Clinical trial NCT02104817
Conditions: Eligible Men or Women Considered High Risk for Atherosclerotic Cardiovascular Disease (CVD)
Keywords: omega-3 carboxylic acid
Sponsor: AstraZeneca
Start date: 2014-10-30; Completion date: 2020-05-27
Enrollment: 13078 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is a randomized, double-blind, placebo-controlled (corn oil), parallel group design that will enroll approximately 13,000 patients with hypertriglyceridemia and low HDL and high risk for CVD to be randomized 1:1 to either corn oil + statin or Epanova + statin, once daily, for approximately 3-5 years as determined when the number of MACE outcomes is reached.

Detailed description:

Arms: arm 1: Epanova + statin, once daily arm 2: Corn oil + Statin
Interventions: intervention 1: Epanova® (omega-3 carboxylic acids) intervention 2: corn oil control
Intervention descriptions: intervention 1: Adjunct to statin therapy and diet in high risk adult patients for the prevention and reduction of major adverse cardiovascular events (MACE) intervention 2: corn oil control arm

Protocol documents:
Prot_000.pdf: 
A Long-Term Outcomes Study to Assess
Protocol D5881C00004
STatin Residual Risk Reduction with EpaNova in HiGh 
Cardiovascular Risk PatienTs with Hypertriglyceridemia (STRENGTH)
May 2015
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A Long-Term Outcomes Study to Assess STatin Residual Risk Reduction with 
EpaNova in HiGh Cardiovascular Risk PatienTs with Hypertriglyceridemia 
(STRENGTH)
Investigational Product: Epanova® (omega-3 carboxylic acids)
IND No.: 107,616
Phase: III
Protocol Number: D5881C00004
EudraCT Number: 2014-001069-28
Document Dates
Original Protocol v1.0:
March 2014
Amended Protocol v2.0
July 2014
Amended Protocol v3.0
September 2014
Administrative Change 
Number 1
October 2014
Amended Protocol v4.0
May 2015
Sponsor:
AstraZeneca AB
151 85 Södertälje, Sweden
Confidentiality Statement
The information in this document is confidential and is not to be disclosed without the written consent of 
AstraZeneca AB, except to the extent that disclosure would be required by law and for the purpose of 
evaluating and/or conducting a clinical study for AstraZeneca. You are allowed to disclose the contents of 
this document only to your Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and 
study personnel directly involved with conducting this protocol. Persons to whom the information is 
disclosed must be informed that the information is confidential and proprietary to AstraZeneca and that it 
may not be further disclosed to third parties.


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Cardiovascular Risk PatienTs with Hypertriglyceridemia (STRENGTH)
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PRINCIPAL INVESTIGATOR SIGNATURE SHEET
A Long-Term Outcomes Study to Assess STatin Residual Risk Reduction with 
EpaNova in HiGh Cardiovascular Risk PatienTs with Hypertriglyceridemia 
(STRENGTH)
Protocol Number: D5881C00004
By my signature below, I attest that I have read, understood, and agree to abide by all 
conditions, instructions, and restrictions contained in this protocol (including 
appendices). I will not initiate this study without approval from the appropriate 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and I 
understand that any changes in the protocol must be approved in writing by AstraZeneca 
AB and the IRB/IEC before they can be implemented, except where necessary to 
eliminate immediate hazards to the patient.
Approval Signature
Principal Investigator: _________________________________ Date _____________
Signature
_________________________________
Printed Name
_________________________________
Name of Facility
_________________________________
Address
_________________________________
City, State, Zip Code
_________________________________
Phone Number
_________________________________
Fax Number
_________________________________
Email Address
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A Long-Term Outcomes Study to Assess
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STatin Residual Risk Reduction with EpaNova in HiGh 
Cardiovascular Risk PatienTs with Hypertriglyceridemia (STRENGTH)
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PROTOCOL SYNOPSIS
TITLE:
A Long-Term Outcomes Study to Assess STatin Residual Risk Reduction with EpaNova in HiGh 
Cardiovascular Risk PatienTs with Hypertriglyceridemia (STRENGTH)
PROTOCOL NUMBER: 
D5881C00004
INVESTIGATIONAL PRODUCT:
Epanova® (omega-3 carboxylic acids)
US IND No. 
107,616
PHASE: III
INDICATION:
Adjunct to statin therapy and diet in high cardiovascular risk adult patients with persistent 
hypertriglyceridemia and low HDL-cholesterol (HDL-C) for the prevention and reduction of 
major adverse cardiovascular events (MACE)
PRIMARY OBJECTIVE and OUTCOME MEASURE:
Primary Objective
The primary objective is to evaluate the effectiveness of adding Epanova to statin therapy (with 
or without ezetimibe) for lowering MACE (cardiovascular death, non-fatal myocardial infarction, 
non-fatal stroke, emergent/elective coronary revascularization, or hospitalization for unstable 
angina) in high cardiovascular risk patients with persistent hypertriglyceridemia and low HDL-
cholesterol (HDL-C).
Primary Outcome Measure
The primary outcome measure is the time to the first occurrence of any component of the 
composite of MACE. Patients will remain in the study until the required number of patients with 
MACE has occurred. We anticipate that patients will be in the study for 3-5 years. Patients who 
discontinue investigational product (IP) will continue to be assessed as specified per the protocol.
POPULATION:
Eligible men or women considered at high risk for atherosclerotic cardiovascular events, with 
low-density lipoprotein cholesterol (LDL-C) <100 mg/dL (<2.59 mmol/L) while on statin 
therapy (with or without ezetimibe), or LDL-C ≥100 mg/dL (≥2.59 mmol/L) while on a high-
intensity or maximum tolerated moderate- or low-intensity statin therapy, with or without 
ezetimibe,for at least 4 weeks, and who have triglycerides (TG) ≥180 and <500 mg/dL (≥2.03
and <5.65 mmol/L) and HDL-C <42 mg/dL (1.09 mmol/L) for men or HDL-C <47 mg/dL (1.22
mmol/L) for women.
STUDY DESIGN AND DURATION:
The study is a randomized, double-blind, placebo-controlled (corn oil), parallel group design that 


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will enroll approximately 13,000 patients with hypertriglyceridemia and at high risk for CVD. 
Patients will be randomized to either Epanova or placebo (corn oil), administered once daily, for 
approximately 3-5 years as determined by the number of patients with MACE. There will be up 
to 3 screening/washout visits, depending on the need for a repeat lab for statin/ezetimibe 
adjustment, discontinuation of excluded lipid-modifying agent, or a borderline TG and/or high-
density lipoprotein (HDL-C) value. During the screening period, patients will maintain a stable 
diet, and after randomization, patients must be willing to adhere to the National Cholesterol 
Education Program (NCEP) Therapeutic Lifestyle Changes (TLC) or equivalent diet at the 
discretion of the investigator. During the screening period, and thereafter, patients will not be 
permitted to use any excluded therapies or products, and will continue or adjust their prescribed 
statin regimen as applicable. Patients who meet all Inclusion Criteria and no Exclusion Criteria 
will be randomized 1:1 (6,500/arm) to receive double-blinded Epanova (4 g daily) or a matching 
placebo (corn oil) (4 g daily) for the study duration. The randomization visit will be Month 0 and 
there will be 11 treatment visits at Months 3, 6 12, 18, 24, 30, 36, 42, 48, 54 and 60. There will 
be a 3-week follow-up visit after an early termination (ET) visit for those patients who undergo 
early permanent IP discontinuation due to a serious adverse event (SAE). All patients should be 
asked to continue the regular study visits thereafter.
INCLUSION CRITERIA
Patients who have provided written informed consent and an authorization for disclosure 
of protected health information must meet the following criteria:
1.
Men or women, ≥18 years of age.
2.
Patient must be on a stable diet and statin* therapy at least 4 weeks prior to randomization 
(Visit 2) and meet the following criteria, where the qualifying lipid parameters should be 
obtained from the same visit:
a.
LDL-C <100 mg/dL (<2.59 mmol/L). Patient will also qualify if LDL-C ≥100 mg/dL
(≥2.59 mmol/L) and if on a high-intensity statin (atorvastatin 40 or 80 mg and 
rosuvastatin 20 or 40 mg) or on maximum tolerated moderate- or low-intensity statin 
dose, with or without ezetimibe therapy, for at least 4 weeks (see Appendix D).  The 
maximum tolerated dosage of a statin is defined as the approved dose per local label that 
the patient can tolerate without unacceptable adverse effects such as muscle 
aches/pain/weakness or elevations in liver enzymes or creatine kinase (CK) that are 
determined by the investigator to be clinically relevant and due to statin therapy.
b. TG ≥180 and < 500 mg/dL (≥2.03 and < 5.65 mmol/L) and HDL-C <42 mg/dL 
(1.09 mmol/L) for men or HDL-C <47 mg/dL (1.22 mmol/L) for women
*co-administration with ezetimibe or fixed-dose ezetimibe/simvastatin 10/10, 10/20, 
10/40 mg (see restrictions regarding 80 mg simvastatin in Section 7.4) or fixed-dose 
ezetimibe/atorvastatin 10/10, 10/20, 10/40, or 10/80 mg is allowed.


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3.
Patient is at high risk for a future cardiovascular event if at least one of the following criteria
(3a, 3b or 3c)* is present via patient history, physical exam, or medical records at the time of 
screening:
a.
Any atherosclerotic CVD  as defined by one or more of the following:
∀
previous clinical myocardial infarction (MI) ≥30 days prior to randomization
∀
percutaneous coronary intervention (PCI) including balloon angioplasty and 
coronary stenting ≥6 months prior to randomization
∀
coronary artery bypass grafting (CABG) ≥30 days prior to randomization
∀
coronary angiogram including computed tomography angiogram (CTA) showing ≥
50% stenosis in at least one native or graft vessel
∀
anginal symptoms with a defect documented by stress testing with nuclear perfusion 
imaging or a wall motion abnormality determined by stress echocardiogram
∀
asymptomatic coronary ischemia documented by stress testing with nuclear 
perfusion imaging or by stress echocardiogram
∀
peripheral vascular disease with symptoms of claudication and ankle brachial index 
<0.9 performed by a vascular lab or angiogram (including CTA) showing ≥50% 
stenosis)
∀
history of peripheral arterial revascularization (surgical or percutaneous) ≥30 days 
prior to randomization
∀
carotid endarterectomy, carotid stenting or more than or equal to 50% stenosis in a 
carotid artery determined by carotid ultrasound or angiogram ≥30 days prior to 
randomization
∀
history of abdominal aortic aneurysm confirmed by imaging, diagnosed ≥30 days 
prior to randomization
∀
ischemic stroke ≥30 days prior to randomization
b.
History of diabetes mellitus (type 1 or 2) and ≥40 years of age for men and ≥50 years of 
age for women, plus one of the following risk factors:
∀
chronic cigarette smoking at screening (at least 1 cigarette per day for > 1 month)
∀
history of hypertension (blood pressure >140/90 mm Hg) or taking antihypertensive 
medication
∀
high-sensitivity C-reactive protein (hs-CRP) > 2.0 mg/L (19.05 nmol/L) determined 
at Visit 1
∀
history of albuminuria (urinary albumin:creatinine ratio [ACR] >30 mg/g).
c.
Male patients >50 years of age or females >60 years of age, with at least one of the 
following risk factors:


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∀
family history (mother, father or sibling) of premature coronary heart disease (father 
or brother <55 years of age, mother or sister <65 years of age)
∀
chronic cigarette smoking at screening (at least 1 cigarette per day for > 1 month)
∀
hs-CRP >2.0 mg/L (19.05 nmol/L) determined at Visit 1
∀
impaired renal function as estimated using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formula81 for glomerular filtration rate 
(eGFR) <45 mL/min per 1.73 m2 (patients on dialysis are excluded).
∀
coronary calcium score >300 Agatston units (AU) at any time in the past.
*If patient will meet CVD secondary prevention criteria (3a) AND primary 
prevention criteria (3b and/or 3c) at the same time, then patient will be considered as 
meeting CVD secondary prevention criteria (3a) for the purpose of identifying the 
inclusion criteria for that patient.
4.
Patient must have been on a stable diet prior to randomization and willing to follow the
NCEP TLC diet, or equivalent diet, throughout the study.
Note a) A patient can, in specific circumstances, be re-screened. For details, see section 6.4. 
Note b) If LDL-C and/or TG and/or HDL-C do not meet the inclusion criteria at Visit 1, the 
patient may return twice (Visit 1a and 1b) during the screening period to reassess lipids (LDL-C, 
TG, and HDL-C) for statin/ezetimibe adjustment, discontinuation of excluded lipid-modifying 
agent, or re-checking a borderline TG and/or HDL-C value (see footnote 2 of Table 6-1 for 
details on lipid reassessments and on statin/ezetimibe dose adjustments during the screening 
period). Repeated values at Visit 1a or 1b may be used directly to qualify if needed. At Visit 1b, 
if lab values do not satisfy all inclusion criteria, the patient will be screen failed.
Note c) Once the patient qualifies, they should be randomized within 14 days. At least 50% of 
randomized patients should satisfy 3a CVD secondary prevention criteria, and <50% of patients 
should satisfy 3b and 3c primary prevention criteria combined; the proportions will be monitored 
and controlled via an Interactive Web Response System (IWRS).
EXCLUSION CRITERIA
Any patient who meets any of the following criteria will not qualify for entry into the study:
1.
Allergy or intolerance to omega-3 carboxylic acids, omega-3 fatty acids, omega-3-acid ethyl 
esters, or corn oil.
2.
Known hypersensitivity to fish and/or shellfish
3.
Use of fibrates, bile acid sequestrants, or niacin or its analogues (>250 mg/day) within 4 
weeks prior to Visit 2. Patients taking these agents may be considered for inclusion in the 
study if these therapies have been discontinued for 4 weeks or more prior to Visit 2.
However, niacin or its analogues at a dose less than or equal to 250 mg/day is permissible.


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4.
Statin naïve at Visit 1.
5.
Use of simvastatin 80 mg or ezetimibe/simvastatin 10/80 mg within 4 weeks prior to Visit 2. 
Patients taking these agents may be considered for inclusion in the study if these therapies 
have been discontinued and replaced with a protocol acceptable statin treatment that is
stabilized for 4 weeks or more prior to Visit 2.
6.
Use of any prescription medications containing eicosapentaenoic acid (EPA) and/or 
docosahexaenoic acid (DHA), e.g. Lovaza® or Vascepa®, within 4 weeks prior to Visit 2. 
Patients taking these agents may be considered for inclusion in the study if these therapies 
have been discontinued for 4 weeks or more prior to Visit 2.
7.
More than one capsule/day (any dose) of omega-3 dietary supplements. Patients taking >1 
capsule/day of omega-3 supplements before Visit 1 DO NOT require a washout period but 
must agree to reduce the number of capsule per day to no more than 1 capsule of 1 g 
promptly after signing the informed consent. No new omega-3 supplements are permitted 
following initiation of screening procedures at Visit 1.
8.
Use of prescription or over-the-counter (OTC) weight loss drugs at any time after Visit 1.
9.
Chronic use of oral corticosteroids during screening (acute use for inflammation for example 
from poison ivy, or intranasal or inhaled steroids for allergies/asthma, or intraarticular 
injections are allowed).
10. Use of tamoxifen, estrogens, progestins, or testosterone, that has not been stable for >4 
weeks at Visit 1, or is unstable prior to Visit 2.
11. Known lipoprotein lipase impairment or deficiency, or apolipoprotein C-II deficiency.
12. Hemoglobin A1c (Hb A1c) >12% at Visit 1.
13. Poorly controlled hypertension (resting blood pressure ≥180 mm Hg systolic and/or ≥100 
mm Hg diastolic) at two consecutive visits prior to randomization at Visit 2.
14. Uncontrolled hypothyroidism, or thyroid stimulating hormone (TSH) >2.0 times upper limit 
of normal (ULN) at Visit 1. Patients who are clinically euthyroid, on stable thyroid 
replacement therapy for 2 months prior to Visit 1 are allowed.
15. History of cancer (except non-melanoma skin cancer, or carcinoma in situ of cervix) within 
the previous two years.
16. Patients on dialysis.
17. Females who are pregnant, planning to be pregnant during the study period, lactating, or 
women of childbearing potential who are not using an acceptable method of contraception. A 
woman is considered of childbearing potential if she is not surgically sterile or if her last 
menstrual period was <12 months prior to Visit 1. Acceptable methods of contraception for 
this study include use of double barrier contraception, intrauterine device, all oral, patch, etc. 
hormonal contraceptives as long as dose and type is stable for 3 months prior to Visit 1. In 


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addition, true abstinence is acceptable when this is in line with the preferred and usual 
lifestyle of the subject.
18. Creatine kinase >5.0 times ULN; aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) >3.0 times ULN; or total bilirubin (TBL) >2.0 times ULN (except 
with a confirmed diagnosis of Gilbert’s disease), at Visit 1. A diagnosis of non-alcoholic 
fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) with stable elevations 
of AST and/or ALT (>3.0 times ULN) is eligible for participation in the study.
19. Excessive use of alcohol or other substance abuse that in the investigator’s opinion would 
jeopardize the patient’s participation in the study or interpretation of the data.
20. Exposure to any investigational agent within 4 weeks prior to Visit 1, including 
randomization in this study.
21. Previous clinical myocardial infarction (MI) <30 days prior to randomization
22. Percutaneous coronary intervention (PCI) including balloon angioplasty and coronary 
stenting<6 months prior to randomization
23. Coronary artery bypass grafting (CABG) <30 days prior to randomization
24. History of peripheral arterial revascularization (surgical or percutaneous) <30 days prior to 
randomization
25. Carotid endarterectomy or more than or equal to 50% stenosis in a carotid artery determined 
by carotid ultrasound or angiogram <30 days prior to randomization
26. History of abdominal aortic aneurysm diagnosed <30 days prior to randomization
27. Ischemic stroke <30 days prior to randomization
28. Any other condition the investigator believes would interfere with the patient’s ability to 
provide informed consent, comply with study instructions, or which might confound the 
interpretation of the study results or put the patient at undue risk.
29. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca or its
representative and/or staff at the study site)
DOSAGE FORMS AND ROUTE OF ADMINISTRATION:
∀
Epanova (omega-3 carboxylic acids) capsules: 4 g (four 1-gram capsules) orally, once 
daily for the duration of the study.
∀
Placebo (corn oil) capsules: 4 g (four 1-gram capsules) orally, once daily for the duration 
of the study.
∀
Statins will be prescribed by the investigator or patient’s health care provider. 


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OUTCOME VARIABLES:
The primary outcome measure is the time to event analysis using the first occurrence of any 
component of the composite of MACE: cardiovascular death, non-fatal MI, non-fatal stroke,
emergent/elective coronary revascularization, or hospitalization for unstable angina. Patients will 
remain in the study until the required number of patients with MACE has occurred.
Secondary outcome measures include:
KEY Secondary outcome measures include:
∀
The composite measure of CV events that include the first occurrence of cardiac death
(including death due to acute myocardial infarction, sudden cardiac death and death due to 
cardiovascular procedures), non-fatal MI, and non-fatal stroke.
∀
The composite measure of coronary events that include the first occurrence of 
cardiovascular death, non-fatal MI, emergent/elective coronary revascularization, or 
hospitalization for unstable angina.
∀
Time to CV Death
Other Secondary outcome measures include:
a) Emergent/elective coronary revascularization
b) Hospitalization for unstable angina
c)
Fatal or non-fatal MI
d) Non-fatal MI
e)
Fatal or non-fatal stroke
f)
Non-fatal stroke 
g) All-cause death
Tertiary outcome measures will include:
∀
The first occurrence of new onset atrial fibrillation (AF)
∀
The composite measure of total thrombotic events that include the first occurrence of 
documented coronary stent thrombosis, any systemic thromboembolism including 
arterial stent (except coronary) thrombosis or venous thromboembolism (VTE), i.e. deep 
vein thrombosis (DVT) and/or pulmonary embolism (PE)
∀
First occurrence of a heart failure event.
Biomarker efficacy endpoints will evaluate differences between placebo (corn oil) and Epanova 
treatments for:
∀
non-HDL-C, TG and HDL-C;
∀
total cholesterol (TC), very low density lipoprotein (VLDL) cholesterol, TC:HDL-C ratio
and calculated LDL-C ( in patients with triglycerides >400mg/dl LDL-C will be directly 


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measured); 
∀
apolipoprotein B-100 (Apo B-100) and apolipoprotein C-III (Apo C-III); 
∀
plasma and red blood cell (RBC) EPA, DHA, docosapentaenoic acid (DPA) and 
arachidonic acid (AA); and hs-CRP. 
A Clinical Events Committee (CEC) will adjudicate all components of the primary and 
secondary endpoints as well as the tertiary heart failure events endpoint.
SAFETY ASSESSMENTS:
Safety assessments will include adverse events, safety laboratory assessments, pregnancy tests, 
electrocardiogram (ECG), and physical examinations. A Data Monitoring Committee (DMC) 
will review data periodically throughout the study and will have the ability to recommend 
stopping the study for safety at any time. Details will be defined in the DMC charter.
SAMPLE SIZE ASSUMPTIONS and STATISTICAL ANALYSES:
Sample Size Assumptions
This event-driven study is designed to have 90% power to detect a 15% relative reduction in risk 
of primary efficacy MACE rate (hazard ratio=0.85) for patients treated with Epanova compared 
to placebo (corn oil) on top of a background of standard care (statin therapy). With an overall 
type I error rate (alpha level) of 5%, a total of 1,600 primary efficacy events are required to 
achieve approximately 90% power to detect the difference between Epanova and placebo (corn
oil) (a constant hazard ratio of 0.85). The estimate of 4% annual event rate on placebo (corn oil)
is based on previous studies investigating MACE, considering populations with documented 
cardiovascular disease and populations with cardiovascular risk factors only. The enrollment of 
patients with documented CVD will be ≥50% of all randomized patients; the enrollment of 
patients with risk factors only (primary prevention) will be less than 50% of all randomized 
patients. These proportions will be monitored and controlled via IWRS.
Assuming total study duration of 4.5 years and a placebo (corn oil) event rate of approximately 
4% per year, a sample size of 13,000 patients (6,500 per treatment group) is required.
Statistical Analyses
The primary outcome measure is the time to first occurrence (TTE; time-to-event) of any 
component of the composite of MACE (cardiovascular death, non-fatal MI, non-fatal stroke, 
emergent/elective coronary revascularization, or hospitalization for unstable angina).The primary 
outcome will be analyzed for the intent-to-treat (ITT) population using adjudicated events.
A Cox proportional hazards model for time to first MACE event will be assessed for comparing 
the two treatment groups, with treatment arm, established CV disease at baseline, multiple risk 
factors without established CV disease at baseline and geographic region as covariates. Event 
rates will be expressed as the percentage of events per follow-up year, taking into account 
censoring of follow-up data. The treatment effect will be assessed at a nominal 5% significance 


