C (direct measurement) 
○ 
○ 
○ 
○ 
○ 
○ 
HDL-C 
○ 
○ 
○ 
○ 
○ 
○ 
VLDL-C 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-AI 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-B 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-CIII 
○ 
○ 
○ 
○ 
○ 
○ 
Lipoprotein (a) 
○ 
○ 
○ 
○ 
○ 
○ 
RLP-C 
○ 
○ 
○ 
○ 
○ 
○ 
FBG 
○ 
○ 
○ 
○ 
○ 
○ 
HbA1c 
○ 
○ 
○ 
○ 
○ 
○ 
Pregnancy status (only for female) 
○ 
○ 
AE 
○ 
○ 
○: Surveyed, tested, or observed
○:
Surveyed, tested, or observed throughout the period 

 
 
 
 
 
Special Drug Use Surveillance Protocol 
Lotriga Granular Capsules Special Drug Use 
Surveillance 
[Long-term use survey] 
 
 
 
 
 
 
 
Version No. 
First Version 
Date Prepared 
December 7, 2012 
Study Sponsor 
Takeda Pharmaceutical Company Limited 
 

Table of Contents 
1.0 
Background .................................................................................................................................................... 1 
2.0 
Objective ........................................................................................................................................................ 1 
3.0 
Target Sample Size and Rationale for Sample Size ........................................................................................ 1 
3.1 
Target Sample Size ..................................................................................................................................... 1 
3.2 
Rationale for Sample Size .......................................................................................................................... 1 
4.0 
Study Population ............................................................................................................................................ 1 
5.0 
Dosage and Administration for Study Population .......................................................................................... 2 
6.0 
Number of Study Sites by Clinical Department ............................................................................................. 2 
7.0 
Study Method ................................................................................................................................................. 2 
7.1 
Observation Period ..................................................................................................................................... 2 
7.2 
Request and Contract to Study Sites .......................................................................................................... 2 
7.3 
Patient Enrollment Method ........................................................................................................................ 2 
7.4 
Data Entry and Electronic Signature to Electronic Case Report Form (eCRF) .......................................... 2 
7.5 
Action Taken at Onset of Serious Adverse Event ....................................................................................... 3 
8.0 
Expected Duration of Study ........................................................................................................................... 3 
9.0 
Survey Items ................................................................................................................................................... 3 
9.1 
Patient Enrollment ...................................................................................................................................... 3 
9.2 
Patient Demographics................................................................................................................................. 3 
9.3 
Treatment Information ................................................................................................................................ 3 
9.4 
Testing/Observation Items .......................................................................................................................... 4 
9.5 
Other Observation Items ............................................................................................................................ 4 
9.6 
Adverse Events (AEs) ................................................................................................................................ 4 
10.0 
Analysis Items and Method ............................................................................................................................ 7 
10.1 
Patient Disposition Items............................................................................................................................ 7 
10.2 
Patient Demographics................................................................................................................................. 7 
10.3 
Treatment Details ....................................................................................................................................... 7 
10.4 
Safety Items ................................................................................................................................................ 7 
 
Onset Status of Adverse Events .......................................................................................................... 7 
10.4.1
 
Factors Likely to Affect Safety ........................................................................................................... 7 
10.4.2
10.5 
Efficacy Items............................................................................................................................................. 8 
 
Changes in Lipid Parameters: TG, TC, LDL-C, HDL-C, Non-HDL-C, etc. ...................................... 8 
10.5.1
 
Factors  Likely to Affect Efficacy .................................................................................................... 8 
10.5.2
11.0 
Organizational Structure for Conducting the Study ....................................................................................... 8 
12.0 
Service Contractor’s Name and Address and Scope of Contract Work .......................................................... 8 
13.0 
Other Necessary Items ................................................................................................................................... 8 
13.1 
Protocol Revision ....................................................................................................................................... 8 
13.2 
Action Taken in Case of Problem or Question ........................................................................................... 9 
Appendix Study Schedule....................................................................................................................................... 
10

