Specified Drug-use Survey of Lotriga Granular Capsules: OCEAN3 (Outcome Prevention on Cardiovascular Events by Antihyperlipidemic Therapy With N3-fatty Acid in Japan)
Conditions: Hyperlipidemia
Sponsor: Takeda

 
 
Title: Specified drug-use survey of Lotriga Granular Capsules: OCEAN3 (Outcome 
prevention on Cardiovascular Events by Antihyperlipidemic therapy with N3-fatty acid 
in Japan) 
 
NCT Number: NCT02285166 
Protocol Approve Date: 01-JUN-2019 
 
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: 
z 
Named persons or organizations associated with the study. 
z 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
z 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
z 
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. 

 
 
 
 
 
Specified Drug-Use Survey Protocol 
Specified Drug-Use Survey of Lotriga Granular 
Capsules 
OCEAN3 
Outcome prevention on Cardiovascular Events by Antihyperlipidemic therapy 
with N3-fatty acid in Japan 
Version Number 
Version 8 
Date of Preparation 
June 1, 2019 
Sponsor 
Takeda Pharmaceutical Company Limited 
Property of Takeda: For non-commercial 
sion 
on 
June 1
une 1
Tak
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use 
8
only and subject to the 
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applicable 
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Terms of Use

 
 
Table of Contents 
1.0
Background .................................................................................................................................................... 1
2.0
Objectives ....................................................................................................................................................... 1
3.0
Survey Design ................................................................................................................................................ 1
4.0
Planned Sample Size and Rationale ............................................................................................................... 1
4.1
Planned sample size ................................................................................................................................... 1
4.2
Rationale .................................................................................................................................................... 2
5.0
Target Patient Population ............................................................................................................................... 2
5.1
Inclusion criteria ........................................................................................................................................ 2
5.2
Exclusion criteria ....................................................................................................................................... 3
6.0
Dosage and Administration ............................................................................................................................ 3
7.0
Planned Number of Survey Sites by Specialty ............................................................................................... 3
8.0
Methods .......................................................................................................................................................... 4
8.1
Duration of observation .............................................................................................................................. 4
8.2
 4
8.3
 4
8.4
 5
8.5
 5
9.0
Planned Survey Period ................................................................................................................................... 7
10.0
Survey Items ................................................................................................................................................... 8
10.1
Patient enrollment ...................................................................................................................................... 8
10.2
Patient demographics information ............................................................................................................. 8
10.3
Treatment information ................................................................................................................................ 8
10.4
Items of the tests and observation .............................................................................................................. 9

Vital signs, electrocardiogram (ECG) ................................................................................................ 9

Laboratory tests .................................................................................................................................. 9

Other observation items ...................................................................................................................... 9

Cardiovascular events ....................................................................................................................... 10

Continuation of observation ............................................................................................................... 11
11.0
Items Concerning Evaluation ....................................................................................................................... 12
11.1
Primary endpoint ...................................................................................................................................... 12
11.2
Analysis of the primary endpoint ............................................................................................................. 12
11.3
Secondary endpoints ................................................................................................................................ 12
11.4
Analysis of the secondary endpoints ........................................................................................................ 12
11.5
Other endpoints ........................................................................................................................................ 12
11.6
Analysis of other endpoints ...................................................................................................................... 12
12.0
Registration of Survey Information .............................................................................................................. 13
13.0
Administrative Structure .............................................................................................................................. 13
13.1
Administrative manager ........................................................................................................................... 13
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13.2
Medical advisors ...................................................................................................................................... 13
13.3
Event assessment committee members .................................................................................................... 13
13.4
Statistical advisor ..................................................................................................................................... 13
14.0
Contract Research Organizations ................................................................................................................. 13
15.0
Other Necessary Items .................................................................................................................................. 14
15.1
Protocol amendments ............................................................................................................................... 14
15.2
Actions to be taken in response to detection of any issues or concerns ................................................... 15
16.0
References .................................................................................................................................................... 15
 