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level. Analysis results will be presented as hazard ratios, 95% confidence intervals and p-value.
For each TTE endpoint, a patient will be censored no later than the date of the last available 
information on that patient, from any source captured in the database. The specific rule(s) for 
each individual TTE will be explicitly specified in the SAP. Kaplan–Meier estimates will be used 
to quantify event rates during the course of the trial. Sensitivity analyses of the primary efficacy 
endpoint will also be performed to assess the robustness of the primary results. The sensitivity 
analyses will be performed for only on-treatment MACE events in the ITT population. 
The secondary outcomes measures will be analyzed using the same model as outlined above for 
the primary outcomes measure, on the ITT population.  The respective censoring rules will be
defined explicitly in the SAP.
The evaluation will be carried out in a hierarchical fashion.  Specifically, if the primary endpoint 
objective is met (2-sided p-value<0.05), the secondary outcomes will be evaluated hierarchically 
at an overall alpha of 0.05 for each comparison, sequentially. Once a key secondary endpoint is 
not met at alpha 0.05, all subsequent comparisons will be considered exploratory.
The hierarchy for sequential testing the following key secondary outcome measures will be 
defined as: 
KEY SECONDARY (tested at #=0,05, conditional on success of the primary)
1.
The composite measure of CV events that include the first occurrence of cardiovascular 
death, non-fatal MI and non-fatal stroke
2.
The composite measure of coronary events that include the first occurrence of cardiac 
death (including death due to acute myocardial infarction, sudden cardiac death and 
death due to cardiovascular procedures), non-fatal MI, emergent/elective coronary 
revascularization, or hospitalization for unstable angina.
3.
Time to CV Death
Other SECONDARY (evaluated at #=0,05; NOT part of the hierarchical testing sequence; that 
is, exploratory)  
Time to:
a) Emergent/elective coronary revascularization
b) Hospitalization for unstable angina
c) Fatal or non-fatal MI
d) Non-fatal MI
e) Fatal or non-fatal stroke


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f)
Non-fatal stroke 
g) All-cause death
Further details will be provided in the SAP.
Tertiary outcome measures will include:
∀
The first occurrence of new onset AF.
∀
The composite measure of total thrombotic events that include the first occurrence of 
documented coronary stent thrombosis, any systemic thromboembolism including 
arterial stent thrombosis (except coronary) or venous thromboembolism (VTE), i.e. deep 
vein thrombosis (DVT) and/or pulmonary embolism (PE).
∀
First occurrence of a heart failure event.
The tertiary outcome measures will be analyzed using methods similar to those for the primary 
and secondary analyses.  The analysis of the tertiary outcomes will be considered observational 
only. Further details will be provided in the SAP.
The analysis of biomarkers (e.g. lipids or other biomarkers) will be based on the differences in 
change from baseline (Month 0) to Month 12 (primary), between placebo (corn oil) and Epanova 
treatments. In addition, biomarker data after Month 12, will be presented in a descriptive manner.
The biomarker variables include:
∀
non-HDL-C, TG and HDL-C;
∀
TC, VLDL cholesterol, TC:HDL-C ratio and calculated LDL-C; in patients with 
triglycerides > 400mg/dl LDL-C will be directly measured
∀
Apo B-100 and Apo C-III; 
∀
EPA, DHA, DPA and AA in plasma and RBC; andhs-CRP. 
A repeated measures mixed model will be used for each biomarker endpoint with patient fitted as 
a random effect and terms included for treatment, visit, baseline value, treatment by visit and 
baseline by visit interactions using log-transformations where appropriate. A point estimate, 95% 
confidence interval and p-value for the mean difference between Epanova and placebo (corn oil)
patients from Month 0 to Month 12 (primary) will be produced based on this repeated measures 
model. Further details in the SAP will specify how each biomarker variable will be analyzed, i.e.
whether as mean change or as percent change.
The CEC will adjudicate all components of the primary and secondary endpoints as well as the 
tertiary heart failure events endpoint.
Safety analyses will include, where appropriate, descriptive statistics, counts and percentages.  At 
each DMC meeting, the committee will review all individual cases of LDL-C increases, 
AST/ALT increases or other increases in liver-related chemistries, new onset diabetes mellitus 
type II, or bleeding related events, in addition to other safety and laboratory data (i.e. fasting 


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glucose, hemoglobin A1c and hematocrit).
SITES: The study will be conducted globally in approximately 600 sites.
SPONSOR: AstraZeneca AB


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STUDY FLOW DIAGRAM


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SCHEDULE OF PROCEDURES
Study Period
Screening2
Randomization and 
treatment
EOT/ET
EOT/ET
Follow-up 
for SAE
Visit1
1
1a
1b
2
3
4
5
6 – 12
13
14
Month (±2 weeks)
0
3
6
12
18, 24, 30, 
36, 42, 48 
and 54
6015
3 weeks 
after 
EOT/ET for 
SAE17
Informed Consent
X
Medical History
X
X
X
X
Prior Medications
X
X
X
X
Physical Exam
X
X
X
Clinical 
Assessments3
X
X
X
X
X
X
X
X
X
Fasting Lipid Panel4,5
X
X
X
X
X13
X13
X13
Hemoglobin A1c
X
X
X13
X13
X13
Eligibility Review
X
X
X
X
hs-CRP
X
X
X
Serum Chemistry6
X
X
X
X7
X7
TSH
X
Urine Pregnancy 
Test8
X
Fasting Plasma 
Glucose
X
X13
X13
X13
Hematocrit
X13
X13
X13
ECG
X
Fasting Special Lipid 
Markers4,9
X
X
X
Plasma and RBC 
Fatty Acids4,10
X
X
X9
Fasting CV Risk 
Markers4,11
X
X
Genetic sample14
X
Counseling on TLC 
or Equivalent Diet
X
AEs, Concomitant 
Medications and 
Endpoint 
Assessments12
X
X
X
X
X16
X18
Telephone Calls12
Randomization
X
Dispense IP
X
X
X
X
X
Assess IP 
Compliance
X
X
X
X
X


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AE = adverse event; 
EOT = End of treatment; EOT is defined for patients who 1) permanently discontinue IP before the study 
has ended but agree for further follow-up assessments (on-site visits or telephone or via third party) until 
end of study 2) complete Visit 12 ( Month 60) and have not discontinued IP early;
ET = Early Termination. ET is defined for patients who permanently discontinue IP before the study has 
ended and decide not to participate with any follow-up assessments (on-site visits or telephone or via third 
party);
TSH = thyroid stimulating hormone; 
hs-CRP = high-sensitivity C-reactive protein; 
ECG = electrocardiogram; 
CV = cardiovascular; 
TLC = Therapeutic Lifestyle Changes; 
IP = Investigational Product. 
RBC= red blood cells
1. If fasting is not normal routine clinical practice, informed consent should be 
obtained prior to request for fasting for the Screening visit. If this is the case, the 
Screening visit should be split into 2 separate visits with informed consent 
obtained and IWRS accessed to obtain the patient number at the initial visit; and 
all other procedures obtained at the subsequent visit. In the event that the 
Screening visit is split into 2 separate visits, the screening visit lab draw must be 
completed within 3 days.  At any subsequent visit, if the patient did not fast for 
the recommended 9-14 hours, the fasted lab may be drawn the next day.
2. If at Visit 1 the patient’s TG, LDL-C, and HDL-C meet the inclusion criteria and 
the patient has been on a stable diet and has met all other inclusion criteria and 
none of the exclusion criteria the patient should return within 2 weeks for 
randomization at Visit 2.  
If at Visit 1 the patient requires an adjustment to their statin regimen and/or a 
washout of other excluded lipid medications, the patient should return 4-6 weeks 
later to have their lipids re-drawn at Visit 1a.
If at Visit 1 the patient does not require an adjustment to their statin regimen 
and/or a washout of other excluded lipid medications and either the patient’s TG 
and/or HDL-C are borderline: TG ≥160 - 179 mg/dL (>1.81 – 2.02 mmol/L) or 
TG ≥500 and <575 mg/dL (>5.65 and <6.49 mmol/L) and/or HDL-C ≤45 mg/dL 
(1.17 mmol/L) for men and ≤50 mg/dL (1.30 mmol/L) for women, the patient can 
return within 2 weeks later to have all lipids re-drawn at Visit 1a. 
If at Visit 1 the patient does not require an adjustment to their statin regimen 
and/or a washout of other excluded lipid medications, and TG and HDL-C values 
are outside of borderline boundaries, the patient is considered screen failed.


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The TG, LDL-C and HDL-C results from Visit 1a will be used to determine 
eligibility in the same way as for Visit 1.  If re-drawn TG and HDL-C values are 
again borderline (as above), lipids can be repeated once more at Visit 1b to 
determine eligibility. Note that all lipid parameters qualifying for randomization 
should be obtained from the same visit.
If the TG, LDL-C and HDL-C criteria are not met after Visit 1b, the patient 
should be screen failed.
Please note the possibility to rescreen in the some situations, please see section 
6.4.
3. Includes height (Visit 1 only), waist circumference and weight (Visit 1, 5, 7, 9, 
11, 13 only), blood pressure, and heart rate. 
4. Fasting blood samples should be drawn after the recommended 9-14 hour fast.
5. Lipid panel includes serum TG, TC, calculated LDL-C (in patients with 
triglycerides > 400 mg/dl LDL-C will be directly measured), HDL-C, calculated 
non-HDL-C, VLDL-C and TC: HDL-C ratio.
6. Serum chemistry includes creatine kinase, ALT, AST, total and direct bilirubin, 
and creatinine. Glomerular Filtration Rate (GFR) will be calculated only at Visits 
1 and 5
7. Only ALT, AST and bilirubin will be analysed, and only at Visits 7, 9, 11 and 13.
8. Females of childbearing potential only (see Exclusion No. 17).
9. Special lipid markers include serum apolipoprotein B-100 (Apo B-100), and 
apolipoprotein C-III (Apo C-III). 
10. Plasma and RBC fatty acids (EPA, DHA, DPA and AA) will be measured from 
the recommended 9-14 hour fasting samples. Note: Plasma and RBC assessments 
are performed only at Visits 2 and 5, or ET before Visit 5.
11. Blood samples will be collected for future analyses on a subset of patients located 
in the US, of lipid fractions, inflammatory markers and other CV markers that 
may be identified during the course of the study.
12. In addition to these scheduled procedures, a well-being phone call will be made 
every 6 months (±2 weeks) starting after Visit 4 that will occur at Months 9, 15, 
21, 27, 33, 39, 45, 51, and 57, except at scheduled visits, to question about 
adverse events, endpoint assessment, changes in medications and any major issues 
with the IP (losses or noncompliance). For further assessment of any identified 
potential or confirmed AE, a physical examination should be carried out if 
clinically appropriate.
13. Fasting lipid panel, Hb A1c, fasting plasma glucose and hematocrit will be 
measured annually at Visits 5, 7, 9, 11 and 13.


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14. Genetic samples will be collected for future analysis on approximately 2000 
patients in the US, see Appendix F for details.The sample should be taken at Visit 
2. 
15. Patients who permanently discontinue taking IP for any reason will be asked to 
continue the regular study visits after the scheduled ET visit and (for permanent 
discontinuation of IP due to SAE) the 3-week Follow-up visit unless they 
withdraw consent for further participation and the use of their data. In this case, 
patient will be asked to provide written documentation (when possible) of 
withdrawal of consent and complete the ET Visit procedures only. If the patient is 
permanently discontinued from study medication and agrees to continue in the 
protocol, then the patient, if possible, should have regularly scheduled study 
visits. 
16. Patients who have early permanent discontinuation of IP due to an SAE and have 
an ET visit, will be required to schedule a 3-week Follow-up (Visit 14) to assess 
the SAE and concomitant medications. The patients should be asked to continue  
the regular study visits as described above thereafter.
17. Visit window is ±1 week for Visit 14 (ET/EOT Follow-up for SAE).
18. At Follow-up Visit 14, other assessments from the procedures table may be 
performed upon investigator discretion to further evaluate the SAE causing ET or 
for SAE identified at EOT.


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TABLE OF CONTENTS
PROTOCOL TITLE PAGE .......................................................................................... 1
PRINCIPAL INVESTIGATOR SIGNATURE SHEET............................................. 2
SPONSOR SIGNATURE SHEET................................................................................. 3
PROTOCOL SYNOPSIS............................................................................................... 4
PROTOCOL SYNOPSIS............................................................................................... 4
STUDY FLOW DIAGRAM......................................................................................... 15
TABLE OF CONTENTS ............................................................................................. 20
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................. 26
1
BACKGROUND AND RATIONALE................................................................. 30
1.1
Background ................................................................................................. 30
1.1.1
Clinical Pharmacology and Efficacy of Epanova............................ 32
1.1.2
Clinical Safety of Epanova .............................................................. 34
1.2
Rationale...................................................................................................... 35
2
OBJECTIVES AND OUTCOMES...................................................................... 40
2.1
Primary Objective and Outcome Measure .................................................. 40
2.2
Secondary Outcome Measures .................................................................... 40
2.2.1
Key Secondary Outcome Measures ............................................................ 40
2.2.2
Other Secondary Outcome Measures.......................................................... 40
2.3
Tertiary Outcome Measures ........................................................................ 41
2.4
Clinical Events Adjudication....................................................................... 41
2.5
Efficacy Endpoints ...................................................................................... 41
2.6
Safety Assessments ..................................................................................... 42
3
INVESTIGATIONAL PLAN ............................................................................... 43
3.1
Overall Study Design .................................................................................. 43
3.2
Discussion of Study Design ........................................................................ 49
4
SELECTION AND WITHDRAWAL OF PATIENTS ...................................... 52
4.1
Inclusion Criteria......................................................................................... 52
4.2
Exclusion Criteria........................................................................................ 55
4.3
Discontinuation of Investigational Product Criteria.................................... 57
4.4
Withdrawal from study (withdrawal of consent) ........................................ 58
5
STUDY TREATMENTS....................................................................................... 60


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5.1
Identity of Investigational Product .............................................................. 60
5.2
Investigational Product Storage and Accountability................................... 60
5.3
Methods of Assigning Patients to Treatment Groups ................................. 61
5.4
Administration of Investigational Product .................................................. 61
5.5
Treatment Accountability and Compliance................................................. 62
5.6
Blinding and Unblinding Method................................................................ 62
6
SCHEDULE OF PROCEDURES AND ASSESSMENTS................................. 64
6.1
Screening Period (Visit 1) ........................................................................... 67
6.2
Screening Period (Visit 1a) ......................................................................... 68
6.3
Screening Period (Visit 1b) ......................................................................... 69
6.4
Re-screening................................................................................................ 69
6.5
Randomization (Visit 2, Month 0) .............................................................. 70
6.6
Treatment (Visit 3, Month 3) ...................................................................... 70
6.7
Treatment (Visit 4, Month 6) ...................................................................... 70
6.8
Treatment (Visit 5, Month 12) .................................................................... 71
6.9
Treatment (Visits 6-12; Months 18, 24, 30, 36, 42, 48, and 54) ................. 71
6.10
Telephone Calls (Months 9, 15, 21, 27, 33, 39, 45, 51, and 57) ................. 72
6.11
End of Treatment (Visit 13; Month 60) or ET ............................................ 72
6.12
Follow-up for SAE causing ET (3 weeks after ET visit)* .......................... 72
6.13
Early Termination Procedures..................................................................... 73
6.14
Patient Completion Criteria......................................................................... 73
6.15
Protocol Deviations ..................................................................................... 73
7
DETAILED DESCRIPTION OF ASSESSMENTS ........................................... 75
7.1
Informed Consent........................................................................................ 75
7.2
Medical History........................................................................................... 75
7.3
Prior Medications and Concomitant Medications....................................... 75
7.4
Prohibited Medications and Dietary Products............................................. 76
7.5
Permitted Medications................................................................................. 77
7.6
Eligibility Review........................................................................................ 79
7.7
Clinical Assessments................................................................................... 79


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7.8
Physical Examination.................................................................................. 79
7.9
Electrocardiogram ....................................................................................... 79
7.10
Diet .............................................................................................................. 80
7.11
Safety Assessments – Adverse Events ........................................................ 80
7.12
Laboratory Assessments and Procedures .................................................... 80
7.12.1
Screening Laboratory Assessments ................................................. 80
7.12.2
Efficacy Laboratory Assessments.................................................... 80
7.12.3
Safety Laboratory Assessments....................................................... 81
7.12.4
Collection, Shipment, and Retention of Laboratory Samples ......... 81
7.12.4.1
Safety and Efficacy Analyses ......................................... 81
7.12.5
Exploratory CV Risk Markers (on a subset of patients located in the 
US)................................................................................................... 82
7.12.5.1
Storage, re-use and destruction of exploratory CV risk 
marker samples ( on a subset of patients located in the 
US). ............................................................................ 82
7.12.5.2. Labelling and shipment of exploratory CV risk marker 
samples (on a subset of patients located in the US)... 82
7.12.5.3
  Chain of custody of exploratory CV risk marker samples 
(on a subset of patients located in the US)................. 82
7.12.5.4
Withdrawal of Informed Consent for donated exploratory 
CV risk marker samples (on a subset of patients located 
in the US) ................................................................... 83
7.12.6
Pharmacogenetics (on a subset of patients located in the US) ........ 83
8
STATISTICAL METHODS................................................................................. 84
8.1
Sample Size Determination......................................................................... 84
8.2
Analysis Populations ................................................................................... 84
8.3
Randomization............................................................................................. 84
8.4 
Statistical Analyses...................................................................................... 85
8.4.1
Primary Outcome Analysis.............................................................. 85
8.4.2 Secondary Outcomes Analyses ............................................................. 86
8.4.3 Tertiary Outcome Analysis ................................................................... 87
8.4.4 Biomarkers of Efficacy ......................................................................... 87


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8.4.5 Evaluation of Efficacy and Safety......................................................... 88
8.4.6 Safety Analyses..................................................................................... 88
8.5
Interim analyses........................................................................................... 89
8.6
Missing Values............................................................................................ 91
8.7
Data Monitoring Committee ....................................................................... 91
9
ADVERSE EVENT MONITORING................................................................... 92
9.1
Definitions................................................................................................... 92
9.2
Procedures ................................................................................................... 93
9.3
Bleeding definitions .................................................................................... 94
9.4
Severity........................................................................................................ 95
9.5
Relationship................................................................................................. 95
9.6
Action Taken and Outcome......................................................................... 96
9.7
Adverse Event Follow-up............................................................................ 96
9.8
Serious Adverse Events............................................................................... 96
9.8.1
Serious Adverse Event Reporting.................................................... 97
9.8.2
Serious Adverse Event Follow-Up .................................................. 97
9.9
Reporting of Serious Adverse Events that are also Endpoints in the Study 98
9.10
Pregnancy.................................................................................................... 99
9.11
Overdose...................................................................................................... 99
10
INVESTIGATOR OBLIGATIONS................................................................... 100
10.1 Ethical and Regulatory Considerations ......................................................... 100
10.2 Institutional Review Board/Independent Ethics Committee ......................... 100
10.3 Informed Consent .......................................................................................... 100
10.4 Patient Confidentiality................................................................................... 101
11
STUDY MONITORING ..................................................................................... 102
11.1 Clinical Monitoring ....................................................................................... 102
11.2 Auditing Procedures ...................................................................................... 102
11.3 Executive Steering Committee ...................................................................... 102
12
CHANGES TO THE PROTOCOL AND STUDY TERMINATION............. 103
12.1
Protocol Amendment and Administrative Change.................................... 103
12.2
Termination of the Study........................................................................... 103


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13
SOURCE DOCUMENTS, CASE REPORT FORMS AND RECORD 
RETENTION....................................................................................... 104
13.1
Source Documents..................................................................................... 104
13.2
Case Report Forms .................................................................................... 104
13.3
Record Retention....................................................................................... 104
14
FINAL REPORT/PUBLICATION STATEMENT.......................................... 106
15
REFERENCES .................................................................................................... 107
APPENDIX A: THERAPEUTIC LIFESTYLE CHANGES DIET ....................... 117
The principles of the TLC diet or equivalent are as follows:....................... 118
APPENDIX B: ACTIONS REQUIRED IN CASES OF COMBINED INCREASE 
OF AMINOTRANSFERASE AND TOTAL BILIRUBIN HY´S LAW:
............................................................................................................... 119
Introduction............................................................................................................ 119
Definitions ............................................................................................................. 119
Identification of potential Hy’s Law cases ............................................................ 120
Follow-up121
Potential Hy’s Law Criteria not met...................................................................... 121
Potential Hy’s Law Criteria met............................................................................ 121
Review and Assessment of potential Hy’s Law cases........................................... 121
References.............................................................................................................. 123
APPENDIX C: STANDARDIZED DEFINITIONS FOR ENDPOINT EVENTS IN 
CARDIOVASCULAR TRIALS ........................................................ 124
A. Death 124
B. Non-fatal Myocardial Infarction ....................................................................... 127
C. Non-fatal Stroke................................................................................................ 129
D. Hospitalization for Unstable Angina ................................................................ 131
E. Cardiac Revascularization Procedure................................................................ 133
F. Heart Failure...................................................................................................... 133
APPENDIX D: 2013 ACC/AHA GUIDELINES FOR HIGH-, MODERATE- AND 
LOW-INTENSITY STATIN THERAPY......................................... 137
APPENDIX E: COVARIATES ................................................................................. 138
APPENDIX F : ADDITIONAL SAFETY INFORMATION.................................. 140