1 
1.0 
Background 
Lotriga Granular Capsules (the “Drug”) is an oral capsule formulation containing the active 
ingredient omega-3 fatty acid ethyl esters (principally EPA-E and DHA-E). The Drug differs 
from general marine oil products, such as supplements, in containing a high concentration of 
omega-3 fatty acid ethyl esters. Since first approved in Norway in September 1994, the Drug 
has been in extensive use overseas, sold in more than 60 countries. In the clinical study of the 
Drug conducted in Japan in patients with hypertriglyceridemia, adverse drug reactions (ADRs) 
including ‘laboratory test abnormal’ were observed in 91 (9.6%) of the 948 patients 
administered at 2 g or 4 g of omega-3 fatty acid ethyl esters, and the major ADR was Diarrhea 
(2.5%). 
Despite the proven track record of extensive use overseas and the fact that the safety of 
long-term use was already evaluated during the clinical study, it is important to evaluate the 
safety of long-term use of the Drug in the general patient population in Japan. 
Special drug use surveillance (hereinafter the "Study") has been therefore designed to evaluate 
the safety and efficacy of long-term use of the Drug in patients with hyperlipidemia in a 
routine clinical setting. 
2.0 
Objective 
To evaluate the safety and efficacy of long-term use of the Drug in patients with 
hyperlipidemia in a routine clinical setting. 
3.0 
Target Sample Size and Rationale for Sample Size Setting 
3.1 
Target Sample Size 
3,000 patients 
3.2 
Rationale for Sample Size Setting 
Bleeding-related events are set as a priority survey item for the Drug. As postmarketing 
surveillance of EPA products in antihyperlipidemic therapy has reported that the incidence of 
bleeding-related ADRs was 0.4% and that the percentage of anticoagulant and antiplatelet 
concomitant use was about 10%, the Study sets a target of 3,000 patients so that anticoagulant 
and antiplatelet concomitant use can be assessed to some degree, in addition to 
bleeding-related ADRs. 
Note that this rationale for the sample size is not based on statistical evidence. 
4.0 
Study Population 
Patients with hyperlipidemia will be eligible for this study; however, those who meet the 
following exclusion criteria were excluded from the study. 
Exclusion criteria: 
(1) Patients with hemorrhage (e.g., hemophilia, capillary fragility, gastrointestinal ulcer, 
urinary tract hemorrhage, hemoptysis, or vitreous hemorrhage) 
(2) Patients with a history of hypersensitivity to ingredients in the Drug 

2 
5.0 
Dosage and Administration for Study Population 
The usual adult dosage is 2 g of omega-3 fatty acid ethyl esters administered orally once daily 
after meals. However, the dosage can be increased up to twice daily (at a dose of 2 g) 
depending on the patient's triglyceride level. 
6.0 
Number of Study Sites by Clinical Department 
 About 200 sites (clinical departments not specified) 
7.0 
Study Method 
7.1 
Observation Period 
12 months 
7.2 
Request and Contract to Study Sites 
The Study will be requested and contracted using a web-based electronic data collection 
system (
). Takeda Pharmaceutical’s MRs (hereinafter "Takeda MRs") will 
adequately explain to investigators about the purpose and description of the Study, 
’s operating procedure, electronic signature, and user ID and password handling for 
request for the Study, based on the Letter of Request for Cooperation in Special Drug Use 
Surveillance, the Implementation Guidance, data input screen images, and the abbreviated 
Operating Manual. Takeda MRs will then conclude a contract in writing with 
study sites to perform the Study within the specified surveillance period. 
7.3 
Patient Enrollment Method 
Patients will be "centrally" enrolled using 
 The investigator will enter into 
 patient enrollment information (see Section 9.1) of patients for whom the Drug has 
been prescribed since the start date of the period of contract with the study site, within 14 days 
after the prescription date of the Drug (the prescription date is defined as "Day 0"; the day 
following the prescription date is defined as "Day 1"). 
7.4 
Data Entry and Electronic Signature to Electronic Case Report Form (eCRF) 
The investigator will enter patient data including demographics and treatment into 
and electronically sign the eCRF in 12 months after the start of treatment with the Drug 
(baseline). 
If a patient discontinues the treatment with the Drug for some reason during the observation 
period, the investigator will be expected to enter their information including demographics and 
treatment into 
 and electronically sign the eCRF within one month after the 
completion of necessary observations. However, if the patient discontinues the treatment with 
the Drug due to the occurrence of an adverse event (AE), the investigator should continue to 
observe them after discontinuation, as long as possible until the AE is resolved or resolving. 
The investigator should then enter the result of the observation into 
 and 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

 
3 
electronically sign the eCRF. 
After review of the information, Takeda Pharmaceutical may request for re-survey, if deemed 
necessary, via 
. The investigator will, upon checking, perform the details of the 
requested re-survey and enter the result of the re-survey into 
 and electronically 
sign the eCRF. 
 