 16 
 18 
 
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1.0 
Background 
Lotriga Granular Capsules (Lotriga) is an omega-3 fatty acid preparation containing highly pure 
eicosapentaenoic acid ethyl ester (EPA-E) and docosahexaenoic acid ethyl ester (DHA-E) made 
from oceanic fish oil. Lotriga has been confirmed to have triglyceride (TG)-lowering effect and 
ameliorate lipid quality, including a larger LDL particle size, in clinical studies in patients with 
hypertriglyceridemia and is indicated for hyperlipidemia. 
The goal of the treatment of hyperlipidemia is not only to ameliorate lipid parameters but also 
to inhibit cardiovascular events attributable to arterial sclerosis associated with hyperlipidemia.  
An epidemiological study conducted overseas [1] suggests a combination therapy with an 
omega-3 fatty acid preparation and an HMG-CoA reductase inhibitor (statin) decreases all-
cause deaths, onset of cardiac failure, etc. as compared with statin monotherapy in patients with 
myocardial infarction. 
In addition, in Study GISSI-Prevenzione [2] conducted overseas, the secondary prevention 
effect of Lotriga on cardiovascular events has been demonstrated in patients with myocardial 
infarction, and Lotriga is indicated for prevention of recurrence of myocardial infarction in EU 
nations, such as the UK, France, Germany, Norway, and Austria. 
However, there have been no results of epidemiological studies showing the status of onset of 
cardiovascular events in patients treated with Lotriga in Japan. 
Therefore, in order to clarify the status of onset of cardiovascular events under long-term 
treatment with Lotriga in patients with hyperlipidemia on statin therapy with a high risk of 
cardiovascular events (patients with high-risk hyperlipidemia), this specific drug-use survey 
(survey) has been planned. 
This survey will be conducted in compliance with the Ministerial Ordinance on Good Post-
Marketing Study Practice (GPSP) and relevant regulatory requirements. 
 
2.0 
Objectives 
To reveal the status of onset of cardiovascular events associated with long-term treatment with 
Lotriga in high-risk hyperlipidemic patients on statin therapy in daily medical practice and to 
collect data from patients treated with Lotriga in this survey in order to compare the status of 
onset of cardiovascular events between patients treated with and without Lotriga just for 
information. 
 
3.0 
Survey Design 
Prospective cohort study with control (patients treated without Lotriga) 
 
4.0 
Planned Sample Size and Rationale 
4.1
Planned sample size 
Patients treated with Lotriga: 7,000 patients 
Patients treated without Lotriga: 7,000 patients 
However, 8,400 patients will be enrolled as patients treated without Lotriga. By doing 
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this, approximately 7,000 patients are expected to be gathered as the control. 
 
 
4.2
Rationale 
In order to gather as many patients as possible within the feasible range in this survey, 
the planned sample size was set with 7,000 patients treated with Lotriga and 7,000 
patients treated without Lotriga. 
In JELIS [3] conducted in Japanese hypercholesterolemic patients, in terms of patients 
with a history of coronary artery disease, the incidences of cardiovascular events in the 
EPA-E group and the control group 5 years after the start of the observation period 
were 8.7% and 10.7%, respectively. By reference to the above, the incidences of 
cardiovascular events in patients treated with Lotriga and patients treated without 
Lotriga 3 years after the start of the observation period are estimated to be 4.8% and 
6.0%, respectively. Given that patients are uniformly enrolled and the observation 
period is 3 years (36 months) in every patient, according to the method of Schoenfeld 
and Richter [4], a power of 80% will be ensured on log-rank test with the significance 
level of 5% (two-sided) in 5,600 each of patients treated with Lotriga and patients 
treated without Lotriga. Therefore, even with dropout of 20% of patients to be surveyed, 
assessment can be made at a certain level. 
 