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FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS ADVERSE EVENT 
(SAE) .................................................................................................... 141
A GUIDE TO INTERPRETING THE CAUSALITY QUESTION............................. 143
APPENDIX G.............................................................................................................. 145
TITLE PAGE 145
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS................................. 146
BACKGROUND AND RATIONALE ...................................................................... 147
GENETIC RESEARCH OBJECTIVES................................................................... 147
GENETIC RESEARCH PLAN AND PROCEDURES ............................................... 148
Selection of genetic research population ............................................................... 148
Study selection record............................................................................................ 148
Inclusion criteria........................................................................................... 148
Exclusion criteria ......................................................................................... 148
Discontinuation of subjects from this genetic research................................ 148
Collection of samples for genetic research............................................................ 148
Coding and storage of DNA samples .................................................................... 149
Genotyping ............................................................................................................ 149
ETHICAL AND REGULATORY REQUIREMENTS........................................... 150
Informed consent ................................................................................................... 150
Subject data protection .......................................................................................... 150
DATA MANAGEMENT............................................................................................ 151
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...... 151
LIST OF REFERENCES........................................................................................... 152
LIST OF TABLES
Table 3-1.
COMPONENTS OF PRIMARY, SECONDARY AND TERTIARY 
OUTCOME ENDPOINTS ................................................................... 47
Table 6-1.
SCHEDULE OF PROCEDURES ........................................................ 64
Table 8-1.
INTERIM ANALYSIS PLAN ............................................................. 90
LIST OF FIGURES
Figure 3.1
STUDY FLOW DIAGRAM ................................................................ 45


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation/Term
Definition
AA
Arachidonic acid
ACCF
American College of Cardiology Foundation
ACCORD
Action to Control Cardiovascular Risk in Diabetes
ACR
Albumin:creatinine ratio
AE
Adverse event
AF
Atrial fibrillation
AHA
American Heart Association
ALT
Alanine aminotransferase
Apo B-100
Apolipoprotein B-100
Apo C-III
Apolipoprotein C-III
ASCVD
Atherosclerotic cardiovascular disease
AST
Aspartate aminotransferase
AU
Agatston units
AUC
Area Under the Curve
BIP
Bezafibrate Infarction Prevention
C5Research
Cleveland Clinic Cardiovascular Coordinating Center for 
Clinical Research
CABG
Coronary Artery Bypass Grafting
CD
Compact disc
CEC
Clinical Endpoint Committee
CFR
Code of Federal Regulations
cGMP
Current Good Manufacturing Practices
CHD
Coronary heart disease
CK
Creatine kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
COMBOS
COMBination of prescription Omega-3 with Simvastatin
CRA
Clinical Research Associate
CRO
Contract Research Organization
CSR
Clinical Study Report
CTA
Computed tomography angiogram
CTT
Cholesterol Treatment Trialists’
CVD
Cardiovascular disease
CV
Cardiovascular


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Abbreviation/Term
Definition
d
Day
dL
Deciliter
DHA
Docosahexaenoic acid
DILI
Drug-induced liver injury
DMC
Data Monitoring Committee 
DPA
Docosapentaenoic acid
DVT
Deep vein thrombosis
ECG
Electrocardiogram
eCRF
Electronic Case Report Form 
EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
EPA
Eicosapentaenoic Acid
EOT
End of Treatment
ET
Early Termination
FDA
Food and Drug Administration
FFA
Free fatty acids
FIELD
Fenofibrate Intervention and Event Lowering in Diabetes
g
Gram
GCP
Good Clinical Practice 
GI
Gastrointestinal
Hb A1c
Hemoglobin A1c
HDL
High-density lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
hs-CRP
high-sensitivity C-reactive protein 
IC
Informed consent
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IND
Investigational New Drug
INR
International Normalized Ratio
IP
Investigational product
IRB
Institutional Review Board or Independent Review Board
ITT
Intent-to-Treat
IWRS
Interactive web response system


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Abbreviation/Term
Definition
JELIS
Japan EPA Lipid Intervention Study
JUPITER
Justification for the Use of statins in Prevention: an 
Intervention Trial Evaluating Rosuvastatin
LDL-C
Low-density lipoprotein cholesterol
MACE
Major adverse cardiovascular events (cardiovascular death, 
non-fatal MI, non-fatal stroke, emergent/elective coronary 
revascularization or hospitalization for unstable angina)
MAR
Missing At Random
MedDRA 
Medical Dictionary for Drug Regulatory Affairs
mg
Milligrams
MI
Myocardial infarction
NAFLD
Non-alcoholic fatty liver disease
NASH
Non-alcoholic steatohepatitis
NCEP
National Cholesterol Education Program
NEPTUNE
National Cholesterol Education Program Evaluation 
ProjecT Utilizing Novel E-Technology
OTC
Over-the-counter
PDF
Portable Document Format
PE
Pulmonary embolism
PI
Principal Investigator
PCI
Percutaneous coronary intervention
PHL
Potential Hy´s Law
PUFA
Polyunsaturated fatty acids
RBC
Red blood cells
RCT
Randomized control trial
RR
Risk reduction
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard Deviation
SFA
Saturated fatty acids
SOC
System Organ Class
STRENGTH
A Long-Term Outcomes Study to Assess STatin Residual 
Risk Reduction with EpaNova in HiGh Cardiovascular 
Risk PatienTs with Hypertriglyceridemia
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event


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Abbreviation/Term
Definition
TSH
Thyroid stimulating hormone
TC
Total cholesterol
TG
Triglycerides
TIA
Transient ischemic attack
TLC
Therapeutic Lifestyle Changes
TTE
Time-to –event
ULN
Upper Limit of Normal
USP
United States Pharmacopeia
VLDL
Very low-density lipoprotein
VLDL-C
Very low-density lipoprotein cholesterol
VTE
Venous thromboembolism
WOSCOPS
West Of Scotland Coronary Prevention Study 


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1
BACKGROUND AND RATIONALE
1.1
Background
In patients with hypertriglyceridemia (≥200 mg/dL), the National Cholesterol Education 
Program (NCEP) Adult Treatment Panel III (ATP) recommended that non-high-density 
lipoprotein cholesterol (non-HDL-C) should be considered as secondary target of 
treatment once low-density lipoprotein cholesterol (LDL-C) goals are achieved.1
Non-HDL-C is routinely calculated as total cholesterol minus HDL-C but is mainly the 
sum of LDL-C and very-low-density lipoprotein (VLDL) and includes cholesterol carried 
by all lipoproteins that contain apolipoprotein B (Apo B-100). When triglycerides (TG) 
are >200 mg/dL most cholesterol in the VLDL fraction is contained in smaller 
(atherogenic remnant) VLDL.1  Therefore, when serum triglycerides are high, VLDL 
cholesterol can reasonably be combined with LDL-C to use non-HDL-C as a secondary 
target of treatment and a means to enhance risk prediction.1
In patients with hypertriglyceridemia, non-HDL-C goals are frequently not achieved. In 
the NEPTUNE II study (National Cholesterol Education Program Evaluation ProjecT 
Utilizing Novel E-Technology), only 4% of patients with TG >200 mg/dL and at very 
high risk were at the optimal non-HDL-C goal of < 100 mg/dL.2 In order to reduce non-
HDL-C in patients with hypertriglyceridemia, combination therapy with statins is 
frequently necessary to maximize goal achievement. The NCEP panel recognized that 
statins are not powerful TG-lowering drugs, and therefore recommended the use of 
specific add-on therapies to lower TG levels in patients with hypertriglyceridemia (fish 
oils to replace some long-chain TG levels in diet, as well as fibrates or nicotinic acid).1
During the last 30 years, epidemiological studies reported a relationship between lower 
serum TG concentrations and the consumption of omega-3 fatty acids-rich fish.3,4
Further, clinical studies have shown that consumption of the omega-3 fatty acids 
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been associated with 
lower serum TG concentrations and reduced risk for cardiovascular disease.5,6,7,8
Marine-based omega-3 fatty acids (EPA and DHA) were shown to be more effective than 
the plant-based alpha-linoleic acid products, with the former lowering serum TG levels 
25-50% after consuming 3-8 g/day EPA+DHA compared to controls.9,10 Therefore, 
marine omega-3 fatty acids represent a class of compounds with demonstrated efficacy in 
reducing severe elevation of TG levels.
A fatty fish diet provides only modest doses of the polyunsaturated omega-3 fatty acids 
(EPA and DHA) needed to treat severe hypertriglyceridemi a.11 Therefore, omega-3 


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concentrates are more suitable for this purpose. Unprocessed marine oil products contain 
only approximately 30% omega-3 fatty acids while the concentrates, after ethanol 
extraction and distillation, contain approximately 80% omega-3 in the form of ethyl 
esters.10,12 In 2004, a concentrate of omega-3-acid ethyl esters (Lovaza®) was approved 
by the Food and Drug Administration (FDA) as an adjunct to diet for the reduction of 
very high TG ( ≥500 mg/dL) levels in adult patients.10 This product provides 84% content 
of EPA+ DHA ethyl esters. Epanova® is a newer formulation that has undergone an 
additional manufacturing step to hydrolyze and distill the ethyl esters into omega-3 free 
fatty acids (FFAs) with a final concentration of 75% EPA + DHA (omega-3 carboxylic 
acids).12 Therefore, intestinal absorption of the omega-3 FFAs in Epanova will not 
require the hydrolysis with pancreatic lipase as is required for the ethyl ester form 
(Lovaza®) in the small intestine. It is also important to note that the molecular weight of 
the free fatty acid EPA and DHA in Epanova is less than the molecular weight of ethyl 
ester EPA and DHA in Lovaza®. Accounting for this difference, 465 mg of ethyl-EPA is 
equivalent to 426 mg of EPA in the free fatty acid form and 375 mg of ethyl-DHA is 
equivalent to 346 mg of DHA in the free fatty acid form. Therefore, the 84% EPA + 
DHA ethyl esters in Lovaza® are comparable to the 75% EPA + DHA in Epanova.
Previous studies have demonstrated that the TG form of marine omega-3 fatty acids, EPA 
and DHA are more resistant to pancreatic lipase hydrolysis compared to other 
polyunsaturated fatty acids.13,14,15 Furthermore, ethyl ester omega-3 fatty acids are up to 
50 times more resistant than the natural TG form to pancreatic lipase 
hydrolysis.16,17,18,19,20 Several studies have compared human intestinal absorption of fish 
oil fatty acids in the form of TG, ethyl ester and FFA and found that FFAs have up to 5 
times more bioavailability as determined by the plasma area under the curve (AUC) than 
the ethyl ester form.17,18,19 In addition, pancreatic lipases are secreted into the intestines in 
response to fat intake. Patients with hypertriglyceridemia are often advised to restrict fat 
intake and therefore pancreatic lipase secretion may be lower with severe 
hypertriglyceridemia which could lead to EPA and DHA malabsorption from the ethyl 
ester formulations.21 Absorption of the FFA form of omega-3 EPA and DHA would not 
be compromised by a fat intake restriction and would therefore offer a therapeutic 
advantage over the ethyl ester to the patient with severe hypertriglyceridemia. Therefore, 
Epanova, a FFA formulation, will have significantly greater bioavailability than the ethyl 
esters form, and would have little dependence on meal fat content.15,16,17,18,19


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1.1.1
Clinical Pharmacology and Efficacy of Epanova
In a Phase IIb, open-label, clinical study of Epanova in which patients were taking 4 g per 
day for 52 weeks without regard to meal timing, trough plasma levels of EPA had 
reached a steady-state level by Week 16 at which EPA levels increased 351% from 
baseline.22 This is in contrast to a Lovaza® study in which 16 weeks of 4 g per day dosing 
increased trough EPA levels only 163% from baseline.23 In the Epanova study, red blood 
cell membrane EPA also stabilized at Week 16.22 In a bioavailability study that compared 
single 4-gram doses of Epanova and Lovaza® administered under low-fat diet conditions 
in healthy subjects, Epanova showed a 4-fold increase in area under the curve to the last 
time point (AUCt) for plasma EPA and DHA relative to Lovaza®.24 The Cmax for EPA 
and DHA during Epanova dosing was 3.7-fold greater than Lovaza® dosing under the 
low-fat diet conditions.24 This improved bioavailability under low-fat meal conditions 
provides Epanova a potential therapeutic advantage over Lovaza® because the NCEP 
ATP III guidelines recommend that patients with severe TG elevations adhere to the 
lower fat Therapeutic Lifestyle Changes (TLC) diet. In addition, on the low-fat diet, 30 of 
51 (58.82%) subjects on Epanova versus 3 of 50 (6.00%) subjects on Lovaza® maintained 
an AUCt that was > 50% of the respective high fat diet AUCt.24 These data suggest that 
Epanova will have superior absorption on either a low-fat or high-fat diet.
The enhanced bioavailability of Epanova and the effectiveness in improving lipid 
parameters were demonstrated in two phase III trials: OM-EPA-003 (EVOLVE) and 
OM-EPA-004 (ESPRIT).25,26
EVOLVE was a phase III, 12-week, multicenter, multinational, placebo–controlled (olive 
oil), randomized, double-blind study evaluating 399 subjects with fasting TG levels ≥500 
and <2000 mg/dL (with or without statin therapy), who were randomized to Epanova 2 
g/day, 3 g/day, 4 g/day, or olive oil control. Subjects were permitted to administer 
Epanova without regard to meal timing. Lipids were measured at all in-clinic visits, 
plasma EPA and DHA were measured pre-treatment for baseline (Week 0) and at end of 
treatment (Week 12). Administration of 2 g, 3 g and 4 g Epanova daily for 12 weeks 
demonstrated large dose-dependent increases (least squares mean; LSM) in plasma EPA 
levels from baseline to end of treatment: approximately 267%, 332 % and 406%, 
respectively. Plasma trough DHA levels also showed a dose-response to Epanova
treatment. Mean percent changes in plasma DHA levels were approximately 57%, 64% 
and 72%, respectively, for the 2 g, 3 g and 4 g/day doses. Furthermore, the dose 
dependent increases in plasma EPA and DHA were associated with dose dependent 


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decreases in plasma arachidonic acid (AA) concentrations of -15%, -16% and -23% from 
baseline with the 2 g, 3 g and 4 g/day doses respectively.
ESPRIT was a phase III, 6-week, U.S. multicenter, placebo–controlled (olive oil), 
randomized, double-blind study evaluating 647 patients with fasting TG levels ≥200 
mg/dL and <500 mg/dL and at high risk for a future cardiovascular disease (CVD) event, 
who were randomized 1:1:1 to olive oil control, 2 g or 4 g/day Epanova. Subjects were 
permitted to administer Epanova without regard to meal timing. At in-clinic visits, 
plasma EPA and DHA were measured pre-treatment for baseline (Week 0) and at end of 
treatment (Week 6). Administration of 2 g and 4 g Epanova, daily for 6 weeks, 
demonstrated large dose-dependent increases from baseline in plasma trough EPA levels 
at the end of treatment. Plasma EPA increased (LSM) approximately 188% and 348% 
from baseline, respectively, with 2 and 4 g/day doses. Plasma DHA also showed a dose-
dependent increase, with LSM percent changes from baseline to end of treatment of 
approximately 50% for the 2 g/day group and 71% for the 4 g/day group. Plasma AA 
decreased in a dose-dependent manner, approximately -11% for the 2 g/day group and
-20% for the Epanova 4 g group.
There was a consistent dose-dependent TG-lowering response with Epanova treatment in 
both trials. The difference in TG reductions between the 2 g and 4 g/day doses in both 
trials was similar: approximately -5% in EVOLVE (from -26% to -31%) and -6% in 
ESPRIT (from -15% to -21%). These data also demonstrated that the 2-3 fold greater TG 
levels in EVOLVE yielded an approximate 10% additional decrease in TG levels for each 
Epanova dose: 2 g/day dose produced a median -25% and -15% TG reduction in the 
EVOLVE and ESPRIT trials, respectively, while the 4 g/day dose lowered TG by 
approximately -31% and -21%, respectively, in the trials. A clinically important result is 
that as the baseline TG increases there is nearly a direct increase in the 2 g dose efficacy: 
-15% in ESPRIT and -26% in EVOLVE. The 4 g dose showed a less direct increase in 
efficacy (about 50% increase in TG lowering between the trials; - 21% to -31%).
Non-HDL cholesterol was the primary endpoint in ESPRIT and the secondary endpoint 
in EVOLVE. Baseline levels were about 1.5 fold greater in EVOLVE than ESPRIT. The 
difference in non-HDL-C reductions between the 2 g and 4 g/day doses was also similar 
in EVOLVE and ESPRIT: approximately -2% in EVOLVE (from LSM -7.6% to -9.6%) 
and -3% in ESPRIT (from 3.9% to -6.9%). Again, the direct relationship between 
baseline lipid levels and 2 g efficacy was apparent: with an approximate 1.5 increase in 
baseline non-HDL-C levels from ESPRIT to EVOLVE, there was an approximate 2-fold 


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increase in efficacy (-4% in ESPRIT and 8% in EVOLVE). The 4 g dose showed closer 
to a 50% increase in non-HDL-C lowering efficacy between the trials (-6.9% to -9.6%).
In summary, both the 2 g/day and 4 g/day Epanova doses had clinically meaningful 
efficacy in lowering plasma TG and non-HDL-C levels in subjects with severe 
hypertriglyceridemia in the EVOLVE trial and in subjects with high triglyceride levels in 
the ESPRIT trial. Further, the Epanova treatments demonstrated lipid lowering in other 
parameters (TC, TC/HDL cholesterol ratio, VLDL cholesterol and Apo C-III). The 
results suggest that both Epanova doses may offer a clinical therapeutic option to start 
therapy at 2 g/day or 4 g/day, or start therapy at 2 g/day and increase to a maximum 
4 g/day, as needed to effectively treat patients with severe hypertriglyceridemia 
(TG ≥500 mg/dL) or high risk patients with persistent hypertriglyceridemia (TG ≥200 
mg/dL and <500 mg/dL) despite receiving statin therapy.
1.1.2
Clinical Safety of Epanova
Epanova capsules are coated with a polyacrylate material that is intended to facilitate 
release of the omega-3 fatty acids in the gut leading to a significant reduction of the 
unpleasant gastrointestinal (GI) side-effects often observed with other omega-3 
products.22,24,25,26,27,28,29,30,31,32,33,34 The safety of Epanova was collectively summarized 
and included 1343 subjects treated with Epanova in 10 clinical 
studies.22,24,25,26,27,28,29,30,31,32  The clinical studies included 2 studies in subjects with 
hypertriglyceridemia (EVOLVE and ESPRIT; N = 731) who received Epanova 2 to 4 g 
daily for 6 to 12 weeks, 4 studies in subjects with Crohn’s disease (N = 432) who 
received Epanova 4 g daily ∃52 weeks, and 4 studies in healthy subjects who received 
Epanova in clinical pharmacology/pharmacokinetic studies (N = 180).
The integrated safety analysis demonstrated that Epanova was safe and well tolerated for 
up to 12 weeks in subjects with hypertriglyceridemia and 3 years in subjects with Crohn’s 
disease. Most treatment-emergent adverse events (TEAEs) were considered by the 
investigator to be mild or moderate in severity. The most common system organ class 
(SOC) of TEAEs was gastrointestinal disorders, with higher incidences of diarrhea, 
nausea, and eructation reported in the Epanova dose groups (2 g, 3 g, or 4 g daily) 
compared with olive oil (placebo). There was no clear dose-related trend among the 
gastrointestinal preferred terms; however, a higher incidence of diarrhea occurred in the 4 
g group. Most GI TEAEs, including diarrhea, were mild or moderate in severity and few 
(%1.1% for each individual GI TEAE) resulted in discontinuation of study drug. This lack 
of a dose-response relationship with the severity and incidence of GI effects following 


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exposure to Epanova is consistent with the published literature reports of adverse events 
following EPA and DHA exposure.34,35,36
1.2
Rationale
Few prospective studies have explicitly examined the predictive CVD risk of non-HDL-C 
levels versus LDL-C levels in persons with hypertriglyceridemia, however, several lines 
of evidence favor use of non-HDL-C over LDL-C in clinical evaluation of risk.1 This 
hypothesis is supported by reports from the follow-up of the Lipid Research Clinic cohort 
which showed a stronger correlation with coronary mortality for non-HDL-C than for 
LDL-C, as well as other studies that showed non-HDL-C is a better predictor of coronary 
heart disease (CHD) risk than LDL-C alone.1,37,38,39 This clinical evidence is consistent 
with metabolic evidence that shows non-HDL-C to be highly correlated with total Apo B-
100, the major apolipoprotein of all atherogenic lipoproteins. Serum Apo B-100 has also 
been shown to have a strong predictive power for severity of coronary atherosclerosis and 
CHD events.1 Therefore, because of the high correlation between non-HDL-C and Apo 
B-100 levels, non-HDL-C represents an acceptable surrogate marker for total Apo B-100 
in routine clinical practice. Standardized measures of Apo B-100 are not widely available 
for routine measurement.
The use of statins to lower cholesterol has been established as an effective method of 
reducing death and myocardial infarction (MI) among patients with CHD. However, a 
significant fraction of individuals who receive statin therapy continue to have high 
residual CHD risk.2,40,41,42 A meta-analysis of 14 statin trials suggests that for every 1% 
reduction in non–HDL-C the relative CHD risk is reduced by approximately 1%.36
Unfortunately, a substantial proportion of patients with elevated non–HDL-C and 
triglyceride levels do not achieve non-HDL-C level goals despite the use of statins.2,41,42
In the NEPTUNE II study, 61% of patients with hypertriglyceridemia (triglyceride level 
≥200 mg/dL) achieved their LDL-C treatment goal, whereas only 39% achieved their 
non–HDL-C goal. Among the subset with hypertriglyceridemia and CHD or CHD-risk 
equivalents, 52% achieved their LDL-C goal, whereas 27% achieved their non–HDL-C 
goal.2 Part of the challenge in achieving the non–HDL-C goal is that statins have less 
robust effects on triglyceride levels relative to their reductions in LDL-C levels and thus 
may not optimally reduce the cholesterol carried by triglyceride-rich lipoproteins, such as 
VLDLs, intermediate-density lipoproteins, and chylomicrons.
Combination therapy appears most appropriate for patients with risk for a high rate of 
CHD events despite being on optimal statin therapy. In addition to lifestyle modification, 