7.5 
Action Taken at Onset of Serious Adverse Event 
The investigator will immediately contact the Takeda MR if a serious AE occurs during the 
observation period. The investigator will also separately provide detailed information thereof 
upon request, if any, from the Takeda MR. 
 
8.0 
Expected Duration of Study 
Surveillance period: May 2013 to September 30, 2016 
Patient enrollment period: May 2013 to May 31, 2015* 
 
*Enrollment may be closed before the end of the enrollment period if the total number of 
patients enrolled in the Study reaches the target sample size. 
 
9.0 
Survey Items 
The investigator will enter the information of the following items into 
. The 
schedule for the Study is provided in the Appendix. 
9.1 
Patient Enrollment 
1) Survey items 
Prescription date of the Date, patient ID number, patient initials, sex, birth date, 
determination with inclusion criteria, and determination with exclusion criteria 
2) Survey timing 
The time of patient enrollment 
 
9.2 
Patient Demographics 
1) Survey items 
Height, weight, time of hyperlipidemia diagnosis, treatment category, menopausal status 
(only for female), complications (presence or absence and details), medical history 
(presence or absence and details), hypersensitivity disposition (presence or absence and 
details), drinking history, smoking history, presence or absence of surgery within one 
month before baseline, and presence or absence of healthier lifestyle education (diet and 
exercise therapies) 
2) Survey time 
Baseline 
 
9.3 
Treatment Information 
1) Survey items 
CCI
CCI
CCI

 
4 
Administration of the Drug (daily dose, treatment duration, and status of completion of 
treatment with the Drug), administration of antihyperlipidemic drugs other than the Drug* 
(presence or absence, drug name, daily dose, and treatment duration), and administration of 
concomitant medications (other than antihyperlipidemic drugs) (presence or absence, drug 
name, and purpose of administration) 
*: Including antihyperlipidemic drugs with which treatment is discontinued within two 
months before baseline. 
2) Survey timing 
Period from baseline to Month 12 (or discontinuation of treatment) 
 
9.4 
Testing/Observation Items 
1) Survey items 
Triglyceride (TG), total cholesterol (TC), LDL cholesterol* (LDL-C), HDL cholesterol 
(HDL-C), VLDL cholesterol (VLDL-C), Apo-AI, Apo-B, Apo-CIII, lipoprotein a, remnant 
lipoprotein cholesterol (RLP-C), fasting blood glucose (FBG), HbA1c   *: When tested 
by direct measurement 
2) Survey timing 
Baseline, Month 3, Month 6, Month 9, and Month 12 (or discontinuation of treatment) test 
timepoints 
 
9.5 
Other Observation Items 
1) Survey items 
Pregnancy status 
If the patient is found to be pregnant during the observation period, the investigator 
will report the Takeda MR. The investigator will, upon request from the Takeda MR, use 
a sheet for pregnant women to provide detailed information (including information 
available up to childbirth, including premature birth or other pregnancy results, if 
possible). 
2) Survey timing 
Period from baseline to Month 12 (or discontinuation of treatment) 
 
9.6 
Adverse Events (AEs) 
1) Survey items 
Presence or absence of AE (see Table 1), AE name, date of onset, seriousness and reason 
for seriousness (see Table 2), action taken to the Drug, date of determination of outcome, 
outcome, and causal relationship to the Drug* (see Table 3) 
If the outcome is not resolved or unknown and the casual relationship is determined as 
unevaluable, follow-up survey should be conducted to some extent possible. 
*If causal relationship to the Drug is determined as not related, reasons that may constitute 
the rationale for determination should be collected if it is unevaluable. 
2) Survey timing 

 
5 
Period from baseline to Month 12 (or discontinuation of treatment) 
3) Priority survey item 
Bleeding-related events occurring after baseline are set as a priority survey item. If 
any bleeding-related event is reported as an AE, laboratory test values related to bleeding 
should be separately collected. 
 