5.0 
Target Patient Population 
Patients who meet the following inclusion criteria and do not meet any of the exclusion criteria 
will be included. Among the patients, patients who will newly receive Lotriga will be enrolled 
as patients treated with Lotriga, and the other patients will be enrolled as patients treated without 
Lotriga. The PRECAUTIONS section of the Lotriga package insert should also be referenced 
for patients treated with Lotriga. 
5.1
Inclusion criteria 
Patients who meet all of the following criteria will be included. 
[1] Patients with hyperlipidemia on statin therapy 
[2] Outpatients 
[3] Male patients DJHG\HDUV or female patients DJHG\HDUV 
[4] Patients with a fasting TG level 150 mg/dL (within 3 months prior to the start 
of the observation period*1) 
[5] Patients with two or more of the following risk factors: 
• 
Hypertension*2 
• 
Type 2 diabetes mellitus*3 
• 
Chronic kidney disease*4 
• 
History of myocardial infarction or angina pectoris 
• 
History of cerebral infarction 
• 
Peripheral arterial disease*5 
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*1 Start date of Lotriga for patients treated with the drug; patient enrollment date (the date on 
which information concerning patient enrollment was entered in PostMaNet and an electronic 
signature was provided (See Section 8.3-2); the same is applicable to the below) for patients 
treated without Lotriga 
*2 Systolic EORRGSUHVVXUH140 mm Hg or diastolic EORRGSUHVVXUH90 mm Hg or under 
antihypertensive therapy 
*3 HbA1c 6.5% (NGSP value) or under treatment with antidiabetic drugs (including insulin) 
*4 Persistence of either/both of eGFR < 60 mL/min/1.73 m2 or/and SRVLWLYHXULQDU\SURWHLQIRU 
3 months prior to the start of observation period 
*5 Ankle-brachial index  0.9 
5.2
Exclusion criteria 
Patients who meet any of the following criteria will be excluded. 
[1] Patients who have experienced coronary artery disease within a month prior to 
the start of the observation period 
[2] Patients who have experienced cerebrovascular accident within a month prior to 
the start of the observation period 
[3] Patients who have undergone cardiac surgery or revascularization (including 
coronary intervention and peripheral artery intervention) within a month prior to 
the start of the observation period 
[4] Patients scheduled to undergo cardiac surgery or revascularization (including 
coronary intervention and peripheral artery intervention) 
[5] Patients receiving treatment of malignant tumors 
[6] Patients who have received eicosapentaenoic acid (EPA) preparations within a 
month prior to the start of the observation period or who are scheduled to receive 
EPA preparations after the start of the observation period 
[7] Patients with bleeding (e.g., hemophilia, capillary fragility, gastrointestinal ulcer, 
urinary tract hemorrhage, hemoptysis, vitreous hemorrhage) 
[8] Patients with a history of hypersensitivity to the ingredients of Lotriga (applicable 
only to patients who will receive Lotriga) 
[9] Patients with a history of receiving Lotriga 
 
6.0 
Dosage and Administration 
The usual adult dosage is 2 g of omega-3 fatty acid ethyl ester administered orally immediately 
after a meal once daily. The dose can be increased up to 2 g twice daily. The PRECAUTIONS 
section of the package insert should also be referenced. 
7.0 
Planned Number of Survey Sites by Specialty 
Approximately 3,000 medical institutions (cardiology, internal medicine, etc.) 
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8.0 
Methods 
8.1
Duration of observation 
36 months from the start date of observation period*. In patients treated with Lotriga, 
observation will be performed for 36 months even in the case of discontinuation of the 
drug. 
*Start date for patients treated with Lotriga and patient enrollment date for patients
treated without Lotriga
8.3
 
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<Matching factors of patient demographics> 
•
Age
< 65 years, 65 years and < 7\HDUV75 years
•
Sex
Male, female
•
Important risk factors
Presence/absence of a history of myocardial infarction, angina pectoris, or cerebral
infarction
•
Fasting TG level
< 200 mg/dL200 mg/dL
Table 1 Patient Groups based on Matching Factors of Patient Demographics 
< 65 years 
65 years 
and 
< 75 years 
75 years 
Male 
With important risk 
factors* 
Fasting TG < 200 mg/dL 
[1] 
[2] 
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risk factors* 
Fasting TG < 200 mg/dL 
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Fasting TG < 200 mg/dL 
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Fasting TG < 200 mg/dL 
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*history of myocardial infarction, angina pectoris, or cerebral infarction
8.5
 
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Table 2 Definition of an Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment. 
An adverse event can therefore be any unfavorable or unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not 
the event is considered causally related to the use of the product. 
Note that the following events will also be handled as adverse events:  
• 
Any manifestation in an infant breastfed by a mother taking this drug 
• 
Any untoward manifestation in a child given this drug 
• 
Any manifestation due to occupational exposure to this drug 
• 
Any manifestation due to a counterfeit product of a prescription drug marketed by Takeda 
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Table 3 Criteria for Seriousness Assessment 
An adverse event is assessed as “serious” if it results in any of the following outcomes: 
1. results in death (Death), 
2. is life-threatening (Life-threatening), 
3. requires hospitalization or prolongation of existing hospitalization (Hospitalization/Prolongation of 
hospitalization), 
4. results in persistent or significant disability/incapacity (Disability), 
5. leads to a congenital anomaly or birth defect (Congenital anomaly), or 
6. is any other important medical event that does not fulfil 1 to 5 above. 
Serious adverse events include events described in the “Takeda Medically Significant AE List.”  
 