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the use of combination therapy in CHD is an acknowledged strategy in optimal 
management to prevent or delay the morbidity and mortality associated with high-risk 
patients including those with combined hyperlipidemia and diabetic dyslipidemia.43 In 
patients with hypertriglyceridemia (≥200 mg/dL), non-HDL-C (VLDL + LDL 
cholesterol) can serve as a secondary target of therapy. A “normal” VLDL-C can be 
defined as that present when triglycerides are <150 mg/dL; this value typically is ≤30 
mg/dL. Conversely, when triglyceride levels are >150 mg/dL, VLDL-C usually is >30 
mg/dL. Thus, a reasonable goal for non-HDL-C is one that is 30 mg/dL higher than the 
LDL-C goal. Because increasing the statin dose to achieve non-HDL-C and triglyceride 
levels has limited efficacy as well as safety concerns, adding other lipid altering therapies 
to statins is a valuable alternative.
CVD risk increases with triglyceride levels over 100 mg/dL, and at triglycerides ≥200 
mg/dL the CVD risk is increased approximately 2-fold.1 The inclusion criterion of 
fasting TG for this protocol was based on recommendations from the NCEP ATP III and 
2004 Update.1,43 In the high-risk patient, the 2004 Update recommends that when 
triglycerides are ≥200 mg/dL, non-HDL-C is a secondary target of therapy, with a goal 
30 mg/dL higher than the identified LDL-C goal.43 For persons with borderline high 
triglycerides (150-199 mg/dL), according the guidelines, the VLDL cholesterol is not 
elevated enough to evoke non-HDL cholesterol as a secondary target. In addition, the 
Secondary Prevention 2010 Guidelines from the American Heart Association (AHA) and 
American College of Cardiology Foundation (ACCF) also recommend the addition of 
second drug to statin therapy for non-HDL-C reduction when the triglycerides exceed 
200 mg/dL.44 In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) 
trial, the primary endpoint CV outcomes benefit for the entire cohort was not significant -
11% (0.16), however, for the subgroup with TG ≥ 204 mg/dL and HDL-C < 42 mg/dL
the benefit was significant (-27%; 0.005).45 In the Action to Control Cardiovascular Risk 
in Diabetes (ACCORD) trial that also investigated fenofibrate, the primary end point was 
not significant yet the subgroup with TG ≥ 204 mg/dL and HDL-C < 34 mg/dL the 
benefit was nearly significant (-31%; 0.06).46,47 In the Japan EPA Lipid Intervention 
Study (JELIS) that investigated the effectiveness of ethyl-EPA, the primary CV endpoint 
was significant -19% (0.011) for the entire cohort but demonstrated a dramatically larger 
significant benefit in the subgroup with TG ≥ 150 mg/dL and HDL-C < 40 mg/dL (-53%; 
0.043).48,49 Omega-3s lower non-HDL-C, primarily by lowering VLDL-C and the greater 
the baseline triglyceride level the more non-HDL-C reduction. Therefore, a baseline TG
of approximately ≥200 mg/dL with HDL-C approximately <40 mg/dL in men or <45
mg/dL in women will result in a greater non-HDL-C reduction with Epanova which is 


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more likely to result in a clinically significant CV benefit. Due to the well known 
variability of these lipids, a variability for the inclusion criteria of 10% at the lower end 
of the TG interval and of 5% at the upper end of the HDL interval is reasonable based on 
reports of high TG/low HDL subgroups in this range from previous outcomes trials46-49.
Thus, the resulting range for inclusion are those stipulated in the inclusion criteria of this 
protocol: TG ≥180 and < 500 mg/dL (≥2.03 and < 5.65 mmol/L) and HDL-C <42 mg/dL 
(1.09 mmol/L) for men or HDL-C <47 mg/dL (1.22 mmol/L) for women. These criteria 
are considered adequate to define a CV high-risk population likely to benefit from an 
intervention with Epanova.
In a study assessing combination therapy with simvastatin 40 mg and omega-3-acid ethyl 
esters 4 g daily (COMBination of prescription Omega-3 with Simvastatin [COMBOS]), 
median percent decreases in non-HDL-C were significantly greater with combination 
therapy compared to placebo (vegetable oil) plus simvastatin (9.0% vs. 2.2% 
respectively, p<0.001).50 In addition, combination therapy significantly lowered TG 
(29.5%) and VLDL-C (27.5%) raised HDL-C (3.4%) and lowered total cholesterol:HDL-
C ratio (9.6%; p < 0.001 vs. placebo for all), although LDL-C increased by 3.5%. In a 
post hoc analysis of the COMBOS study, the baseline LDL-C predicted the LDL-C 
response.51 The median LDL-C responses among the baseline LDL-C levels were +9.5% 
(first tertile, <80.4 mg/dL), -0.9% (second tertile), and -6.4% (third tertile, ≥99.0 mg/dL). 
Non-HDL-C, VLDL-C, HDL-C, and triglyceride responses did not vary significantly by 
baseline LDL-C tertile. The reductions in VLDL-C concentrations were greater than the 
increases in LDL-C, where present, resulting in a net decrease in the concentration of 
cholesterol carried by atherogenic particles associated with non-HDL-C, in all baseline 
LDL-C tertiles. In conclusion, these results suggest that the increase in LDL-C that 
occurred with the addition of omega-3-acid ethyl esters therapy to simvastatin therapy in 
subjects with mixed dyslipidemia was confined predominantly to those with low baseline 
LDL-C levels. In addition, LDL-particle number and Apo B-100 were reduced with the 
combination therapy suggesting that the increase in LDL-C was associated with an 
increase in LDL particle size rather than particle number.
A recent simulation study assessed the risk of CV events in 5000 individuals with severe 
hypertriglyceridemia (>500 mg/dL) and normal LDL-C levels (<100 mg/dL) using the 
Archimedes Model.52 At 10 years and 20 years respectively, the rate per individual at 
baseline of total MIs was estimated to be 14.6% and 32.5%, the rate of ischemic stroke 
was 3.5% and 7.9%, CHD death was 5% and 11.8%, CVD death was 7.1% and 16.7%, 
and the cumulative fraction of people with composite major adverse cardiovascular event 


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(MACE) were 16.2% and 31.5%. Individuals with severe hypertriglyceridemia are more 
than twice as likely to suffer an adverse cardiac outcome as compared with individuals 
with normal TG levels; the corresponding incidence rates for CHD mortality are 0.20% 
per year for the general US adult population and 0.45% for individuals with severe 
hypertriglyceridemia.
There are no long-term CV outcomes studies that specifically assess the impact of adding 
omega-3 fatty acids to statins in reducing the risk of cardiovascular events associated 
with persistent hypertriglyceridemia. The current protocol will investigate the 
effectiveness of adding Epanova to statin, with or without ezetimibe, as needed, for 
lowering MACE (cardiovascular death, non-fatal MI, non-fatal stroke, emergent/elective 
coronary revascularization, or hospitalization for unstable angina) in patients with 
persistent hypertriglyceridemia and high risk for CVD. The primary outcome measure is 
the time to the first occurrence of any component of the composite of MACE.
In the STRENGTH trial, all patients will be on statin therapy, with or without ezetimibe
therapy, in order to achieve LDL-C <100 mg/dL (<2.59 mmol/L). If a patient is not at 
this LDL-C goal at Visit 1 and not at the maximum tolerated statin dose, the statin must 
be titrated to the maximum tolerable dose. Another option is to treat with a high intensity 
statin such as either atorvastatin 40 or 80 mg, or rosuvastatin 20 or 40 mg, based on 
current 2013 ACC/AHA Guidelines.53 Rather than LDL-C or non-HDL-C targets, this 
guideline used the intensity of statin therapy as the goal of treatment (Appendix D). 
Through a rigorous process, 4 groups of individuals were identified for whom an 
extensive body of randomized control trial (RCT) evidence demonstrated a reduction in 
atherosclerotic cardiovascular disease (ASCVD) events with a good margin of safety 
from moderate- or high-intensity statin therapy:
1. Individuals with clinical ASCVD
2. Individuals with primary elevations of LDL-C ≥190 mg/dL
3. Individuals 40 to 75 years of age with diabetes and LDL-C 70 to 189 mg/dL 
without clinical ASCVD
4. Individuals without clinical ASCVD or diabetes who are 40 to 75 years of age 
with LDL-C 70 to 189 mg/dL and have an estimated 10-year ASCVD risk of 
7.5% or higher.
For patients who do not tolerate statins in doses needed to reach 100 mg/dL or the high 
intensity doses of atorvastatin and rosuvastatin described in the ACC/AHA 2013 
guidelines, the maximum tolerable dose of any statin should be used. 


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If the patient is already at the maximum tolerated statin dose, then ezetimibe 10 mg may 
be added (if available in the country). Bile acid sequestrants are contraindicated in these 
patients due to elevated triglyceride levels. Fibrates do not lower LDL-C in patients with 
hypertriglyceridemia and they carry cautions for use in combination with the maximum 
doses of statins. Niacin requires doses of 2000 mg to significantly lower LDL-C and it
carries cautions for use in combination with the maximum doses of certain statins and has 
not been proven to provide cardiovascular benefits. Therefore, no additional therapy is 
either available or safe to combine with high dose statins in patients with 
hypertriglyceridemia.
In the STRENGTH protocol, male patients >50 years of age with HDL-C <40 mg/dL or 
females >60 years of age with HDL-C <45 mg/dL, with at least one risk factor (family 
history of premature CHD, cigarette smoking, elevated high-sensitivity C-reactive protein 
[hs-CRP] or impaired renal function), have high risk for CHD and are therefore good 
candidates for the present study. Further, the West Of Scotland Coronary Prevention 
Study (WOSCOPS) demonstrated that patients with multiple risk factors treated with 
statin therapy continued to have a high rate of CHD events (10.2%).53 In the Cholesterol 
Treatment Trialists' (CTT) metanalysis,55 the elderly, defined as greater than 65 years of 
age, had a 30% greater risk of CHD events on statin therapy compared to those less than 
age 65. In the CTT analysis, the subgroup of subjects in the highest tertile (TG >177
mg/dL), which is comparable to the population for STRENGTH, had a significantly 
higher risk of CHD events on statin therapy. Therefore, hypertriglyceridemic patients 
greater than 65 years of age with two or more major risk factors have a significantly 
elevated risk of incidence of CHD events and will be an important subpopulation in the 
STRENGTH trial to evaluate the potential cardiovascular benefits of Epanova.


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2
OBJECTIVES AND OUTCOMES
2.1
Primary Objective and Outcome Measure
The primary objective is to evaluate the effectiveness of adding Epanova to statin therapy 
(with or without ezetimibe) for lowering MACE (cardiovascular death, non-fatal MI,
non-fatal stroke, emergent/elective coronary revascularization, or hospitalization for 
unstable angina) in high cardiovascular risk patients with persistent hypertriglyceridemia
and low HDL-C.
The primary outcome measure is the time to the first occurrence of any component of the 
composite of MACE. Patients will remain in the study until the required number of 
patients with MACE has occurred. We anticipate that patients will be in the study for 3-5 
years. Patients who discontinue investigational product (IP) will continue to be assessed 
as specified per the protocol.
2.2
Secondary Outcome Measures
2.2.1
Key Secondary Outcome Measures
∀
The composite measure of CV events that include the first occurrence of 
cardiovascular death, non-fatal MI, and non-fatal stroke.
∀
The composite measure of coronary events that include the first occurrence of 
cardiac death (including death due to acute myocardial infarction, sudden cardiac 
death and death due to cardiovascular procedures), non-fatal MI, emergent/elective 
coronary revascularization, or hospitalization for unstable angina.
∀
Time to CV Death
2.2.2
Other Secondary Outcome Measures
Other secondary outcome measure will include:
a) Emergent/elective coronary revascularization
b) Hospitalization for unstable angina
c) Fatal or non-fatal MI
d) Non-fatal MI
e) Fatal or non-fatal stroke
f)
Non-fatal stroke 
g) All-cause death


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2.3
Tertiary Outcome Measures
Tertiary endpoints will include:
∀
The first occurrence of new onset atrial fibrillation (AF).
∀
The composite measure of total thrombotic events that include the first occurrence 
documented coronary stent thrombosis, any systemic thromboembolism including 
arterial stent (except coronary) thrombosis or venous thromboembolism (VTE), 
i.e. deep vein thrombosis (DVT) and/or pulmonary embolism (PE).
∀
First occurrence of a heart failure event.
2.4
Clinical Events Adjudication
An independent Clinical Events Committee (CEC) will systematically identify and 
adjudicate all components of the primary and secondary endpoints as well as the tertiary 
heart failure events endpoint. The CEC will be comprised of qualified adjudicators from a 
pre-established group at the Cleveland Clinic Cardiovascular Coordinating Center for 
Clinical Research (C5Research) located at the Cleveland Clinic, 9500 Euclid Ave., 
Cleveland, OH 44195, U.S. Members of the CEC will be blinded to treatment 
assignment. The CEC-adjudicated data will be used in the final analysis.
Events will be analyzed per pre-specified definitions provided in a separate CEC charter 
and will be agreed upon by the CEC and the Executive Committee. Standardized 
definitions for endpoint events are provided by the Standardized Data Collection for 
Cardiovascular Trials Initiative (Appendix C: Standardized Definitions for Endpoint 
Events in Cardiovascular Trials). For the purposes of this protocol, MACE are defined as 
cardiovascular death, non-fatal MI, non-fatal stroke, emergent/elective coronary 
revascularization, and hospitalization for unstable angina. Non-fatal MI will NOT include 
silent MI. Unstable angina will require evidence of myocardial ischemia.
2.5
Efficacy Endpoints
Biomarker efficacy endpoints will evaluate the differences in change from baseline 
(Month 0) to Month 12 (primary), between placebo (corn oil) and Epanova treatments. In 
addition, biomarker data after Month 12, will be presented in a descriptive manner. 
Biomarker variables include non-HDL-C, TG, HDL-C, total cholesterol (TC), VLDL-C, 
TC:HDL-C ratio and calculated LDL-C (in patients with triglycerides > 400 mg/dl LDL-
C will be directly measured);apolipoprotein B-100 (Apo B-100) and apolipoprotein C-III 


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(Apo C-III); EPA, DHA, docosapentaenoic acid (DPA) and AA in plasma and red blood 
cells (RBC), hs-CRP. 
2.6
Safety Assessments
The study will provide long-term safety assessments of Epanova administration, 
including adverse events, safety laboratory assessments, pregnancy tests and physical 
examinations.
An independent Data Monitoring Committee (DMC) will review safety data periodically 
and may recommend stopping the study for safety concerns at any time.


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3
INVESTIGATIONAL PLAN
3.1
Overall Study Design
The study is a randomized, double-blind, placebo-controlled (corn oil), parallel group 
design that will enroll approximately 13,000 patients with hypertriglyceridemia and high 
risk for CVD to be randomized 1:1 to either placebo (corn oil) + statin or Epanova + 
statin, once daily, for approximately 3-5 years as determined when the number of patients 
with MACE outcomes is reached. There will be up to 15 scheduled clinic visits (1, 1a and
1b screening visits, one randomization [Visit 2], and 11 treatment visits [3, 6, 12, 18, 24,
30, 36, 42, 48, 54 and 60 months]), and a 3-week follow-up visit (Visit 14) for those 
patients who undergo early permanent IP discontinuation due to an SAE. Patients will 
remain in the study until the required number of patients with MACE have occurred; see 
Table 6-1 Schedule of Procedures and Study Flow Diagram Figure 3.1. Patients with 
potential, per investigator opinion, to achieve a fasting TG level of approximately ≥180
and <500 mg/dL (≥2.03 and <5.65 mmol/L) will undergo an initial screening period 
during which they will discontinue use of any excluded therapies or products and
continue or adjust their current statin regimen (statin adjustments may be permitted per 
investigator discretion, see Section 7.5). There will be up to 3 screening visits, depending 
on the need for repeated laboratory sample assessments or statin/ezetimibe adjustment. 
During the screening period, patients will maintain a stable diet, and after randomization,
be willing to adhere to the NCEP TLC or equivalent diet. Patients who meet all Inclusion 
Criteria and no Exclusion Criteria will be randomized 1:1 (6,500/arm) to receive double-
blinded Epanova (4 g daily) or a matching placebo (corn oil; 4 g daily) for the study 
duration.
The selection of the study population, i.e. patients with persistent hypertriglyceridemia 
despite statin therapy and a high risk for CVD, is in agreement with NCEP ATP III 
guidelines,1 as well as with more recent evidence-based reports.44,56,57,58,59,60 Adding a 
‘low HDL criterion’ increases the chance of showing benefit with triglyceride lowering 
therapy46-49. The study population is not restricted to a Framingham 10-year risk >20% 
for cardiovascular events and allows for both primary and secondary prevention 
populations. The study has inclusion criteria for patients with confirmed medical history 
of CVD as well as for patients with risk for CVD based on other conditions: type 1 or 2 
diabetes mellitus, elevated coronary calcium score, impaired renal function and advanced 
age. 1,53 55,56,57,58,59,60,61 In addition, the study may include patients based on hs-CRP 
levels which is associated with significant risk for CVD.57,58,59 The Justification for the 


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Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) 
trial demonstrated that the absolute risk of major vascular events increased with 
increasing hs-CRP, and that the absolute risk reduction associated with rosuvastatin was 
also greatest among those with the highest baseline hs-CRP levels.57
Patients will be allowed entry into the study if they are at the NCEP ATP III LDL 
cholesterol goal of <100 mg/dL (2.59 mol/L), if they are on treatment with a high 
intensity statin (atorvastatin 40 or 80 mg and rosuvastatin 20 or 40 mg) based on the 2013 
ACC/AHA lipid guidelines, or if they have an LDL-C ≥100 mg/dL and on the highest 
tolerated, moderate- or low-intensity statin therapy (with or without ezetimibe). The 
maximum tolerated dosage of a statin is defined as the maximum approved dose per local 
label or the maximal dose that the patient can tolerate without unacceptable adverse 
effects such as muscle pain or elevations in liver enzymes or creatine kinase (CK) felt by 
the investigator to be clinically relevant and due to statin therapy. 
The study allows for intra-patient variability of lipid measurements. For example, 
borderline values of TG > 160-179 mg/dL (>1.81-2.02 mmol/L) or TG ≥500 and <575 
mg/dL (>5.65 and <6.49 mmol/L) and/or borderline values of HDL-C ≤ 45 mg/dL (1.17 
mmol/L) for men and ≤50 mg/dL (1.30 mmol/L) for women, may require a repeat test.
Repeated lab values may be used to qualify if needed. Day-to-day variability of lipid 
measurements with different statin treatments as well as the variability between statins in 
achieving LDL cholesterol goals despite optimal dosing is well known.62,63,64
A total of 13,000 patients will be randomized into the 2 treatment arms according to the 
Study Flow Diagram (Figure 3.1).


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Figure 3.1
STUDY FLOW DIAGRAM
The CEC will adjudicate all MACE components of the primary endpoint, all MACE 
components and composite of the secondary endpoints, and the tertiary heart failure
endpoint (Table 3-1). The MACE primary endpoint is based on the 2008 FDA guidance63
“Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to 
Treat Type 2 Diabetes”, the published JUPITER outcomes trial,66 and the draft guidance 
on the standardized definitions for endpoint events provided by the Standardized Data 
Collection for Cardiovascular Trials Initiative (Appendix C: Standardized Definitions for 
Endpoint Events in Cardiovascular Trials).


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In JUPITER, the primary objective investigated whether treatment with rosuvastatin, 20 
mg daily, as compared with placebo, would decrease the rate of first major cardiovascular 
events.66 The primary outcome was the occurrence of a first major cardiovascular event, 
defined as non-fatal MI, non-fatal stroke, hospitalization for unstable angina, an arterial 
revascularization procedure, or confirmed death from cardiovascular causes.
The JUPITER results showed that healthy men and women with elevated levels of hs-
CRP who were treated with rosuvastatin had a significantly reduced incidence of major 
cardiovascular events. The decrease in events occurred despite the fact that nearly all 
study participants had lipid levels at baseline that were well below the threshold for 
treatment according to current prevention guidelines. Rosuvastatin also significantly 
reduced the incidence of death from any cause. These effects were consistent in all 
subgroups evaluated with elevated levels of hs-CRP, including subgroups customarily 
considered to be at low risk, such as people with Framingham risk scores of 10% or less, 
those with LDL cholesterol levels of 100 mg/dL or less, those without the metabolic 
syndrome, but no other major risk factor. The trial also showed robust reductions in 
cardiovascular events with statin therapy in women and black and Hispanic populations 
for which data on primary prevention are limited. Therefore, the JUPITER design for 
MACE proved to be adequate for an outcomes study.