 
 

 
6 
Table 1 Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient administered a medicinal 
product and which does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
The following should be also handled as an AE: 
• A symptoms or other problem occurring in an infant breastfed from a mother taking the medicinal 
product 
• A symptom or other problem occurring in a child administered the medicinal product 
• A symptom or other problem occurring in a patient administered or taking more than the approved 
dose of the medicinal product 
 
Table 2 Seriousness Criteria 
An event is classified as serious if: 
1. resulting in death (death), 
2. being life-threatening (at risk of death), 
3. requiring inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization), 
4. resulting in persistent or significant disability/incapacity (disorder), 
5. being a congenital anomaly/birth defect (birth defect), or 
6. being any other medically serious condition that does not fall under any of 1 to 5 above. Note that 
all those listed in the Takeda Medically Significant AE List are included in this criterion. 
(Examples include bronchospasm, which requires short-term intensive care in emergency room 
settings.) 
 
Takeda Medically Significant AE List 
• Acute respiratory failure/acute respiratory distress 
syndrome (ARDS) 
• Anaphylactic shock 
• Torsade de pointes/ventricular 
fibrillation/ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizure (including spasm and 
epilepsy) 
• Pulmonary fibrosis (including interstitial lung 
disease) 
• Agranulocytosis 
• Neuroleptic malignant syndrome/malignant 
hyperthermia 
• Aplastic anaemia 
• Spontaneous abortion/stillbirth and foetal death 
• Toxic epidermal necrolysis/muco-cutaneo-ocular 
syndrome (Stevens-Johnson syndrome) 
• Confirmed or suspected transmission of infection 
by a medicinal product 
• Hepatic necrosis 
• Confirmed or suspected endotoxin shock 
• Acute hepatic failure 
 
 

 
7 
Table 3 Criteria for Casual Relationship between Adverse Event and the Drug 
Determination 
Criteria 
Related 
(if the Drug is suspected to 
have contributed to the event) 
There is temporally evident correlation between the Drug and the 
event (including results from discontinuation of treatment). 
Or the event is an AE considered likely to have been caused by the 
Drug although it is presumed to have been contributed by other 
factors, such as primary disease, complications, concomitant 
medications, or combined treatments. 
Not related 
(if the Drug is considered 
unlikely to have contributed to 
the event) 
There is no temporally evident correlation between the Drug and the 
event. Or the event is adequately considered to have been contributed 
by other factors, such as primary disease, complications, concomitant 
medications, or combined treatments. 
Unevaluable 
There is lack of information necessary for evaluation of the event, 
including temporal correlation (including results from discontinuation 
of treatment), primary disease, complications, concomitant 
medications, and combined treatments. 
 
10.0 
Analysis Items and Method 
10.1 Patient Disposition Items 
Compile information including the number of enrolled patients, number of patients with 
eCRFs collected, numbers of safety- and efficacy-evaluable patients, and the number of 
patients excluded from analysis and reasons for exclusion. 
 
10.2 Patient Demographics 
Compile patient demographic information including sex, age, hypersensitivity disposition, and 
complications. 
 
10.3 Treatment Details 
Compile information on administration of the Drug and of concomitant medications. 
 
10.4 Safety Items 
Compile the following regarding the safety-evaluable population. AEs, coded using MedDRA, 
will be summarized by preferred term (PT) and by system organ class (SOC). 
 Onset Status of Adverse Events 
10.4.1
Compile the incidence of AEs occurring during the observation period, in terms of, e.g., 
causal relationship with the Drug, type, seriousness. Note that bleeding-related events 
should be separately compiled because such events are set as a priority survey item. 
 
 Factors Likely to Affect Safety 
10.4.2
Compile the incidence of ADRs occurring during the observation period, by stratification 
variables: patient baseline characteristics (sex, age, presence or absence of renal 

 
8 
dysfunction, presence or absence of hepatic dysfunction, etc.) and treatment regimen 
(administration of the Drug, administration of concomitant medications such as 
anticoagulant drugs, antiplatelet drugs). 
 