Takeda Medically Significant AE List 
• Acute respiratory failure / Acute respiratory 
distress syndrome (ARDS) 
• Torsade de pointes / Ventricular fibrillation / 
Ventricular tachycardia 
• Malignant hypertension 
• Convulsive seizure (including convulsion and 
epilepsy) 
• Agranulocytosis 
• Aplastic anaemia 
• Toxic epidermal necrolysis / 
Oculomucocutaneous syndrome (Stevens-Johnson 
syndrome) 
• Hepatic necrosis 
• Acute hepatic failure 
• Anaphylactic shock 
• Acute renal failure 
• Pulmonary hypertension 
• Pulmonary fibrosis (including interstitial 
pneumonia) 
• Neuroleptic malignant syndrome/ Malignant 
hyperthermia 
• Spontaneous abortion / Stillbirth and fetal death 
• Confirmed or suspected transmission of infectious 
agent by a medicinal product 
• Confirmed or suspected endotoxin shock 
 
9.0 
Planned Survey Period 
Survey period: October 2014 to December 31, 2019 
Patient enrollment period* 
Patients treated with Lotriga: October 2014 to December 31, 2016 
Patients treated without Lotriga: October 1, 2015 to December 31, 2016 
*Patients treated with Lotriga shall not be enrolled (entered in PostMaNet) on or after January 
1, 2017 even though they have received a prescription of the drug by December 31, 2016. 
If the total number of the patients enrolled in the entire survey reach the planned sample size 
before December 31, 2016, patient enrollment may be closed before the end of the patient 
enrollment period. 
If the patient enrollment period is shortened, the surveillance period will also be changed 
according to the shortened enrollment period. 
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10.0 Survey Items 
The survey investigator shall enter the following data in PostMaNet. The schedule of this 
survey is shown in Appendix 1. 
10.1 Patient enrollment 
1) Survey items 
Category of the target patients of the survey (patients treated with Lotriga or patients 
treated without Lotriga), prescription date (patients treated with Lotriga), enrollment 
date (patients treated without Lotriga: automatically entered), patient identification 
number, patient initials, sex, date of birth, assessment on the basis of the inclusion 
criteria, fasting TG level within 3 months prior to the start of observation, time of 
the onset of the most recent myocardial infarction or cerebral infarction prior to the 
start of observation period and the number of previous episodes (in patients with a 
history of myocardial infarction or cerebral infarction), assessment on the basis of 
the exclusion criteria, presence/absence of a history of percutaneous transluminal 
coronary angioplasty (PCI), coronary artery bypass grafting (CABG), or peripheral 
artery intervention and the time of the most recent procedure prior to the start of 
observation period 
2) Time of data collection 
At enrollment of the patient 
10.2
Patient demographics information 
1) Survey items 
Height, weight, smoking history, drinking history, frequency of hospital visits, 
frequency of fish intake, presence/absence of a history or concurrence of 
cerebral/cardiac/vascular disorders*, time of onset of the most recent episode of 
cerebral hemorrhage or subarachnoid hemorrhage prior to the starting day of 
observation period and the number of previous episodes (if the patient has a history of 
cerebral hemorrhage or subarachnoid hemorrhage), family history of coronary artery 
disease and cerebrovascular accident (parents, brothers/sisters) 
*Atrial fibrillation, left ventricular hypertrophy, cardiac failure, cerebral hemorrhage, 
subarachnoid hemorrhage, transient ischemic attack (TIA), aortic aneurysm, aortic dissection 
2) Time of data collection 
At the start of the observation period 
10.3
Treatment information 
1) Survey items 
Status of the treatment with statin (drug name, daily dose, start and end dates), status 
of the treatment with Lotriga (daily dose, start and end dates), status of the treatment 
with EPA preparations (presence/absence, if present, with start and end dates, and 
indication), status of the treatment with activated vitamin D preparations 
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(presence/absence, if present, with start and end dates), presence/absence of diet 
therapy*, presence/absence of exercise therapy*, status of intake of OTC or dietary 
supplements (presence/absence and the details if present)*, status of treatment with 
antihyperlipidemic 
drugs 
(other 
than 
statins/Lotriga/EPA 
preparations), 
antihypertensives, antidiabetics, antiplatelets, and anticoagulants (presence/absence, if 
present, with details)*, presence/absence of the treatment with nitrates* 
 
2) Time of data collection 
From the start of observation until at 36 months (or at discontinuation of observation) 
*At the start of observation period, at 6, 12, 18, 24, 30, and 36 months (or at 
discontinuation of observation) 
10.4
Items of the tests and observation 
 Vital signs, electrocardiogram (ECG) 
1) Measurement items 
Blood pressure measured at a medical institution (systolic/diastolic), pulse rate, ECG 
2) Time of data collection 
At the start of the observation period, and the points of measurement at 6, 12, 18, 24, 
30 and 36 months (or at discontinuation of observation) 
 