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Table 3-1.
COMPONENTS OF PRIMARY, SECONDARY AND TERTIARY OUTCOME ENDPOINTS
Primary 
Endpoint
KEY Secondary Endpoint
Other 
Secondary 
Endpoint
Tertiary Endpoint
Component:
TTE; 
First 
occurrence 
(composite) of 
any component 
of
Composite
of
Composite 
of
Time 
to
Time to
Time to
Composite 
of
CV Death
X
X
X
Cardiac Death3
X
Non-fatal MI1
X
X
X
X
Non-fatal Stroke
X
X
X
Emergent/ elective coronary 
revascularization
X
X
X
Hospitalization for unstable angina2
X
X
X
Fatal or non-fatal MI
X
Fatal or non-fatal Stroke
X
All-cause death
X


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New onset AF
X
Coronary stent thrombosis
X
Systemic stent thrombosis
X
VTE/PE
X
HF
X
1 Note: Excludes silent myocardial infarction (MI); AF = atrial fibrillation; VTE = venous thromboembolism. PE = pulmonary embolism; HF = heart failure.
2 Note: Unstable angina must be confirmed by evidence of myocardial ischemia.
3 Note: Cardiac death includes death due to acute myocardial infarction, sudden cardiac death and death due to cardiovascular procedures


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3.2
Discussion of Study Design
Despite the widespread use of statin therapy, a considerable residual risk of 
cardiovascular events remains.67 While statins reduce the relative risk of cardiovascular 
events by approximately 20% to 50%, depending on the degree of LDL-C reduction, 
there remains considerable risk of future events in some subgroups of patients.55,68 One of 
the strongest predictors of residual risk is hypertriglyceridemia associated with low levels 
of HDL-C.67,69,70 In the ACCORD Lipid trial, patients with diabetes on simvastatin 
monotherapy in the upper tertile of triglycerides (TG ≥204 mg/dL) and the lower tertile 
of HDL-C (≤34 mg/dL) had a cardiovascular event frequency of 17.3% compared with 
10.1% in all other patients receiving simvastatin monotherapy.69 This subgroup of 
patients with high TG and low HDL-C represented approximately 17% of the study 
population receiving statin monotherapy, but accounted for 25% of the cardiovascular 
events. The high TG and low HDL-C subgroup in the ACCORD Lipid trial had not only 
a greater cardiovascular event rate, but also a 29% relative risk reduction on fenofibrate 
combination therapy with simvastatin, compared with simvastatin monotherapy (12.4% 
vs. 17.3% events; p=0.057). However, the patients outside of this dyslipidemic subgroup 
did not benefit from the addition of fenofibrate to simvastatin therapy (10.1% vs. 10.1% 
events, p=0.06 for the treatment-by-subgroup interaction). These results are consistent 
with those from the five other cardiovascular outcome trials that evaluated the benefits of 
a TG-lowering therapy in the subgroup of patients with significant 
hypertriglyceridemia.45,71,72,73,74
The benefits of triglyceride lowering agent such as Epanova is significantly more likely 
to occur in patients with a fasting triglyceride level greater than approximately 180
mg/dL. A combination of higher triglycerides and low HDL-C is also a stronger predictor 
of both residual CV risk on a statin as well as outcome benefits in randomized clinical 
trials in the subgroup of patients that received a triglyceride lowering therapy. Therefore, 
the clinical study inclusion criteria were adopted to maximize the potential CV outcome 
benefits of Epanova, which is predominately a treatment to lower triglycerides, VLDL-C 
and non-HDL-C in patients with elevated CV risk due to residual hypertriglyceridemia on 
a statin.
The inclusion criterion of fasting TG level ≥180 and <500 mg/dL is also based on 
recommendations from the NCEP ATP III and 2004 Update. 1,43 Although CVD risk 
increases with TG levels over 100 mg/dL, only at TG ≥200 mg/dL does the CVD risk 
increase by 2-fold. 1 Further, in the high-risk patient, the 2004 Update concurs that when 
triglycerides are ≥200 mg/dL, non-HDL-C is a secondary target of therapy, with a goal 


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30 mg/dL higher than the identified LDL-C goal. In clinical trials with fenofibrate or 
bezafibrate, the CV benefit of these TG lowering drugs are not achieved unless the 
triglyceride level is >200 mg/dL (FIELD, ACCORD, Bezafibrate Infarction Prevention 
[BIP] trials).75 Omega-3s lower non-HDL-C primarily by lowering VLDL-C and the 
greater the baseline TG level the more non-HDL-C reduction. Therefore, a baseline TG 
of approximately ≥200 mg/dL will result in a greater non-HDL-C reduction with 
Epanova, which is more likely to result in a clinical benefit. Due to the well known 
variability of these lipids, a variability for the inclusion criteria of 10% at the lower end 
of the TG interval and of 5% at the upper end of the HDL interval is reasonable based on 
reports of the results for high TG/low HDL subgroups in this range from previous 
outcomes trials46-49. Thus, the resulting range for inclusion are those stipulated in the 
inclusion criteria of this protocol: TG ≥180 and < 500 mg/dL (≥2.03 and < 5.65 mmol/L) 
and HDL-C <42 mg/dL (1.09 mmol/L) for men or HDL-C <47 mg/dL (1.22 mmol/L) for 
women. These criteria are considered adequate to define a CV high-risk population likely 
to benefit from an intervention with Epanova.
Regarding the choice of statin as the standard of care in this study, the NCEP guidelines 
recommend statins as a first-line treatment for targeting LDL-C goals.1 If the patient at 
LDL-C goal has persistent hypertriglyceridemia while on an optimal or maximum 
tolerated statin dose, the recommendation is to add a second lipid-lowering therapy to 
target non-HDL-C.
The current study is referred to as a ‘superiority’ trial in which the effects of Epanova 
will be compared to placebo (corn oil). The choice of corn oil, rich in omega-6 
polyunsaturated fatty acids (n-6 PUFA) as the control is based on both epidemiologic and 
interventional studies that suggest that although substituting n-6 PUFA-rich foods for 
saturated fatty acid (SFA)-rich foods in the diet can potentially lower total plasma 
cholesterol concentrations, this substitution provides only a modest reduction in 
cardiovascular events.76 In a meta-analysis of randomized clinical trials of replacing SFA 
with n-6 PUFA, the overall pooled risk reduction was 19% (RR = 0.81, 95% confidence 
interval [CI] 0.70-0.95, p = 0.008), corresponding to 10% reduced CHD risk (RR = 0.90, 
95% CI = 0.83-0.97) for each 5% energy of increased PUFA.77 Therefore a 4 gram dose 
or approximately 1% of energy from of corn oil would be expected to achieve 
approximately a 2% reduction in CHD risk. Extra virgin olive oil has been demonstrated 
in an interventional trial to reduce CV events by approximately 30 % over 4.8 years of 
median follow up.77 In recent literature, it was shown that olive oil (or more likely oleic 
acid) has an impact on overall and CVD mortality in that there was a reduction in CVD 


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mortality of 13% for each 10 g of olive oil intake.78 Extrapolating this result to a 4 g dose 
would result in a 5.2% reduction. Therefore, based on the published literature, either 
common olive oil or extra virgin olive oil would provide a greater CV risk reduction than 
corn oil.
Liquid paraffin or mineral oil has also been used in a few clinical trials as a control for 
evaluating the effects of omega-3’s but has been associated with increased 
gastrointestinal side effects, adverse lipid effects and potentially may interfere with the 
absorption of certain drugs.79 Mineral oil also does not provide caloric control which may 
result in an imbalance in the consumption of other nutrients such as carbohydrates that 
may lead to an exacerbation of hypertriglyceridemia. Other oils such a medium chain 
triglycerides or miglyol have been used as a control for short-term omega-3 lipid and 
have potential lipid changes that may affect CV outcomes. In addition, there is a lack of 
data regarding the long-term health effects of these oils. Therefore, the preferred option 
for the control selected for this study is corn oil (United States Pharmacopeia [USP] 
standard) even though modest changes in lipid parameters are expected as well as a slight 
reduction in CV risk. Further, the sample size assumptions for this study have taken into 
account the potential beneficial health effects of corn oil. 


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4
SELECTION AND WITHDRAWAL OF PATIENTS
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule.  Patients 
who are enrolled, but subsequently found not to meet all the eligibility criteria must not 
be randomized or initiated on treatment, and must be withdrawn from the study.
Where a patient does not meet all of the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the Quintiles Medical 
Monitor study physician immediately, and a discussion should occur between the 
Quintiles Medical Monitor and the investigator regarding whether to continue or 
discontinue the patient from treatment.  A patient who does not meet all of the eligibility 
criteria, is subsequently discontinued from treatment but has received at least 1 dose of 
randomized IP must be followed-up until End of the study in order to collect safety 
information and vital status (see Section 6.13).  The Quintiles Medical Monitor must 
ensure all decisions are appropriately documented.
4.1
Inclusion Criteria 
Patients who have provided written informed consent and authorization for disclosure of 
protected health information must meet the following criteria:
1. Men or women, ≥18 years of age.
2. Patient must be on a stable diet and statin* therapy at least 4 weeks prior to 
randomization (Visit 2) and meet the following criteria,where the qualifying lipid 
parameters should be obtained from the same visit:
a. LDL-C <100 mg/dL (<2.59 mmol/L). Patient will also qualify if LDL-C ≥100 
mg/dL (≥2.59 mmol/L) and if on a high-intensity statin (atorvastatin 40 or 80 mg 
and rosuvastatin 20 or 40 mg) or on highest tolerated moderate- or low-intensity 
statin dose, with or without ezetimibe therapy, for at least 4 weeks (see Appendix 
D).  The maximum tolerated dosage of a statin is defined as the approved dose 
per local label that the patient can tolerate without unacceptable adverse effects 
such as muscle aches/pain/weakness or elevations in liver enzymes or creatine 
kinase (CK) that are determined by the investigator to be clinically relevant and 
due to statin therapy.
b. TG ≥180 and < 500 mg/dL (≥2.03 and < 5.65 mmol/L) and HDL-C <42 mg/dL 
(1.09 mmol/L) for men or HDL-C <47 mg/dL (1.22 mmol/L) for women.


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*co-administration with ezetimibe or fixed-dose ezetimibe/simvastatin 10/10, 
10/20, 10/40 mg (see restrictions regarding 80 mg simvastatin in Section 7.4) or 
fixed-dose ezetimibe/atorvastatin 10/10, 10/20, 10/40, or 10/80 mg is allowed. 
3. Patient is at high risk for a future cardiovascular event if at least one of the following 
criteria (3a, 3b or 3c)* is present via patient history, physical exam, or medical 
records at the time of screening:
a. Any atherosclerotic CVD as defined by one or more of the following:
∀
previous clinical myocardial infarction (MI) ≥30 days prior to randomization
∀
percutaneous coronary intervention (PCI) including balloon angioplasty and 
coronary stenting ≥ 6 months prior to randomization
∀
coronary artery bypass grafting (CABG) ≥30 days prior to randomization
∀
coronary angiogram including computed tomography angiogram (CTA) 
showing ≥  50% stenosis in at least one native or graft vessel
∀
anginal symptoms with a defect documented by stress testing with nuclear 
perfusion imaging or a wall motion abnormality determined by stress 
echocardiogram
∀
asymptomatic coronary ischemia documented by stress testing with nuclear 
perfusion imaging or by stress echocardiogram
∀
peripheral vascular disease with symptoms of claudication and ankle brachial 
index <0.9 performed by a vascular lab or angiogram (including CTA) 
showing ≥50% stenosis)
∀
history of peripheral arterial revascularization (surgical or percutaneous) ≥30 
days prior to randomization
∀
carotid endarterectomy, carotid stenting or more than or equal to 50% stenosis 
in a carotid artery determined by carotid ultrasound or angiogram ≥30 days 
prior to randomization
∀
history of abdominal aortic aneurysm confirmed by imaging, diagnosed ≥30 
days prior to randomization
∀
ischemic stroke ≥30 days prior to randomization
b. History of diabetes mellitus (type 1 or 2) and ≥40 years of age for men and ≥50 
years of age for women, plus one of the following risk factors:


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∀
chronic cigarette smoking at screening (at least 1 cigarette per day for > 1 
month)
∀
history of hypertension (blood pressure >140/90 mm Hg) or taking 
antihypertensive medication
∀
high-sensitivity C-reactive protein (hs-CRP) > 2.0 mg/L (19.05 nmol/L) 
determined at Visit 1
∀
history of albuminuria (urinary albumin:creatinine ratio [ACR] >30 mg/g).
c.
Male patients >50 years of age or females >60 years of age, with at least one of 
the following risk factors:
∀
family history (mother, father or sibling) of premature coronary heart disease 
(father or brother <55 years of age, mother or sister <65 years of age)
∀
chronic cigarette smoking at screening (at least 1 cigarette per day for > 1 
month)
∀
hs-CRP >2.0 mg/L (19.05 nmol/L) determined at Visit 1
∀
impaired renal function as estimated using the Chronic Kidney Disease 
Epidemiology Collaboration(CKD-EPI)81formula for glomerular filtration rate 
(eGFR) <45 mL/min per 1.73 m2 (patients on dialysis are excluded).
∀
coronary calcium score >300 Agatston units (AU) at any time in the past.
*If patient will meet CVD secondary prevention criteria (3a) AND primary 
prevention criteria (3b and/or 3c) at the same time then patient will be considered 
as meeting CVD secondary prevention criteria (3a) for the purpose of identifying 
the inclusion criteria for that patient.
4.
Patient must have been on a stable diet prior to randomization and willing to follow 
the NCEP TLC diet, or equivalent diet, throughout the study.
Note a) A patient can, in specific circumstances, be re-screened. For details, see section
6.4. 
Note b): If LDL-C and/or TG and/or HDL-C do not meet the inclusion criteria at Visit 1, 
the patient may return twice (Visit 1a and 1b) during the screening period to reassess 
lipids for statin/ezetimibe adjustment, discontinuation of excluded lipid-modifying agent, 
or re-checking a borderline TG and/or HDL-C value (see footnote 2 of Table 6-1 for 
details on lipid reassessments and on statin/ezetimibe dose adjustments during the 


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screening period). Repeated values at Visit 1a may be used directly to qualify if needed. 
At Visit 1b, if lab values do not satisfy all inclusion criteria, the patient will be screen 
failed.
Note c): Once the patient qualifies, they should be randomized within 14 days. Atleast
50% of randomized patients should satisfy 3a CVD secondary prevention criteria, and 
<50% of patients should satisfy 3b and 3c primary prevention criteria combined; the 
proportions will be monitored and controlled via an Interactive Web Response System 
(IWRS).
4.2
Exclusion Criteria 
Any patient who meets any of the following criteria will not qualify for entry into the 
study:
1. Allergy or intolerance to omega-3 carboxylic acids, omega-3 fatty acids, omega-3-
acid ethyl esters or corn oil.
2. Known hypersensitivity to fish and/or shellfish
3. Use of fibrates, bile acid sequestrants, or niacin or its analogues (>250 mg/day) 
within 4 weeks prior to Visit 2. Patients taking these agents may be considered for 
inclusion in the study if these therapies have been discontinued for 4 weeks or more 
prior to Visit 2. However, niacin or its analogues at a dose less than or equal to 250 
mg/day is permissible.
4. Statin naïve at Visit 1.
5. Use of simvastatin 80 mg or ezetimibe/simvastatin 10/80 mg within 4 weeks prior to 
Visit 2. Patients taking these agents may be considered for inclusion in the study if 
these therapies have been discontinued and replaced with a protocol acceptable statin 
treatment that is stabilized for 4 weeks or more prior to Visit 2.
6. Use of any prescription medications containing eicosapentaenoic acid (EPA) and/or 
docosahexaenoic acid (DHA), e.g. Lovaza® or Vascepa®, within 4 weeks prior to 
Visit 2. Patients taking these agents may be considered for inclusion in the study if 
these therapies have been discontinued for 4 weeks or more prior to Visit 2.
7. More than one capsule/day (any dose) of omega-3 dietary supplements. Patients 
taking >1 capsule/day of omega-3 supplements before Visit 1 DO NOT require a 
washout period but must agree to reduce the number of capsules per day to more than 
1 capsule of 1 g promptly after signing the informed consent. No new omega-3 
supplements are permitted following initiation of screening procedures at Visit 1.


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8. Use of prescription or over-the-counter (OTC) weight loss drugs at any time after 
Visit 1.
9. Chronic use of oral corticosteroids during screening (acute use for inflammation for 
example from poison ivy, or intranasal or inhaled steroids for allergies/asthma, or 
intraarticular injections are allowed).
10. Use of tamoxifen, estrogens, progestins, or testosterone, that has not been stable for 
>4 weeks at Visit 1, or is unstable prior to Visit 2.
11. Known lipoprotein lipase impairment or deficiency, or apolipoprotein C-II 
deficiency.
12. Hemoglobin A1c (Hb A1c) >12% at Visit 1.
13. Poorly controlled hypertension (resting blood pressure ≥180 mm Hg systolic and/or 
≥100 mm Hg diastolic) at two consecutive visits prior to randomization at Visit 2.
14. Uncontrolled hypothyroidism, or thyroid stimulating hormone (TSH) >2.0 times 
upper limit of normal (ULN) at Visit 1. Patients who are clinically euthyroid, on 
stable thyroid replacement therapy for 2 months prior to Visit 1 are allowed.
15. History of cancer (except non-melanoma skin cancer, or carcinoma in situ of cervix) 
within the previous two years.
16. Patients on dialysis.
17. Females who are pregnant, planning to be pregnant during the study period, lactating, 
or women of childbearing potential who are not using an acceptable method of 
contraception. A woman is considered of childbearing potential if she is not 
surgically sterile or if her last menstrual period was <12 months prior to Visit 1. 
Acceptable methods of contraception for this study include use of double barrier 
contraception, intrauterine device , all oral, patch, etc. hormonal contraceptives as 
long as dose and type is stable for 3 months prior to Visit 1. In addition, true 
abstinence is acceptable when this is in line with the preferred and usual lifestyle of 
the subject.
18. Creatine kinase >5.0 times ULN; aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) >3.0 times ULN; or total bilirubin (TBL) >2.0 times ULN 
(except with a confirmed diagnosis of Gilbert’s disease), at Visit 1. A diagnosis of 
non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) 
with stable elevations of AST and/or ALT (>3.0 times ULN) is eligible for 
participation in the study.


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19. Excessive use of alcohol or other substance abuse that in the investigator’s opinion 
would jeopardize the patient’s participation in the study or interpretation of the data.
20. Exposure to any investigational agent within 4 weeks prior to Visit 1, including 
randomization in this study.
21. Previous clinical myocardial infarction (MI) <30 days prior to randomization
22. Percutaneous coronary intervention (PCI) including balloon angioplasty and 
coronary stenting<6 months prior to randomization
23. Coronary artery bypass grafting (CABG) <30 days prior to randomization
24. History of peripheral arterial revascularization (surgical or percutaneous) <30 days 
prior to randomization
25. Carotid endarterectomy or more than or equal to 50% stenosis in a carotid artery 
determined by carotid ultrasound or angiogram <30 days prior to randomization
26. History of abdominal aortic aneurysm diagnosed <30 days prior to randomization
27. Ischemic stroke <30 days prior to randomization
28. Any other condition the investigator believes would interfere with the patient’s ability 
to provide informed consent, comply with study instructions, or which might 
confound the interpretation of the study results or put the patient at undue risk.
29. Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca or its representative and/or staff at the study site).
4.3
Discontinuation of Investigational Product Criteria 
Every effort should be made by site study staff to encourage patients to remain in the 
study. Patients may discontinue the IP for reasons including the following:
1. Patient is unwilling to continue taking IP or has difficulties to comply with study visit 
schedule or investigational procedures.
2. During the study, patient has the need for medications or dietary products that are 
excluded (see Section 7.4, “Prohibited Medications and Dietary Products”).
3. Occurrence of any adverse event (AE) or condition that could, in the Investigator’s 
opinion, interfere with the evaluation of the treatment effect or put the patient at 
undue risk. See Appendix B (Actions Required in Cases of Combined Increase of 


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Aminotransferase and Total Bilirubin Hy´s Law) which provides criteria for 
determining potential serious hepatotoxicity of the IP according to Hy’s Law. Patients 
will discontinue for drug-induced liver injury (DILI).
Patients must discontinue IP and statin during pregnancy.
Patients who permanently discontinue taking IP for any reason will be asked to continue 
the regular study visits after the scheduled ET visit and (for permanent discontinuation 
due to an SAE) the 3-week Follow-up visit unless they withdraw consent for further 
participation and the use of their data. In this case, patient will be asked to provide 
written documentation (when possible) of withdrawal of consent and complete the ET
visit only. Therefore, all patients who are permanently discontinued from study 
medication and agree to continue in the protocol should have regularly scheduled study 
visits.
SAEs will be recorded at all visits for the patients who prematurely discontinue IP. Non-
serious AEs will be collected until the final visit but not more than 30 days after last dose 
of IP.
Data collection and procedures should continue according to the study protocol until 
study closure. If the patient does not agree to this option (which must be documented), a 
modified follow-up (e.g., regular telephone contacts or a contact at study closure) should 
be arranged, if agreed to by the patient and in compliance with local data privacy 
laws/practices in order to collect at least the study endpoint information. It is 
recommended that anyone being followed by regular telephone contacts or a contact at 
study closure attend the final visit in person. If Visit 13 (Month 60) is done in person then 
all protocol required procedures (Treatment Visits 6-12) must be done except IP 
dispensing/collection. The approach taken should be documented in the electronic case 
report form (eCRF), medical records and informed consent (IC) form.
Administration of IP may be interrupted for any reason during the study. The Investigator 
will judge if re-starts of the IP will provide a potential benefit that outweighs the risk in 
any patient. If judged by the investigator to be necessary, the protocol allows for 
unlimited statin interruptions. Temporary IP interruption of 7 days or more will be 
recorded in the eCRF.
4.4
Withdrawal from study (withdrawal of consent)
Patients are at any time free to withdraw from study (study medication and assessments), 
without prejudice to further treatment. Withdrawal of consent must be ascertained and 
documented by the Investigator who must consult with the Quintiles Medical Monitor
and document the withdrawal of consent in the eCRF as well as in the IC form and 
medical records. The IC form should be resigned and dated by both the patient and the 


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investigator, if possible. Such patients will always be asked about the reason(s) and the 
presence of any adverse events.
At the time of withdrawal, patients should, if possible do the Early Termination (ET) 
visit. The patient should return study medication. To ensure validity of study data, it is 
very important to collect as much data as possible throughout the study and especially 
vital status (dead or alive) at study closure. AstraZeneca or its delegate will therefore 
attempt to collect information on all patients’ vital status from publicly available sources
at study closure, even if informed consent has been withdrawn completely.
Adequate documentation of withdrawal of consent for follow-up is present only if both 
criteria below are met:
1) The patient explicitly refused all possible avenues for follow-up
2) There is written documentation by the PI that the patient has declined even a single
telephone call at the end of the trial and follow-up through medical records.