10.5 Efficacy Items 
Compile the following regarding the efficacy-evaluable population. 
 Changes in Lipid Parameters: TG, TC, LDL-C, HDL-C, Non-HDL-C, etc. 
10.5.1
Tabulate observed values and changes (observed value at each observational timepoint after baseline 
minus observed value at baseline) at each observational timepoint for TG, TC, LDL-C (by 
converted value calculated by direct measurement, Friedewald formula*), HDL-C, 
Non-HDL-C (converted value**), VLDL cholesterol, Apo-AI, Apo-B, Apo-CIII, 
lipoprotein a, and RLP-C. 
*: LDL-C = TC-HDL-C - TG / 5 
**: Non-HDL-C = TC-HDL-C 
Note that LDL-C, Non-HDL-C, TC/LDL-C ratio, LDL-C/HDL-C ratio, and LDL-C/Apo-B 
ratio should be calculated from test results. 
 
 Factors Likely to Affect Efficacy 
10.5.2
Compile TG values by stratification variables: patient baseline characteristics (sex and age) 
and treatment regimen (administration of the Drug, administration of concomitant 
medications, etc.). 
 
11.0 
Organizational Structure for Conducting the Study 
Study Chair 
Pharmacovigilance 
Department, 
Pharmaceutical 
Development 
Division, 
Takeda 
Pharmaceutical Co., Ltd. 
 
 
12.0 
Service Contractor’s Name and Address and Scope of Contract Work 
Contractor: 
 
 
Scope of contract work: Data management and statistical analysis 
 
13.0 
Other Necessary Items 
13.1 Protocol Revision 
During the surveillance period, keep track of, e.g., the progress of the Study, the onset of 
unexpected ADRs or serious ADRs based on the precautions, presence or absence of increased 
incidence of specified ADRs, the appropriateness of survey items. If needed, review and revise 
this protocol. If partial change approval is obtained for dosage and administration or 
indications during the surveillance period, examine whether to revise this protocol if necessary 
and revise it if necessary. 
PPD
PPD

 
9 
 
13.2 Action Taken in Case of Problem or Question 
If any problem is found in the safety or efficacy of the Drug, carefully review the data and 
examine what needs to be done. 

 
10 
Appendix Study Schedule 
Survey and Data Entry Timing 
 
Survey Item 
Observation Period 
Patient 
enrollme
nt
Baseline 
Month 
3 
Month 
6 
Month 
9 
Month 
12 
Discon- 
tinuation 
Patient Enrollment 
Prescription date of the Drug 
○ 
 
 
 
 
 
 
Patient ID number 
○ 
Patient initials 
○ 
Sex 
○ 
Birth date 
○ 
Inclusion criteria/exclusion criteria 
○ 
Patient demographics 
Height, Weight 
○ 
 
 
 
Time of hyperlipidemia diagnosis 
○ 
 
 
 
Treatment category 
○ 
 
 
 
Menopausal status (only for female) 
○ 
 
 
 
Complications 
○ 
 
 
 
Medical history 
○ 
 
 
 
Hypersensitivity disposition 
 
○ 
 
 
 
Drinking history, smoking history 
 
○ 
 
 
 
Presence or absence of surgery before 
baseline 
 
○ 
 
 
 
Presence or absence of healthier 
lifestyle education (diet and exercise 
therapies) 
 
○ 
 
 
 
 
 
Treatment 
Information 
Administration of the Drug 
○ 
○ 
Administration of other 
antihyperlipidemic drugs 
○ 
○ 
Administration of concomitant 
medications (other than 
antihyperlipidemic drug) 
 
○ 
○ 
Testing /Observation Items 
TG 
○ 
○ 
○ 
○ 
○ 
○ 
TC 
○ 
○ 
○ 
○ 
○ 
○ 
LDL-C (direct measurement) 
○ 
○ 
○ 
○ 
○ 
○ 
HDL-C 
○ 
○ 
○ 
○ 
○ 
○ 
VLDL-C 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-AI 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-B 
○ 
○ 
○ 
○ 
○ 
○ 
Apo-CIII 
○ 
○ 
○ 
○ 
○ 
○ 
Lipoprotein a 
○ 
○ 
○ 
○ 
○ 
○ 
RLP-C 
○ 
○ 
○ 
○ 
○ 
○ 
FBG 
○ 
○ 
○ 
○ 
○ 
○ 
HbA1c 
○ 
○ 
○ 
○ 
○ 
○ 
Pregnancy status (only for female) 
○ 
○ 
AE 
○ 
○ 
○: Surveyed, tested, or observed     ○:     Surveyed, tested, or observed throughout the period