 Laboratory tests 
1) Test items 
TG*, total cholesterol (TC)1), HDL-cholesterol (HDL-C)1), LDL-cholesterol (LDL-
C)1)2), 
EPA, 
docosahexaenoic 
acid 
(DHA), 
arachidonic 
acid 
(AA), 
dihomogammalinolenic acid (DHLA), HbA1c (NGSP value) 
1) The status of a meal at blood collection (fasting or postprandial) will be 
investigated. 
2) In the case of direct measurement 
2) Time of data collection 
At the start of the observation period, and the points of test at 6, 12, 18, 24, 30 and 36 
months (or at discontinuation of observation) 
 Other observation items 
1) Observation items 
Presence/absence of pregnancy during the observation period (only in female patients 
treated with Lotriga) 
Any pregnancy found during the observation period should be immediately notified to 
a Takeda representative. Based on a request by a Takeda representative, the survey 
investigator shall provide detailed information (wherever possible up to the outcome 
of pregnancy, such as premature delivery) separately using a pregnancy report form. 
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2) Time of data collection 
From the start of observation period until at 36 months (or at discontinuation of 
observation) 
 Cardiovascular events 
The following are defined as cardiovascular events. The definitions of the cardiovascular 
events are shown in Appendix 2. 
• 
Major cardiovascular events 
Cardiovascular death [sudden death, fatal myocardial infarction, fatal cardiac 
failure, fatal stroke (cerebral infarction, cerebral hemorrhage, subarachnoid 
hemorrhage), other cardiovascular deaths] 
Non-fatal myocardial infarction 
Non-fatal stroke (cerebral infarction, cerebral hemorrhage, subarachnoid 
hemorrhage) 
• 
Angina pectoris requiring hospitalization* 
• 
Angina pectoris requiring coronary revascularization (PCI or CABG) 
• 
Cardiac failure requiring hospitalization 
• 
Transient ischemic attack requiring hospitalization 
• 
Peripheral artery disease requiring hospitalization* 
• 
Peripheral artery disease requiring surgery or peripheral artery intervention 
*Including single-day percutaneous revascularization 
1) Survey items 
Presence/absence and details of cardiovascular events and non-cardiovascular deaths 
(cardiovascular events, etc.), rationale for diagnosis, presence/absence of diagnosis by 
a specialist, date of onset, date of death (in fatal cases), outcome, date of outcome 
assessment, causality between cardiovascular events, etc. and Lotriga (only in patients 
treated with Lotriga) (Table 4) 
Follow-up investigation should be performed to the extent possible when the outcome 
of cardiovascular event, etc. is ‘unresolved’ or ‘unknown’ (non-fatal cardiovascular 
events) and when the causality between the cardiovascular event, etc. and Lotriga is 
determined to be unassessable. 
2) Time of data collection 
From the start of observation until at 36 months (or at discontinuation of observation) 
 
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11 
 
 Continuation of observation 
1) Survey items 
Presence/absence of continuous observation, reason for discontinuation of observation, 
the last date of observation 
2) Time of data collection 
At 12 and 36 months after the start of the observation period (or at discontinuation of 
observation) 
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11.0 Items Concerning Evaluation 
11.1
Primary endpoint 
Time to the initial onset of one of the following cardiovascular events: 
Any of the composite of the major cardiovascular events (See Section 10.4.4), angina 
pectoris requiring coronary revascularization (PCI or CABG), peripheral artery disease 
requiring surgery or peripheral artery intervention 
 
11.2 Analysis of the primary endpoint 
The cumulative incidence will be estimated using Kaplan-Meier method at each point. 
Just for information, an analysis in consideration of the covariates (e.g., analysis using 
Cox proportional hazard model) will be performed for the period from the start of the 
observation period until the onset of an event to compare patients treated with Lotriga 
with patients treated without Lotriga. An analysis using propensity scores (e.g., 
propensity score matching) will be performed on an as-needed basis. 
In addition, the same analysis will be performed respectively according to 
presence/absence of a history of myocardial infarction, angina pectoris, coronary 
revascularization, cerebral infarction, or cerebral hemorrhage. 
11.3
Secondary endpoints 
[1] Time to all-cause death (cardiovascular deaths and non-cardiovascular deaths) 
[2] Time to the initial onset of any of the composite of the major cardiovascular events 
[3] Time to the initial onset of any of all cardiovascular events (See Section 10.4.4) 
[4] Time to the onset of individual cardiovascular events 
 