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5
STUDY TREATMENTS 
5.1
Identity of Investigational Product 
The IP will be 1 g capsules of either corn oil or Epanova. The IP will be supplied in 
bottles of 60 and/or 120 capsules. 
Investigational product
Dosage form and strength
Manufacturer
Omega-3 carboxylic acids 
(Epanova)
1g capsules*
Catalent Germany Eberbach 
GmbH (encapsulation)
Catalent Germany Schorndorf 
GmbH (capsule coating/bulk 
packaging)
Corn oil
1g capsules*
Catalent Germany Eberbach 
GmbH (encapsulation)
Catalent Germany Schorndorf 
GmbH (capsule coating/bulk 
packaging)
*
The lot number will be recorded in the study master file and identified in the Clinical Study Report (CSR).
The methods used in, and the facilities and controls used for the manufacturing, 
processing, packaging, and holding of this drug substance conform with Current Good 
Manufacturing Practices (cGMP) in accordance with 21 Code of Federal Regulations 
(CFR) Parts 210 and 211. AstraZeneca will maintain certificates of analysis for each 
ingredient, documenting its purity and potency.
Study labels will be consistent with the requirements of local regulatory authorities in 
each country. 
5.2
Investigational Product Storage and Accountability 
Investigational product will be stored at controlled room temperature (77 °F, 25 °C) in a 
locked area with limited access. Excursions between 59-86 °F (15-30 °C) are permitted
as per USP controlled room temperature criteria with minor excursions of 2 °C to 40 °C, 
which could occur during shipment and storage. Investigational product should not be 
frozen. 
Investigational product will be shipped to the study site. The Principal Investigator (PI) or 
designee will inventory and acknowledge receipt of all shipments of IP. The PI or 
designee must keep accurate records of IP via the master IP accountability logs and the 
patient IP accountability logs. Supplies of IP will be checked and accountability records 


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will be reviewed by the Clinical Research Associate (CRA) at monitoring visits. When 
the final accountability review has been completed, the original, completed accountability 
logs will be collected by the CRA and all unused, partially used, empty or unopened kits 
or bottles will be returned or destroyed according to the instructions from AstraZeneca or 
its representative. Written explanation will be required for any missing product. 
Investigational supplies should be used only in accordance with this protocol and under 
supervision of the PI. All records must be available for inspection by the contract 
research organization (CRO) and AstraZeneca personnel or their designees, and are
subject to inspections by the regulatory authorities (e.g., FDA) at any time.
5.3
Methods of Assigning Patients to Treatment Groups
Each clinical site will be assigned a unique number. At each clinical site, a unique 
screening number will be assigned to each patient after written informed consent is 
obtained. Patient screening numbers will be assigned sequentially by an IWRS. Each 
patient will have a unique identifier that combines both the site and screening number. At 
Visit 2 (Month 0), a randomization number will be assigned to each patient by an IWRS
in a sequential manner as he or she becomes eligible for randomization. The 
randomization number will correspond to a predetermined sequence of treatments that 
will provide a balanced allocation of patients to the treatment arms. Randomization 
numbers must not be re-used once assigned, even if the patient does not take the IP.
5.4
Administration of Investigational Product
Starting at Visit 1, patients will continue with, or adjust, their previous statin treatment 
throughout the study period. If a patient is not at their LDL-C goal of 100 mg/dL at Visit 
1, and not using a high intensity statin (atorvastatin 40 or 80 mg and rosuvastatin 20 or 40 
mg) , the statin must be titrated to the maximum tolerable statin dose or to a high 
intensity statin. If the patient is already at the maximum tolerated dose then ezetimibe 10 
mg may be added (if available in the country). On the days of all clinic visits throughout 
the study, the daily dose of statin, with or without ezetimibe, and investigational product
should not be taken until after the fasting blood draws.
After randomization at Visit 2 (Month 0), all patients will be treated with either 4 g 
once/day Epanova (4 capsules) or 4 g once/day placebo (corn oil) (4 capsules). Patients 
should take the first dose at the clinic at Visit 2 (Month 0) and the final dose should be 
taken no later than the night before the last visit (Visit 13 or ET). The IP may be taken 
without regard to meals.


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If the patient has intolerability symptoms with study drug dose of 4 g/day, a dose 
reduction may be required. The investigator should contact Quintiles Medical Monitor or 
designee to discuss alternative dosing strategies if needed, it is essential to try to maintain 
study treatment at a tolerated dose. Even a low dose of study medication is preferred to 
no study medication. Titrations may be performed through telephone contacts, if judged 
appropriate by the investigator.
If the patient has mild intolerability symptoms with 4 g/day, the recommendation is that 
the patient reduces the dose to 1 capsule twice a day with meals.
A temporary stop of study treatment for 1-2 weeks may be necessary if symptoms persist 
despite dose reduction, or as a first step if suspected adverse symptoms are intolerable to 
the extent that rapid resolution is required. Once symptoms subside, every attempt to 
titrate the patient back to 4 g/day, or the highest tolerable dose, should be made. The up-
titration can, if judged appropriate by the investigator, be performed stepwise with 
weekly increases up to the highest tolerable dose. The patient can begin with 1 capsule 
once daily for a week, then 1 capsule twice a day, thereafter 3 capsules per day and 
finally 4 capsules per day, if the increasing doses are tolerated by the patient. If a dose 
increase results in recurrence of symptoms the patient should go back to the highest 
tolerated dose. Unlimited temporary stops of intake of the study drug during the study 
period are allowed. Even after a longer stop of several months, a restart of slowly up-
titrated study treatment can be attempted if acceptable to the patient.
At randomization Visit 2, and all following visits, the daily dose of IP should not be taken 
until after the fasting blood draws.
5.5
Treatment Accountability and Compliance
Accountability of IP consumption will be evaluated by site staff through patient interview 
and the counting of unused IP returned to the clinic at Visits 3 through 13 (Months 3, 6, 
12, 18, 24, 30, 36, 42, 48, 54 and 60). The patient will be asked to bring the used and 
unused containers to each visit. Compliance (percent) = (the number consumed) ÷ (the 
number prescribed) x 100. Lost or discarded IP should not be included in the calculation. 
If compliance is less than 80%, patients will receive additional instructions about 
treatment regimens. 
5.6
Blinding and Unblinding Method
Investigational product will be administered in a double-blinded fashion. Access to the 
randomization schedule and treatment codes will be maintained through the IWRS. 


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Routines for this will be described in the IVRS/IWRS user manual that will be provided 
to each site.
In an emergency, the study blind may be broken only if:
∀
in the opinion of the Medical Monitor and/or the PI, it is in the patient's best 
interest to do so 
∀
knowledge of the treatment will alter the clinical management of the patient
In the case of an emergency that requires unblinding, the Investigator can enter IWRS to 
unblind the patient without prior contact with the Medical Monitor although follow-up 
between the Investigator and Medical Monitor must occur so that all parties are aware of 
the unblinding. A series of questions must be answered to ensure that the Investigator 
does not accidently unblind a patient. Although it is recommended that the Investigator 
contact the Medical Monitor prior to unblinding any patient, in instances where this is not 
feasible or advisable the PI directly access the patient's treatment assignment using the 
IWRS.
The emergency contact telephone number will be provided for each Medical Monitor.
Sponsor AstraZeneca retains the right to break the code for SAEs that are unexpected and 
are suspected to be causally related to an investigational product and that potentially 
require expedited reporting to regulatory authorities. Treatment codes will not be broken 
for the planned analyses of data until all decisions on the evaluability of the data from 
each individual patient have been made and documented.


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6
SCHEDULE OF PROCEDURES AND ASSESSMENTS
Table 6-1 represents the schedule of procedures and assessments at each of the scheduled 
visits. Details of each visit are provided in Sections 6.1 through 6.13.
Table 6-1.
SCHEDULE OF PROCEDURES
Study Period
Screening2
Randomization and 
treatment
EOT/ET
EOT/ET
Follow-up 
for SAE
Visit1
1
1a
1b
2
3
4
5
6 – 12
13
14
Month (±2 weeks)
0
3
6
12
18, 24, 30, 
36, 42, 48 
and 54
6015
3 weeks 
after 
EOT/ET for 
SAE17
Informed Consent
X
Medical History
X
X
X
X
Prior Medications
X
X
X
X
Physical Exam
X
X
X
Clinical 
Assessments3
X
X
X
X
X
X
X
X
X
Fasting Lipid Panel4,5
X
X
X
X
X13
X13
X13
Hemoglobin A1c
X
X
X13
X13
X13
Eligibility Review
X
X
X
X
hs-CRP
X
X
X
Serum Chemistry6
X
X
X
X7
X7
TSH
X
Urine Pregnancy 
Test8
X
Fasting Plasma 
Glucose
X
X13
X13
X13
Hematocrit
X13
X13
X13
ECG
X
Fasting Special Lipid 
Markers4,9
X
X
X
Plasma and RBC 
Fatty Acids4,10
X
X
X9
Fasting CV Risk 
Markers4,11
X
X
Genetic sample14
X
Counseling on TLC 
or Equivalent Diet
X
AEs, Concomitant 
Medications and 
Endpoint 
X
X
X
X
X16
X18


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Assessments11
Telephone Calls12
Randomization
X
Dispense IP
X
X
X
X
X
Assess IP 
Compliance
X
X
X
X
X
AE = adverse event; 
EOT = End of treatment; EOT is defined for patients who 1) permanently discontinue IP before the study 
has ended but agree for further follow-up assessments (on-site visits or telephone or via third party) until 
end of study 2) complete Visit 12 ( Month 60) and have not discontinued IP early;
ET = Early Termination. ET is defined for patients who permanently discontinue IP before the study has 
ended and decide not to participate with any follow-up assessments (on-site visits or telephone or via third 
party);
TSH = thyroid stimulating hormone; 
hs-CRP = high-sensitivity C-reactive protein; 
ECG = electrocardiogram; 
CV = cardiovascular; 
TLC = Therapeutic Lifestyle Changes; 
IP = Investigational Product. 
RBC= red blood cell
1. If fasting is not normal routine clinical practice, informed consent should be 
obtained prior to request for fasting for the Screening visit. If this is the case, the 
Screening visit should be split into 2 separate visits with informed consent 
obtained and IWRS accessed to obtain the patient number at the initial visit; and 
all other procedures obtained at the subsequent visit. In the event that the 
Screening visit is split into 2 separate visits, the screening visit lab draw must be 
completed within 3 days.  At any subsequent visit, if the patient did not fast for 
the recommended 9-14 hours, the fasted lab may be drawn the next day.
2. If at Visit 1 the patient’s TG, LDL-C, and HDL-C meet the inclusion criteria and 
the patient has been on a stable diet and has met all other inclusion criteria and 
none of the exclusion criteria the patient should return within 2 weeks for 
randomization at Visit 2.  
If at Visit 1 the patient requires an adjustment to their statin regimen and/or a 
washout of other excluded lipid medications, the patient should return 4-6 weeks 
later to have their lipids re-drawn at Visit 1a.
If at Visit 1 the patient does not require an adjustment to their statin regimen 
and/or a washout of other excluded lipid medications and either the patient’s TG 
and/or HDL-C are borderline: TG ≥160 - 179 mg/dL (>1.81 – 2.02 mmol/L) or 
TG ≥500 and <575 mg/dL (>5.65 and <6.49 mmol/L) and/or HDL-C ≤45 mg/dL 
(1.17 mmol/L) for men and ≤50 mg/dL (1.30 mmol/L) for women, the patient can 
return within 2 weeks later to have all lipids re-drawn at Visit 1a.


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If at Visit 1 the patient does not require an adjustment to their statin regimen 
and/or a washout of other excluded lipid medications, and TG and HDL-C values 
are outside of borderline boundaries, the patient is considered screen failed.
The TG, LDL-C and HDL-C results from Visit 1a will be used to determine 
eligibility in the same way as for Visit 1.  If re-drawn TG and HDL-C values are 
again borderline (as above), lipids can be repeated once more at Visit 1b to 
determine eligibility. Note that all lipid parameters qualifying for randomization 
should be obtained from the same visit.
If the TG, LDL-C and HDL-C criteria are not met after Visit 1b, the patient 
should be screen failed.
Please note the possibility to rescreen in the some situations, please see section 6.4.
3. Includes height (Visit 1 only), waist circumference and weight (Visit 1, 5, 7, 9, 
11, 13 only), blood pressure, and heart rate. 
4. Fasting blood samples should be drawn after the recommended 9-14 hour fast.
5. Lipid panel includes serum TG, TC, calculated LDL-C (in patients with 
triglycerides > 400 mg/dl LDL-C will be directly measured), HDL-C, calculated 
non-HDL-C, VLDL-C and TC: HDL-C ratio.
6. Serum chemistry includes creatine kinase, ALT, AST, total and direct bilirubin, 
and creatinine. Glomerular Filtration Rate (GFR) will be calculated only at Visits 
1 and 5. 
7. Only ALT, AST and total bilirubin will be analyzed, and only at Visits 7, 9, 11 
and 13.
8. Females of childbearing potential only (see Exclusion No. 17).
9. Special lipid markers include serum apolipoprotein B-100 (Apo B-100), and 
apolipoprotein C-III (Apo C-III). 
10. Plasma and RBC fatty acids (EPA, DHA, DPA and AA) will be measured from 
the recommended 9-14 hour fasting samples. Note: Plasma and RBC assessments 
are performed only at Visits 2 and 5, or ET before Visit 5.
11. Blood samples will be collected for future analyses on a subset of patients located 
in the US, of lipid fractions, inflammatory markers and other CV markers that 
may be identified during the course of the study.
12. In addition to these scheduled procedures, a well-being phone call will be made 
every 6 months (±2 weeks) starting after Visit 4 that will occur at Months 9, 15,
21, 27, 33, 39, 45, 51, and 57, except at scheduled visits, to question about 
adverse events, endpoint assessment, changes in medications and any major issues 
with the IP (losses or noncompliance). For further assessment of any identified 


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potential or confirmed AE, a physical examination should be carried out if 
clinically appropriate.
13. Fasting lipid panel, Hb A1c, fasting plasma glucose and hematocrit will be 
measured annually at Visits 5, 7, 9, 11 and 13.
14. Genetic samples will be collected for future analysis on approximately 2000 
patients in the US, see Appendix F for details. The sample should be taken at 
Visit 2. 
15. Patients who permanently discontinue taking IP for any reason will be asked to 
continue the regular study visits after the scheduled ET visit and (for permanent 
discontinuation of IP due to SAE) the 3-week Follow-up visit unless they 
withdraw consent for further participation and the use of their data. In this case, 
patient will be asked to provide written documentation (when possible) of 
withdrawal of consent and complete the ET Visit procedures only. If the patient is 
permanently discontinued from study medication and agrees to continue in the 
protocol, then the patient, if possible, should have regularly scheduled study 
visits. 
16. Patients who have early permanent discontinuation of IP due to an SAE and have 
an ET visit, will be required to schedule a 3-week Follow-up (Visit 14) to assess 
the SAE and concomitant medications. The patients should be asked to continue  
the regular study visits as described above thereafter.
17. Visit window is ±1 week for Visit 14 (ET/EOT Follow-up for SAE).
18. At Follow-up Visit 14, other assessments from the procedures table may be 
performed upon investigator discretion to further evaluate the SAE causing ET or 
for SAE identified at EOT.
6.1
Screening Period (Visit 1)
∀
Written IC
∀
Relevant medical history
∀
Prior medications taken within the last 4 weeks. Doses will be recorded 
only for statins, anticoagulants and diabetes medications
∀
Physical examination
∀
Clinical assessments (height, weight, waist circumference measured at the 
umbilicus, blood pressure, heart rate)
∀
Fasting lipid panel (recommended 9-14 hour fast)
∀
Hemoglobin A1c (Hb A1c)
∀
Eligibility review
∀
hs-CRP 
∀
Serum chemistry 


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∀
TSH
∀
Urine pregnancy test 
∀
TLC or equivalent diet counseling
∀
Remind patients of the recommended 9-14 hour fast prior to next visit
This visit may be conducted over two days in order to complete all procedures and obtain 
fasting laboratory tests. At Visit 1, if LDL-C is <100 mg/dL (2.59 mmol/L), OR ≥100 
mg/dL and patient is on high intensity statin treatment (atorvastatin 40 or 80 mg and 
rosuvastatin 20 or 40 mg) or on maximum tolerated medium-low intensity statin dosing 
regimen, with or without ezetimibe, patient will qualify to return for Visit 2 provided all 
other inclusion criteria are met and no exclusion criteria are met. If neither of the LDL-C 
criteria are met at Visit 1, patient will have statin/ezetimibe adjustment and return 4-6
weeks later at Visit 1a. At Visit 1a, if neither LDL-C criteria are met and patient is not on 
high intensity statin or on maximum tolerated dose of a medium- or low intensity statin, 
patient will have a second statin/ezetimibe adjustment and return 4-6 weeks later at Visit 
1b. At Visit 1a or 1b, patients who meet either LDL-C Inclusion Criteria will qualify to 
return for randomization at Visit 2 provided that all inclusion and none of the exclusion 
criteria are met at the same visit.
If LDL-C, TG or HDL-C do not meet Inclusion Criterion No. 2 at Visit 1, the patient may 
return twice during the screening period to reassess lipids. For example, if TG ≥160-179 
mg/dL (≥1.81-2.02 mmol/L) or TG ≥500 and <575 mg/dL (>5.65 and <6.49 mmol/L) the 
patient will return within 2 weeks for a scheduled repeat test. 
6.2
Screening Period (Visit 1a)
∀
Medical history
∀
Prior medications – any relevant changes since last visit
∀
Clinical assessments (blood pressure, heart rate)
∀
Fasting lipid panel (recommended 9-14 hour fast)
∀
Eligibility review
∀
Remind patients of the recommended 9-14 hour fast prior to next visit
At Visit 1a, patient will qualify to return for Visit 2 provided all other inclusion criteria, 
including the LDL-C criteria, are met and no exclusion criterion is met at the same 
visit.


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If neither LDL-C criteria are met and patient is not on maximum  tolerated dose, patient 
will have a second statin/ezetimibe adjustment and return 4-6 weeks later at Visit 1b.
If the TG or HDL-C value for Inclusion Criteria is borderline (TG ≥160-179 mg/dL 
[≥1.81-2.02 mmol/L] or TG ≥500 and <575 mg/dL (>5.65 and <6.49 mmol/L) and/or 
HDL-C ≤ 45 mg/dL (1.17 mmol/L) for men and ≤50 mg/dL (1.30 mmol/L) for women at 
Visit 1a, the patient will return within two weeks for a scheduled repeat test of all lipid 
parameters. Values at Visit 1a may be used directly to qualify if needed.  If TG or HDL-
C results from visit 1a are exclusionary, the subject will be screen failed.
6.3
Screening Period (Visit 1b) 
∀
Medical history
∀
Prior medications – any relevant changes since last visit
∀
Clinical assessments (blood pressure, heart rate)
∀
Fasting lipid panel (recommended 9-14 hour fast)
∀
Eligibility review
∀
Remind patients of the recommended 9-14 hour fast prior to next visit
At Visit 1b, patient will qualify to return for Visit 2 provided all other inclusion criteria 
are met and no exclusion criteria are met at the same visit.
If LDL-C criteria are not met and patient is still not on maximum tolerated dose, patient
will be screen failed.
If any TG or HDL-C value for Inclusion Criteria is borderline at Visits 1b, the patient 
will be screen failed.
6.4
Re-screening
In some circumstances, the patient is allowed for re-screening. A patient can return on
one occasion to redo screening procedures, starting from a re-screening Visit 1, if:
∀
A permanent change has occurred in eligibility criteria (medical status or 
laboratory findings) that previously led to screen failure. 
∀
Any of the 3 a-c inclusion criteria or any of the exclusion criteria for age, or time 
elapsed after a previous event,were not fulfilled at initial screening but the patient 
becomes eligible after additional time has elapsed. 
In addition, any patient that based on criteria used in a previous protocol version failed to 
be randomized due to TGs between 180 to 200 mg/dL (>2.23 to 2.26 mmol/L) and/or 


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HDL-C 40 to 41 mg/dL (1.04 and 1.06mmol/L) for men or 45 to 46 mg/dL (1.17 to 1.19 
mmol/L) for women can return for re-screening.
6.5
Randomization (Visit 2, Month 0)
∀
Medical history 
∀
Prior medications
∀
Clinical assessments (blood pressure, heart rate)
∀
Fasting lipid panel (recommended 9-14 hour fast)
∀
Eligibility review
∀
Hb A1c
∀
hs-CRP
∀
Serum chemistry 
∀
Fasting plasma glucose (recommended 9-14 hour fast)
∀
ECG
∀
Fasting plasma and RBC fatty acids (recommended 9-14 hour fast)
∀
Fasting blood samples for CV risk markers (on a subset of approximately 
2000 patients located in the US)
∀
Genetic sample ( on a subset of approximately 2000 patients in the US)
∀
Randomization
∀
Dispense IP (Epanova/placebo (corn oil)) and dosing instructions. Patients 
will take first dose at the clinic.
6.6
Treatment (Visit 3, Month 3) 
∀
Clinical assessments (blood pressure, heart rate)
∀
Fasting blood samples for CV risk markers ( on a subset of approximately 
2000 patients located in the US)
∀
Adverse events: selected collection see Section 9.2
∀
Endpoint Assessment
∀
Concomitant medications - relevant changes since last visit to be recorded 
for statins, anticoagulants or diabetes medications
∀
Dispense IP (Epanova/placebo (corn oil))
∀
Collect IP (Epanova/placebo (corn oil)) and assess compliance
6.7
Treatment (Visit 4, Month 6)
∀
Clinical assessments (blood pressure, heart rate)
∀
Adverse events: selected collection see Section 9.2
∀
Endpoint Assessment
∀
Concomitant medications - relevant changes since last visit to be recorded 
for statins, anticoagulants or diabetes medications


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∀
Dispense IP (Epanova/placebo (corn oil))
∀
Collect IP (Epanova/placebo (corn oil)) and assess compliance
∀
Remind patients of the recommended 9-14 hour fast prior to next visit
6.8
Treatment (Visit 5, Month 12)
∀
Physical examination
∀
Clinical assessments (waist circumference, weight, blood pressure, heart 
rate)
∀
Fasting lipid panel (recommended 9-14 hour fast)
∀
Hb A1c
∀
Serum chemistry 
∀
Fasting plasma glucose
∀
Hematocrit
∀
Fasting plasma and RBC fatty acids (recommended 9-14 hour fast)
∀
Adverse events: selected collection see Section 9.2
∀
Endpoint Assessment
∀
Concomitant medications - relevant changes since last visit to be recorded 
for statins, anticoagulants or diabetes medications
∀
Dispense IP (Epanova/placebo (corn oil))
∀
Collect IP (Epanova/placebo (corn oil)) and assess compliance
6.9
Treatment (Visits 6-12; Months 18, 24, 30, 36, 42, 48, and 54)
∀
Clinical assessments (blood pressure, heart rate)
∀
Clinical assessments (waist circumference and weight at visits 7, 9, and 11
only)
∀
Fasting lipid panel (Visits 7, 9, 11)
∀
Hb A1c (Visits 7, 9, 11)
∀
Serum chemistry (ALT, AST, total bilirubin only) (Visits 7, 9, 11)
∀
Fasting plasma glucose (Visits 7, 9, 11)
∀
Hematocrit (Visits 7, 9, 11)
∀
Adverse events: selected collection see Section 9.2
∀
Endpoint Assessment
∀
Concomitant medications - relevant changes since last visit to be recorded 
for statins, anticoagulants or diabetes medications
∀
Dispense IP (Epanova/placebo (corn oil))
∀
Collect IP (Epanova/placebo (corn oil)) and assess compliance
∀
Remind patients of the recommended 9-14 hour fast prior to next visit


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6.10 Telephone Calls (Months 9, 15, 21, 27, 33, 39, 45, 51, and 57)
A well-being telephone call will be made to assess:
∀
Adverse event experiences
∀
Endpoint assessment
∀
Changes in concomitant medications -relevant changes since last phone 
call to be recorded for statins, anticoagulants or diabetes medication
∀
Issues with IP (losses, compliance) 
For further assessment of any identified potential or confirmed AE, a physical 
examination should be carried out if clinically appropriate. 
6.11 End of Treatment (Visit 13; Month 60) or ET
∀
Physical examination
∀
Clinical assessments (blood pressure, heart rate, waist circumference and 
weight)
∀
Fasting lipid panel (recommended 9-14 hour fast)
∀
Hb A1c
∀
hs-CRP
∀
Fasting plasma glucose (recommended 9-14 hour fast)
∀
Serum chemistry (ALT, AST & total bilirubin only)
∀
Hematocrit
∀
Fasting plasma and RBC fatty acids (recommended 9-14 hour fast)
assessed only for ET before Visit 5
∀
Adverse events: selected collection see Section 9.2
∀
Endpoint Assessment
∀
Concomitant medications - relevant changes since last visit to be recorded 
for statins, anticoagulants or diabetes medication
∀
Collect IP (Epanova/placebo (corn oil)) and assess compliance
Note: Patients will be treated by their primary care provider after the study is completed.
The Sponsor does not intend to keep supplying the treatment to patients after the study 
ends.
6.12 Follow-up for SAE causing ET (3 weeks after ET visit)*
Patients who have an Early Termination (ET) of IP due to a serious adverse event (SAE) 
will be required to schedule the 3-week Follow-up visit.  The patient may be contacted by 
telephone if they are not available to attend an onsite visit. After the 3-week Follow-up 
visit the patient should be asked to follow the regular scheduled study visits.


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∀
Adverse events: selected collection see Section 9.2
∀
Concomitant medications - relevant changes since last visit to be recorded 
for statins, anticoagulants or diabetes medication
*Note: other assessments from the procedures table may be performed upon investigator 
discretion to further evaluate the SAE causing permanent IP discontinuation.
6.13 Early Termination Procedures
The term "Early Termination" refers to a patient’s non-completion of a study whether by 
his or her own choice, or the investigator’s decision, or due to discontinuation of the 
study by the Sponsor. Non-completion by a patient’s choice is defined for those who 
withdraw consent via written notification by the patient, discontinue IP, and who decide 
not to participate with any follow-up assessments (visit or telephone). The primary reason 
for a patient withdrawing prematurely should be recorded on the eCRF.  In the absence of 
a medical contraindication or significant protocol violation, every effort will be made by 
the Investigator to keep the patient in the study. For patients who withdraw from the 
study, direct ascertainment of health status at the end of the study will be performed in 
compliance with local privacy laws/regulations/practices.
Patients who discontinue IP but agree to participate with any follow-up assessments (visit 
or telephone) will undergo the ET visit, and the 3-week Follow-up visit for 
discontinuation from an SAE, and be asked to follow the regularly scheduled study visit 
assessments thereafter. 
The investigator must contact the Quintiles Medical Monitor promptly when deciding if a 
patient should be withdrawn, or if the study is stopped at their site by the IRB/IEC, or if 
the investigator elects to stop the study.
6.14 Patient Completion Criteria
For purposes of this study, patients who complete Visit 13 (Month 60) or are active 
participants when the specified number of patients with MACE endpoints is reached, and 
who have not discontinued IP early, will be defined as study completers.
6.15 Protocol Deviations
This study is intended to be conducted as described in this protocol. In the event of a 
significant deviation from the protocol due to an emergency, accident, or mistake, the 
investigator or designee must notify the Medical Monitor by submitting a form that 


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documents the deviation for approval for the patient to continue participation in the study
unless it is necessary to stop IP for safety/tolerability reasons.
Significant deviations that require review by the Medical Monitor include deviations 
from inclusion/exclusion criteria and use of prohibited medications during the study. 


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7
DETAILED DESCRIPTION OF ASSESSMENTS
7.1
Informed Consent
Written IC for the study will be obtained from each patient. For each country or region, a 
copy of the IC form, as approved by the respective IRB/IEC, will be given to all 
potentially eligible patients to read.
The protocol will be discussed in detail with each potentially eligible patient. The PI or 
qualified designee will explain all aspects of the study in lay language and answer all the 
patient's questions regarding the study. The PI or qualified designee will inform the 
patient as to the nature, aims, duration, potential hazards, and procedures to be performed
during the study and that his or her medical records may be reviewed. The PI or qualified 
designee will also explain that the patient is completely free to refuse to enter the study or 
to withdraw from it at any time. Patients who refuse to participate or who withdraw from 
the study will be treated without prejudice.
The study patient must sign the IC form if he/she decides to participate in the study. No 
study procedures will be performed and IP will not be administered to any patient who 
has not signed the IC form.
Withdrawal of consent must be ascertained and documented by the Investigator who must 
consult with the Quintiles Medical Monitor and document the withdrawal of consent in 
the eCRF as well as in the IC form and medical records. The IC form should be resigned 
and dated by both the patient and the investigator, if possible. Such patients will always 
be asked about the reason(s) for withdrawal and the presence of any adverse events.
7.2
Medical History
A relevant medical history, will be obtained at Visit 1. Medical History will also be 
updated until randomization at Visit 2. Medical information necessary for the enrollment 
in the study can, if no written information is available, be based on the patients´ verbal 
confirmation.
7.3
Prior Medications and Concomitant Medications
Any therapy taken by the patient during the 4 weeks before Visit 1 or during screening 
and stopped before Visit 2 will be defined as a prior medication. Doses will only be 
recorded for statins, anticoagulants and diabetes medication. Any therapy started or 


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stopped by the patient after randomization (Visit 2) will be regarded as concomitant 
therapy.
Relevant prior and concomitant medications will be documented and must include the 
following information:
∀
Medication name
∀
Indication
∀
Treatment prior to study start
∀
Stop date or “Ongoing”
∀
Dose for statin, anticoagulants and diabetes medications only.
7.4
Prohibited Medications and Dietary Products
Use of the following medications or dietary products are prohibited during the study at 
any time after Visit 1:
The following 4 types of medications or dietary supplements are prohibited as they may 
have an effect on lipids that interferes with the ability to evaluate the results of the study:
∀
Bile acid sequestrants, fibrates, or niacin or its analogues (>250 mg/day)
∀
Use of any prescription medications containing EPA and/or DHA (e.g., Lovaza® or 
Vascepa®). Patients taking >1 capsule/day of omega-3 dietary supplements before 
Visit 1 DO NOT require a washout period but must agree to reduce the number of 
capsules per day to no more than 1 capsule of 1 g promptly after signing the informed 
consent. No new omega-3 supplements are permitted following initiation of screening 
procedures at Visit 1.
∀
Prescription or OTC weight loss drugs such as phentermine, diethylpropion, 
benzphetamine, phendimetrazine, orlistat (Xenical® prescription; Alli™OTC),
sibutramine, lorcaserin, topiramate+phentermine (Qsymia®), bupropion+naltrexone , 
and bupropion+zonisamide
∀
Chronic use of oral corticosteroids is prohibited (acute use for inflammation for 
example from poison ivy, or intranasal or inhaled steroids for allergies/asthma, or 
intraarticular injections is allowed)


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The following 2 types of prohibited medications are related to the background statin 
treatment and are prohibited as they are known to have a potential for side effects or a 
potential for interactions with statins:
∀
Specific instructions for simvastatin: The dose should always be lower than 
Simvastatin 80 mg or ezetimibe/simvastatin 10/80 mg. Patients taking verapamil or
diltiazem should not exceed 10 mg/day simvastatin. Patients taking amiodarone, 
amlodipine or ranolazine should not exceed 20 mg/day simvastatin. All statins should 
always be prescribed in compliance with the local product label/prescribing 
information, including dose adjustments if drugs potentially interacting with the statin 
need to be prescribed.
∀
Oral erythromycin, telithromycin, clarithromycin, cyclosporine, itraconazole, 
ketoconazole, protease inhibitors, or nefazodone are examples of drugs that should 
generally be avoided during the study. If such treatment is clinically important the 
statin should be stopped, or the doses of statins should be adjusted, according to local 
prescribing information.
If a patient begins taking a prohibited medication or dietary product, the Medical Monitor 
should be notified of the deviation. Approval of certain medications or dietary products 
may generally be considered if the exposure was brief. Prohibited medications started in 
violation of the protocol (for example, those instituted by the patient’s general 
practitioner) should ideally be stopped, but may be continued if the concomitant 
medication treatment in addition to study drug will not put the patient at risk.  If a 
prohibited medication is to be continued, but the concomitant treatment with study drug 
is judged to infer risk to the patient, the study drug must be stopped. These decisions will 
be left at the discretion of the investigator but should be communicated to the Medical 
Monitor as indicated above.
Patients who need to discontinue IP should always be asked to continue the regular study 
visits after the scheduled ET visit.
7.5
Permitted Medications 
A statin adjustment period(s) will be permitted after Visit 1 under the following 
circumstances:
∀
Patients who are on simvastatin 80 mg or ezetimibe/simvastatin 10/80 mg at Visit 
1 (see Section 7.4 for all restricted simvastatin dosing) an adjustment must be 
made to a lower dose of simvastatin, or an alternative statin in order to continue in 


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the study. If patients are taking simvastatin 20-40 mg/day and a coumarin 
anticoagulant (e.g. warfarin ) the International Normalized Ratio (INR) should be 
appropriately monitored
∀
Patients who require a statin/ezetimibe adjustment at Visit 1 to achieve LDL-C 
criteria, will be permitted to return 4-6 weeks later at Visit 1a to qualify. If the 
LDL-C criteria are not met, another repeat visit will be scheduled for Visit 1b as 
needed. If the lab criteria are not met by Visit 1b, the patient will be screen failed.
Note: if ezetimibe is added to warfarin, a coumarin anticoagulant, the International 
Normalized Ratio (INR) should be appropriately monitored.
Every attempt should be made to maintain LDL-C levels at National Guidelines goals 
(e.g. NCEP goals1), at a minimum achieving LDL-C below 100 mg/dL (2.59 mmol/L) by 
adjusting statin dose to the maximum tolerated dose or combination therapy with 
ezetimibe. However, if LDL-C is ≥100 mg/dL and the patient is on a high intensity statin 
according to the 2013 ACC/AHA guidelines (i.e. atorvastatin 40 or 80 mg or rosuvastatin 
20 or 40 mg) or on the maximum tolerated moderate or low-intensity statin dose (with or 
without ezetimibe coadministration), then the patient may be eligible for randomization.
The maximum tolerated dosage of a statin is defined as the maximum approved dose per 
local label or the maximal dose that the patient can tolerate without unacceptable adverse 
effects such as muscle pain or elevations in liver enzymes or CK as determined by the 
investigator to be clinically relevant and due to statin therapy. Statin dose adjustments 
during the study can be made at the discretion of the investigator, if needed for safety 
reasons. If judged by the investigator to be necessary, the protocol allows for unlimited 
statin interruptions.
Acute use of inhaled or intranasal corticosteroids (such as products commonly used for 
asthma or seasonal allergies) is permitted. Topical antifungals, corticosteroids, and 
limited use of oral or intra-articular corticosteroids are permitted. 
Stable use (>4 weeks prior to Visit 1) of estrogens, tamoxifen, progestins or selective 
estrogen receptor modulator is allowed. All oral, patch, etc. hormonal or contraceptives 
are allowed as long as dose and type are stable for 3 months prior to screening. Topical 
estrogens for local vaginal symptoms, and daily use of testosterone patches will be 
allowed. 
Patients who are clinically euthyroid, on stable thyroid replacement therapy for 2 months
prior to screening will be allowed adjustment during the study.


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7.6
Eligibility Review 
Eligibility criteria are reviewed at each screening visit and the randomization visit and the 
patient must meet all of the inclusion and none of the exclusion criteria prior to 
randomization. If lipid laboratory values are abnormal and are reasonably expected to fall 
within the allowable range upon repeat testing, the test may be repeated at the additional 
screening visits 1a and 1b.  All repeat laboratory testing will be performed by the central 
laboratory.
Screen Failure: A screen failure is defined as a patient who has consented but who has 
not been randomized.
7.7
Clinical Assessments 
Height (at Visit 1 only). Weight and waist circumference will be measured at Visit 1, 5, 
7, 9, 11, 13. Resting blood pressure and heart rate will be measured at all clinic visits. 
Three blood pressure and heart rate measurements 3 minutes apart will be taken after at 
least 3 minutes of seated rest. The first measurement will be ignored. The average of the 
last 2 measurements will be recorded for both blood pressure and heart rate.
7.8
Physical Examination
A physical examination consisting of an evaluation of the head, neck, eyes, ears, nose, 
throat, chest, heart, lungs, abdomen, skin, extremities, and the neurological and 
musculoskeletal systems will be performed at Visit 1 and Visits 5 as well as on Visit 
13/EOT/ET.
For further assessment of any identified potential or confirmed AE, a physical 
examination should be carried out if clinically appropriate. 
Any clinically significant finding observed up to and including Visit 2 will be considered 
Medical History. Any new or worsened clinically significant finding observed after Visit 
2 through Visit 13/EOT/ET will be considered an adverse event and recorded in the 
source documents. Findings associated with a change in dose or discontinuation of IP 
should be reported in the eCRF.
7.9
Electrocardiogram 
A 12-lead ECG will be performed after patient has been supine at rest for at least 5 
minutes at Visit 2. The ECG will be read by the investigator at each clinical site. Any 
clinically significant finding observed at Visit 2 will be included in the Medical History. 


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7.10 Diet
At the first clinic visit, patients will receive dietary counseling regarding the NCEP TLC
or equivalent diet at the discretion of the investigator and be willing to adhere to during 
the treatment period. (see Appendix A for details).
A weight maintenance version of the TLC or equivalent diet will be employed. 
7.11 Safety Assessments – Adverse Events
Information on SAEs, AE criteria in accordance with Section 9.1, and adverse events 
leading to a change of IP dose or interruption of IP will be collected at each clinic visit 
and at each well-being telephone call. Temporary IP interruption of 7 days or more will 
be recorded in the eCRF. A DMC will review safety data periodically and may
recommend stopping the study for safety concerns at any time. At each DMC meeting, 
the committee will review all individual cases of LDL-C increases, AST/ALT increases
or other increases in liver-related chemistries, new onset diabetes mellitus, or bleeding 
related events, in addition to other safety and laboratory data (i.e. fasting glucose, 
hemoglobin A1c and hematocrit) refer to Section 9.2 for details on selected adverse event 
collection. For this study, it will be assumed that all undetermined cases of bleeding are 
included in the hemorrhagic category since use of other omega-3 agents has been 
associated with an increase in bleeding risk. See Appendices B and C for details 
regarding “increases in liver related chemistries” and hemorrhagic stroke. A sensitivity 
analysis will be performed in which the undetermined strokes are included with the 
ischemic stroke category. See Section 9.3 for details about bleeding definitions.
7.12 Laboratory Assessments and Procedures
An approximate maximum of 160 mL of whole blood will be collected from each patient 
throughout the study.
7.12.1
Screening Laboratory Assessments
For the screening period, a maximum of 5.4 mL of blood will be collected to assess 
lipids, chemistry, hs-CRP and TSH. Two mL of blood will be collected at Visit 1 for 
assessment Hb A1c.
7.12.2
Efficacy Laboratory Assessments
For efficacy laboratory testing of fasting lipids (TG, TC, calculated LDL-C [in patients 
with triglycerides > 400mg/dl LDL-C will be directly measured], HDL-C, calculated 


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non-HDL-C, VLDL-C and TC: HDL cholesterol ratio) 1-mL blood samples are collected 
at Visits 2, 5, 7, 9, 11 and 13/EOT/ET. Three 1-mL blood samples will be collected for 
measurement of Apo C-III, and three 2-mL samples will be collected for Apo B-100 at 
Visits 2, 5 and 13/EOT/ET. A 6 mL blood sample for plasma and RBC fatty acids (EPA, 
DHA, DPA and AA) will be collected at each Visit 2, 5 and ET for early termination 
before Visit 5. 
Starting at Visit 2, the lipid panel, special lipid markers, and fatty acids are blinded. All 
fasting blood samples will be drawn after the recommended 9-14 hour fast.
7.12.3
Safety Laboratory Assessments
Safety laboratory testing on all patients in the study, on IP or not, includes serum 
chemistry (creatine kinase, ALT, AST, total and direct bilirubin, and creatinine) at Visits 
2 and 5; approximately 2 mL of blood will be collected at each visit. At Visits 7, 9, 11 
and 13/EOT/ET, only ALT, AST and total bilirubin are measured; , approximately 2 mL
of blood will be collected at each visit. The eGFR will be calculated only at Visits 1 and 
5. Two mL of blood will be collected to measure fasting plasma glucose at Visits 2, 5, 7, 
9, 11 and 13/EOT/ET. Hb A1c is measured at Visits 2, 5, 7, 9, 11 and 13/EOT/ET; 
approximately 2 mL of blood will be collected at each visit. Hematocrit is evaluated at 
Visits 5, 7, 9, 11 and 13/EOT/ET; approximately 2 mL of blood will be collected at each 
visit. Assessment of hs-CRP at Visits 2 and 13/EOT/ET will be sampled from the 
chemistry blood draws.
Urine pregnancy tests will be conducted only on women of childbearing potential. A 
woman is considered of childbearing potential if she is not surgically sterile or is less 
than 1 year since last menstrual period. Urine pregnancy tests will be conducted by the 
site.
7.12.4
Collection, Shipment, and Retention of Laboratory Samples
7.12.4.1
Safety and Efficacy Analyses
All safety and efficacy laboratory analyses (except urine pregnancy tests) will be 
performed by a central laboratory. The central laboratory (Quintiles Laboratory) will 
provide all collection materials and instructions for sample collection, packaging, and 
shipment


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7.12.5
Exploratory CV Risk Markers (on a subset of patients located in the 
US)
The subject’s consent to the use of donated biological samples is mandatory ( included in 
the Inform Consent for the main trial). Blood samples will be collected at baseline ( Visit 
2) and 12 weks ( Visit 3) for future analyses of lipid fractions, inflamatary markers and 
other CV markers that may be identified during the course of the study. The samples will 
be collected on a subset of approximately 2000 patients located in the US. Two tubes of 
blood will be collected at baseline and 1 tube at 12 weeks after randomization. Plasma 
and serum will be extracted by the central laboratory, aliquoted into 250-300 μL samples 
and stored at -80 ºC until analysis is performed. The samples will be transferred from 
Quintiles Laboratory to the AstraZeneca BioBank. 
7.12.5.1
Storage, re-use and destruction of exploratory CV risk marker 
samples ( on a subset of patients located in the US).
The CV risk marker samples will be shipped from the cental lab to the AstraZeneca 
BioBank in United Kingdom. Samples will be stored for a maximum of 15 years from the 
date of the Last Subject’s Last Visit, after which they will be destroyed. The results of 
this biomarker research will be reported either in the Clinical Study Report itself or as an 
addendum, or separately in scientific report or publication. 
7.12.5.2. 
Labelling and shipment of exploratory CV risk marker samples (on a 
subset of patients located in the US)
The Principal Investigator ensures that samples are labelled and shipped in accordance 
with the Laboratory Manual.
7.12.5.3
  Chain of custody of exploratory CV risk marker samples (on a 
subset of patients located in the US)
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at each centre keeps full traceability of collected biological 
samples from the subjects while in storage at the centre until shipment or disposal (where 
appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use 
until used or disposed of or until further shipment..


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AstraZeneca keeps oversight of the entire life cycle through internal procedures, 
monitoring of study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the AstraZeneca Biobank during the 
entire life cycle.
7.12.5.4
Withdrawal of Informed Consent for donated exploratory CV risk 
marker samples (on a subset of patients located in the US)
If a subject withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed, and the action documented.  If samples are already analysed, 
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological samples is an optional part of the study, then the subject 
may continue in the study.
The Principal Investigator:
∀
Ensures subjects’ withdrawal of informed consent to the use of donated 
samples is notified immediately to AstraZeneca
∀
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented
∀
Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, 
the action documented and the signed document returned to the study site
∀
Ensures that the subject and AstraZeneca are informed about the sample 
disposal.
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about 
the withdrawn consent immediately and that samples are disposed of/destroyed and the 
action documented and returned to the study site.
7.12.6 Pharmacogenetics (on a subset of patients located in the US)
Genetic samples will be collected for future analysis on approximately 2000 patients in 
the US, see Appendix F for details.