11.4 Analysis of the secondary endpoints 
The same analysis as that for the primary endpoint will be performed. 
11.5
Other endpoints 
[1] Time to the initial onset of any of the following: fatal myocardial infarction, non-
fatal myocardial infarction, or angina pectoris requiring hospitalization 
[2] Time to the initial onset of any of the following: fatal stroke, non-fatal stroke, or 
transient ischemic attack 
[3] Changes in the vital signs (blood pressure and pulse rate), changes in the laboratory 
test values (serum lipids, EPA, DHA, AA, DHLA, and HbA1c), onset of any 
clinically problematic change on ECG 
 
11.6 Analysis of other endpoints 
The same analysis as that for the primary endpoint will be performed for [1] and [2] of 
Section 11.5. 
Among the items listed in [3] of Section 11.5, the test values and the amounts of change 
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13 
(values at each testing after the start of the observation period ̽ baseline values) will be 
aggregated for vital signs and the changes in the laboratory test values. In addition, 
assessment results will be aggregated for ECG according to the point of testing. 
12.0 Registration of Survey Information 
Before the start of the survey, Takeda Pharmaceutical Company Limited will register the 
survey information with online public clinical trials registries: 
• Japan Pharmaceutical Information Center (JAPIC) Clinical Trials Information 
• National Institute of Health Clinical Trial Registration System: Clinical Trials.gov 
 
13.0 Administrative Structure 
13.1
Administrative manager 
Post-marketing survey manager, Takeda Pharmaceutical Company Limited 
13.2
Medical advisors 
The medical advisors shall provide advice on interpretation, publication, etc. of the 
survey plan and the results. 
13.3
Event assessment committee members 
The committee members shall determine how to handle the cardiovascular events 
reported by the survey investigator and request additional information to the survey 
investigator on an as-needed basis. Event assessment shall be made with blinding of 
the surveyed patients (patients treated with Lotriga, patients treated without Lotriga). 
13.4
Statistical advisor 
The statistical advisor shall provide advice on preparation of the statistical analysis 
plan, etc. 
14.0 Contract Research Organizations 
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14 
Duty: Data management 
Duties: Data management, statistical analysis, and medical writing 
Duties: Storage of records, PDF conversion of AE reports and supportive activities related 
to provision of information 
 
Duties: Construction and operation of PostMaNet 
 
Duty: Management of progress of monitoring 
 
Duty: Monitoring 
 
Duty: Monitoring 
 
Duty: Monitoring 
 
15.0 Other Necessary Items 
15.1
Protocol amendments 
During the survey period, monitoring shall be performed regarding the progress of the 
surveillance, occurrence of ADRs unpredictable on the basis of the PRECAUTIONS and 
serious ADRs, any increase in the incidence of particular ADRs, appropriateness of the 
survey items, etc., and the protocol shall be reviewed and amended as necessary. If any 
partial change to the DOSAGE AND ADMINISTRATION, INDICATIONS, etc. is 
approved during the surveillance period, necessity of protocol amendments shall be 
discussed, and the protocol shall be amended as necessary. 
PPD
PPD
PPD
PPD
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PPD
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15 
 
15.2
Actions to be taken in response to detection of any issues or concerns 
When any issue is found regarding the safety or efficacy, the data will be investigated in 
detail, and necessary actions will be determined. 
 
 
16.0 References 
[1] Macchia A, Romero M, D'Ettorre A, Tognoni G, Mariani J. Exploratory analysis on the 
use of statins with or without n-3 PUFA and major events in patients discharged for 
acute myocardial infarction: an observational retrospective study. PLoS One. 2013 May 
6;8(5):e62772. 
[2] Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Dietary 
supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial 
infarction: results of the GISSI Prevenzione trial. Lancet. 1999;354:447-455. 
[3] Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, 
Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, 
Shirato K. Effects of eicosapentaenoic acid on major coronary events in 
hypercholesterolaemic patients (JELIS): A randomised open-label, blinded endpoint 
analysis. Lancet. 2007;369:1090–1098. 
[4] Schoenfeld DA, Richter JR. Nomograms for calculating the number of patients needed 
for a clinical trial with survival as an endpoint. Biometrics. 1982 Mar;38(1):163-170. 
Property of Takeda: For non-commercial use only
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Prope
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Use