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8
STATISTICAL METHODS
8.1
Sample Size Determination
This event-driven study is designed to have 90% power to detect a 15% reduction in risk 
of primary efficacy MACE rate (hazard ratio=0.85) for patients treated with Epanova 
compared to placebo (corn oil) on top of a background of standard care (statin therapy). 
With an overall type I error rate (alpha level) of 5%, a total of 1,600 primary efficacy 
events are required to achieve approximately 90% power to detect the difference between 
Epanova and placebo (corn oil) (a constant hazard ratio of 0.85). The estimate of 4%
annual event rate for control is based on previous studies investigating MACE, 
considering populations with documented cardiovascular disease and populations with 
cardiovascular risk factors only. The enrollment of patients with documented CVD 
will be ≥50% of all randomized patients; the enrollment of patients with risk factors 
only (primary prevention) will be less than 50% of all randomized patients; these 
proportions will be monitored and controlled via IWRS. 
Assuming a total study duration of 4.5 years and a placebo (corn oil) event rate of 
approximately 4% per year, a sample size of 13,000 patients (6,500 per treatment group) 
is required.
8.2
Analysis Populations
Intent-to-Treat Population
The intent-to-treat (ITT) population will comprise all patients who were randomized. If 
patients stop taking IP, patients should continue to be followed for the study duration. A 
patient will be considered randomized as soon as a treatment number is assigned by an
IWRS. Patients will be summarized by their randomized treatment. All data collected 
throughout the duration of the study will be analyzed based on randomized treatment. 
Safety Population
All randomized patients who received at least 1 dose of IP will be included in the safety
population.
8.3
Randomization
An IWRS will be implemented to obtain a balanced allocation to each treatment group. 


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8.4 
Statistical Analyses
A Statistical Analysis Plan (SAP) will describe in detail the statistical analyses for the 
study. If circumstances arise during the study that make these analyses inappropriate or if 
improved methods become available, the SAP may be revised. Any revisions (both 
alternative and additional methods) to the SAP, and reasons for such revisions, will only 
be made while study is still blinded and will be described in the final Clinical Study 
Report (CSR). In general, descriptive statistics, unless otherwise noted, will include the 
number of patients (n), mean, standard deviation (SD), median, minimum value, and 
maximum value. Median will be presented together with Q1 and Q3. Percentages will be 
calculated using the number of patients within each treatment. Unless otherwise stated, 
all summary tables will present descriptive statistics and/or frequency by visit for each 
treatment group. 
8.4.1
Primary Outcome Analysis
The primary outcome measure is the time to first occurrence (TTE; time-to-event) of any 
component of the composite of MACE (cardiovascular death, non-fatal MI, non-fatal
stroke, emergent/elective coronary revascularization, or hospitalization for unstable 
angina). The primary outcome will be based on the ITT population using adjudicated 
events.
A Cox proportional hazards model for time to first MACE event will be assessed for 
comparing the two treatment groups, with treatment arm, established CV disease at 
baseline, multiple risk factors without established CV disease at baseline and geographic 
region as covariates (Appendix E). Event rates will be expressed as the percentage of 
events per follow-up year, taking into account censoring of follow-up data. 
For each TTE endpoint, a patient will be censored no later than the date of the last 
available information on that patient, from any source captured in the database. The 
specific rule(s) for each individual TTE will be explicitly specified in the SAP. Kaplan–
Meier estimates will be used to quantify event rates during the course of the trial. 
The assumption for proportional hazards for the treatment groups will be assessed:
1. visually by using log-cumulative hazard plots.  The effects of any departures 
from the proportional hazards will be discussed as part of the presentation of 
results of the analyses.


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2. Treatment-by-time interaction, defined as time-varying covariate, will be tested.  
In the event of a statistically meaningful interaction, an additional analysis will be 
carried out with the interaction term in the model
3. Schönfeld Residual will be plotted for each covariate versus log(time) and for 
treatment group versus observation
Sensitivity analyses of the primary efficacy endpoint will also be performed to assess the 
robustness of the primary results. The sensitivity analyses will be performed for only on-
treatment MACE events in the ITT population.
Further details will be provided in the SAP. All comparisons described above will use a 
Cox proportional hazards model to estimate the relative effect of Epanova versus placebo 
(corn oil). The treatment effect will be assessed at a nominal 5% significance level. 
Analysis results will be presented as hazard ratios, 95% confidence intervals and p-value.
8.4.2 Secondary Outcomes Analyses
The secondary outcomes measures will be analyzed using the same model as outlined 
above for the primary outcomes measure, on the ITT population. The respective 
censoring rules will be defined explicitly in the SAP.  The evaluation will be carried out 
in a hierarchical fashion.  Specifically, if the primary endpoint objective is met(2-sided p-
value<0.05), the secondary outcomes will be evaluated hierarchically at an overall alpha 
of 0.05 for each comparison, sequentially. Once a key secondary endpoint is not met at 
alpha 0.05, all subsequent comparisons will be considered exploratory.
The hierarchy for sequential testing the following key secondary outcome measures will 
be defined as: 
KEY SECONDARY (tested at #=0,05, conditional on success of the primary)
1. The composite measure of CV events that include the first occurrence of 
cadiovascular death, non-fatal MI and non-fatal stroke
2.The composite measure of coronary events that include the first occurrence of 
cardiac death (including death due to acute myocardial infarction, sudden cardiac death 
and death due to cardiovascular procedures), non-fatal MI, emergent/elective coronary 
revascularization, or hospitalization for unstable angina.
3.Time to CV Death


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Other SECONDARY (evaluated at #=0,05; NOT part of the hierarchical testing 
sequence; that is, exploratory)  
Time to:
1. Emergent/elective coronary revascularization
2. Hospitalization for unstable angina
3. Fatal or non-fatal MI
4. Non-fatal MI
5. Fatal or non fatal stroke
6. Non-fatal stroke 
7.
All-cause death
Further details (including individual censoring rules) will be provided in the SAP.
8.4.3 Tertiary Outcome Analysis
Tertiary outcome measures will include:
∀
The first occurrence of new onset AF.
∀
The composite measure of total thrombotic events that include the first occurrence 
of documented coronary stent thrombosis, any systemic thromboembolism 
including arterial stent thrombosis (except coronary) or venous thromboembolism 
(VTE), i.e. deep vein thrombosis (DVT) and/or pulmonary embolism (PE).
∀
First occurrence of a heart failure event.
The tertiary outcome measures will be analyzed using methods similar to those for the 
primary and secondary analyses. The analysis of the tertiary outcomes will be considered 
observational only. Further details will be provided in the SAP.
8.4.4 Biomarkers of Efficacy
The analysis of biomarkers (e.g. lipids or other biomarkers) will be based on the 
differences in change from baseline (Month 0) to Month 12 (primary), between placebo 
(corn oil) and Epanova treatments. In addition, biomarker data after Month 12, will be 
presented in a descriptive manner. The biomarker variables include:
∀
non-HDL-C, TG and HDL-C;


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∀
TC, VLDL cholesterol, TC:HDL-C ratio and calculated LDL-C ( in patients with 
triglycerides > 400mg/dl LDL-C will be directly measured); 
∀
Apo B-100 and Apo C-III; 
∀
EPA, DHA, DPA and AA in plasma and RBC; and
∀
hs-CRP
A mixed model will be used for each biomarker endpoint with patient fitted as a random 
effect and terms included for treatment, visit, baseline value, treatment by visit and 
baseline by visit interactions using log-transformations where appropriate. A point 
estimate, 95% confidence interval and p-value for the mean difference between Epanova 
and placebo (corn oil) patients from Month 0 to Month 12 (primary) will be produced 
based on this repeated measures model. Further details in the SAP will specify how each 
biomarker variable will be analyzed, i.e. whether as mean change or as percent change.
The CEC will adjudicate all components of the primary and secondary endpoints as well 
as the tertiary heart failure events endpoint.
8.4.5 Evaluation of Efficacy and Safety
The DMC will review data periodically throughout the study and will have the ability to 
recommend stopping the study for safety at any time. Details will be defined in the DMC 
charter.
8.4.6 Safety Analyses
Safety analyses will include, where appropriate, descriptive statistics, counts and 
percentages.
Adverse Events
Adverse experiences will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by System Organ Class (SOC) and Preferred Term for each 
treatment group. Only AEs that are considered serious, lead to discontinuation or result in
a dose modification, new onset diabetes mellitus, TIA, potential Hy´s Law (PHL) cases 
or bleeding-related events will be captured starting after randomization through the final 
visit (Visit 13/ EOT/ET (see Section 9).
SAEs will be recorded at all visits for the patients who prematurely discontinue IP. Non-
serious AEs will be collected until the final visit but not more than 30 days after last dose 
of IP.


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Adverse events and suspected adverse reactions will be summarized by presenting:
∀
the number and percentage of patients experiencing any AE
∀
the number and percentage of patients experiencing any AE by SOC
∀
the number and percentage of patients experiencing any SAE
∀
the number and percentage of patients experiencing any AE associated with study 
discontinuation. 
8.5
Interim analyses
Accrual of a total of 1600 MACE (primary efficacy) events are required to maintain a 
power of at least 90% in this study (See section 0). The study is designed to continue 
until this number of events is observed. However, 2 interim analyses of the primary 
endpoint are planned and the study may be recommended for termination by the DMC 
early if the stopping rule for superiority or futility is met. The Executive Steering 
Committee and the Sponsor may choose to enforce the DMC´s recommendation.
A blinded independent statistician will carry out all analyses in support of the “open” 
session of DMC meetings. For more information about the DMC (see Section 0).
A group sequential design will be used to preserve the overall type 1 error probability of 
0.05.
Planned interim analyses on MACE will be performed around the time when 50% (800) 
of MACEs have occurred and again when 75% (1200) of MACEs have occurred. The 
final analysis is scheduled when at least 1600 MACEs have occurred. The group 
sequential superiority boundaries abs(z-score) for the 1st and 2nd interim analyses are 
3.719. Boundaries abs(z-score) for futility at the 1st and 2nd interim look are 0.3085 and 
1.2375, respectively. The significance threshold (z-score) for the final analysis is 1.9602, 
which correspond to a nominal p-value if 0.025. Confidence interval for the main 
Primary analysis on MACE will be constructed at the 95% level.  All thresholds are 
constructed accounting for DMC recommendations for stopping for efficacy to be “non-
binding”.
Superiority boundaries are defined based on Haybittle-Peto rule.  Specifically, this uses a 
1-sided p-value threshold held constant at 0.0001 for each look prior to final. The final 
comparison will be carried out at a 2-sided alpha of 0.05. Futility boundaries are based on 
Lan-DeMets alpha spending function that approximates an O’Brien-Fleming boundary in 
the setting of unequal analysis times. More details on the thresholds for stopping are 


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displayed in Table 8-1.  Parallel thresholds in the hazard-ratio and the p-value scale are 
also presented.  
In the event that this trial is stopped for overwhelming benefit at either of the two interim 
looks then all hierarchical Secondary tests will be carried out at #=0.0001.
Table 8-1.
INTERIM ANALYSIS PLAN
Interim 
analysis
Number of Events (%)
Approximate 
Time from 
FPFV (months)a
Boundaries (z-scale)b
Superiority
Futility
1
800 (50%)
32
abs()
> 3,719
()
< 0.3085
 < 0,7682
 > 0,9785
 < 0,0002c
 > 0,7578c
2
1200 (75%)
43
()
> 3,719
()
< 1,2375
 < 0,8063
 > 0,9312
 < 0,0002c
 > 0,216c
Final
1600 (100%)
54
() > 1,9602
 < 0,9064
 < 0,05
FPFV = First Patient First Visit
a Based on simulations of 10000 trials
b Non-binding boundaries


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c2-sided
8.6
Missing Values 
Extensive efforts will be made to collect data from patients after premature 
discontinuation of study treatment, if agreed to by the patient and in compliance with 
local privacy laws/regulations/practices, to avoid missing MACE status as much as 
possible. Patients who are not reporting any event in the primary composite efficacy 
endpoint will be censored at the time of study closure, the time of death from non-
cardiovascular causes, or at the time point after which the occurrence of any components 
of the primary endpoint could not be assessed. Since the absence of laboratory 
measurements for each patient may not be  “completely at random”, missing laboratory 
data will be analyzed using approaches assuming Missing At Random (MAR) two-step 
procedure80. Further details will be provided in the SAP.
8.7
Data Monitoring Committee
The DMC is responsible for monitoring the safety of the study participants, ensuring that 
the study is being conducted with the highest scientific and ethical standards and making 
appropriate recommendations based on the data seen. The DMC may recommend at any 
time during the conduct of the STRENGTH trial, modification of the protocol or
discontinuation of the study for safety reasons. In addition, should outstanding benefit of
the investigational drug compared with placebo be demonstrated during the STRENGTH 
trial, the DMC may recommend that consideration be given to stopping the study while
taking into account the need to accumulate further safety data to allow adequate
assessment of benefit- risk.


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9
ADVERSE EVENT MONITORING
9.1 Definitions
An AE is defined as any untoward medical occurrence associated with use of a drug in 
humans, whether or not considered drug related. An AE can be any unfavorable and 
unintended sign (including an abnormal finding), symptom, or disease temporally 
associated with the use of a drug, without any judgment about causality.
This includes any occurrence that is new in onset or aggravated in severity or frequency 
from the baseline condition (including the physical examination), or abnormal results of 
diagnostic procedures (including laboratory test abnormalities).
Events should be considered AEs if they:
∀
result in discontinuation from the study, 
∀
require treatment or any other therapeutic intervention, 
∀
require further diagnostic evaluation (excluding a repetition of the same 
procedure to confirm the abnormality), 
∀
are associated with clinical signs or symptoms judged by the investigator to 
have a significant clinical impact
In this study, only AEs that are considered serious, lead to discontinuation or result in a 
dose modification, overdose, new onset diabetes mellitus, TIA, PHL cases or bleeding-
related events will be captured starting after randomization through the final visit.
For further assessment of any identified potential or confirmed AE, a physical 
examination should be carried out if clinically appropriate. 
Clinically Significant Laboratory Changes: It is the investigator’s responsibility to review 
the results of all laboratory tests as they become available. For each abnormal result, the 
investigator needs to ascertain whether the abnormality presents a clinically significant 
change from baseline. If the change is due to the expected course of the patient’s 
underlying disease, it is not considered an adverse event unless the abnormality is more 
severe than expected. A laboratory test may be confirmed by repeat testing or other 
diagnostic tests before being considered an adverse event. If the laboratory abnormality is 
a significant change from baseline for the patient, then it should be considered an adverse 
event. See Appendix B (Actions Required in Cases of Combined Increase of 


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Aminotransferase and Total Bilirubin Hy´s Law) which provides criteria for determining 
potential serious hepatotoxicity of the IP according to Hy’s Law. 
At each DMC meeting, the committee will review all individual cases of LDL-C 
increases, AST/ALT increases or other increases in liver-related chemistries, new onset 
diabetes mellitus type II, or bleeding related events, in addition to other safety and 
laboratory data (i.e. fasting glucose, hemoglobin A1c and hematocrit) refer to Section 9.2
for details on selected adverse event collection.
An Adverse Event is not:
∀
A surgical procedure
∀
A situation where an untoward event did not occur, (e.g. a social 
hospitalization)
∀
The disease being studied, unless progression is more severe than 
anticipated
∀
Lack of efficacy
∀
Baseline conditions that have not worsened in severity or frequency
∀
Clinically significant abnormal laboratory findings or test results related to 
the disease being studied (unless more severe than expected)
∀
A study endpoint described in Section 9.8
An adverse reaction means any adverse event caused by a drug. Adverse reactions are a 
subset of all suspected adverse reactions for which there is reason to believe the drug 
caused the event. Suspected adverse drug reaction means any adverse event for which 
there is a reasonable possibility that the drug caused the adverse event. For the purposes 
of Investigational New Drug (IND) safety reporting, “reasonable possibility” means there 
is evidence to suggest a causal relationship between the drug and the adverse event. A 
suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction, which means any adverse event caused by a drug. 
9.2 Procedures
An untoward event that occurs after screening (Visit 1) and before the first dose of IP at 
Visit 2 will be recorded as an update to the medical history. Some events may make the 
patient ineligible for randomization. Unanticipated events, including those associated 
with withdrawal from prior medications, should be reported to the IRB/IEC, according to 
its requirements.


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Patients will be questioned at every visit and will receive well-being telephone calls after 
the randomization until the last visit regarding the occurrence and nature of any AEs.
A description of the event or diagnosis including dates, severity, relationship to the IP, 
action taken and outcome, and seriousness must be reported on the AE eCRF for each 
adverse event recorded in the patient’s chart.
For the STRENGTH trial, selective collection of AEs will be conducted in accordance 
with FDA Draft Guidance dated February 2012 “Determining the Extent of Safety Data 
Collection Needed in Late Stage Premarket and Post approval Clinical Investigations” 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM291158.pdf). Only AEs that are considered serious, lead to discontinuation or 
result in a dose modification, new onset diabetes mellitus, TIA, or bleeding-related events
will be captured starting after randomization through the final visit. The rationale for 
selective AE collection is based on the extensive safety information of Epanova already 
provided in 10 clinical trials, and the well-known safety profile of omega-3 products (see 
Section 1.2 Clinical Safety of Epanova) .
SAEs will be recorded at all visits for the patients who prematurely discontinue IP. Non-
serious AEs will be collected until the final visit but not more than 30 days after last dose 
of IP.
9.3 Bleeding definitions
The investigator will report any blood loss in the eCRF and the bleedings will in the 
Clinical Study Report be classified according to the TIMI non- CABG bleeding 
definitions 81 shown below:
Major
-Any intracranial bleeding (excluding microhemorrhages)
-Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥ 5 g/dL 
-Fatal bleeding (bleeding that directly results in death within 7 days)
Minor
-Clinically overt (including imaging), resulting in hemoglobin drop of 3 to <5 g/dL


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Requiring medical attention
-Any overt sign of hemorrhage that meets one of the following criteria and does not meet 
criteria for a major or minor bleeding event, as defined above
-Requiring intervention (medical practitioner-guided medical or surgical treatment to stop 
or treat bleeding, including temporarily or permanently discontinuing or changing the 
dose of a medication or study drug)
-Leading to or prolonging hospitalization
-Prompting evaluation (leading to an unscheduled visit to a healthcare professional and 
diagnostic testing, either laboratory or imaging)
Minimal
-Any overt bleeding event that does not meet the criteria above.
9.4 Severity
Adverse events are first graded according to seriousness and then severity. The 
seriousness of an event is determined by the regulatory criteria in Section 9.8.
The investigator will evaluate the severity of each AE. Adverse events will be graded as:
Mild:
Awareness of symptoms but easily tolerated 
Moderate:
Discomfort enough to interfere with but not prevent daily activity
Severe:
Unable to perform usual activity
9.5 Relationship
The investigator will judge the likelihood that the AE was related to the IP according to 
the following criteria: 
Not related: There is no temporal or causal relationship to the IP. 
Suspected: There is a reasonable possibility of a causal relationship to the IP.
Related: The adverse event was caused by the IP.


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9.6 Action Taken and Outcome
The Action Taken with IP for every AE will be reported as either “Dose Not Changed”, 
“Dose Reduced”, “Dose Interrupted”, or “Dose Withdrawn”. The Outcome of each AE 
will be entered as either: Recovered/Resolved, Recovered/Resolved with Sequelae, Not 
Recovered/Not Resolved, Fatal, or Unknown.
9.7 Adverse Event Follow-up
Investigators should follow AEs until the event has resolved, the condition has stabilized, 
is well characterized, or referred to appropriate medical management, whichever comes 
first. Events and follow-up information occurring after the last visit should be recorded in 
the source documentation. 
9.8 Serious Adverse Events
An adverse event or suspected adverse reaction is considered serious if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: 
∀
Death (note that death is the outcome of an SAE and the cause of death should be 
listed as the AE)
∀
Life-threatening event
∀
In-patient hospitalization or prolongation of existing hospitalization
∀
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions
∀
Congenital anomaly or birth defect
∀
Other important medical events that may not result in death, be life-threatening, or 
require hospitalization, may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. DILI 
should be reported as an SAE, if laboratory abnormalities meet the criteria in 
Appendix B (Actions Required in Cases of Combined Increase of 
Aminotransferase and Total Bilirubin Hy´s Law).
Hospitalization for elective surgery for a prior condition that did not worsen or 
hospitalization for social reasons will not be treated as serious.


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Events that are related to the primary efficacy endpoints or outcomes will not be reported 
as SAEs and will not be subject to expedited reporting regardless of expectedness or 
causality before termination of the study. This includes all cardiovascular deaths, MI, 
non-ischemic stroke, unstable angina or event associated with emergent/elective coronary 
revascularization procedure. Test results associated with these events will not be 
reportable as SAEs. These events will be adjudicated by an Endpoint Committee and 
safety will be evaluated by the DMC. If the committees find that an increased frequency 
of an endpoint is a suspected serious adverse reaction, then these events will become 
reportable by the Sponsor.
9.8.1
Serious Adverse Event Reporting
Any SAE which occurs after randomization and until Visit 13/EOT/ET must be reported 
to the Quintiles Medical Monitor whether or not it is judged related to the IP. SAEs will 
be recorded at all visits also for patients who prematurely discontinue IP.
To report the SAE, complete the SAE form electronically in the Electronic Data Capture 
(EDC) system for the study. When the form is completed, CRO personnel will be notified 
electronically and will retrieve the form. If the event meets serious criteria and it is not 
possible to access the internet, send an email to the CRO @ 
, or call the CRO SAE hotline  (toll free phone and fax 
number will be listed in the safety manual), and fax the completed SAE report form to the 
designated CRO fax number within 24 hours of awareness. When the EDC system becomes 
available, the SAE information must be entered within 24 hours of the system becoming 
available. CRO personnel are available for SAE reporting on a 24-hour basis. Reports are 
reviewed during normal U.S.business hours.
The investigator will provide, at a minimum, the protocol number, patient’s initials, 
patient number, date of the SAE, SAE term and relationship to IP. Information 
identifying the patient must be obliterated before transmitting to the CRO.
The PI will notify the IRB or IEC of the SAE according to its requirements. The CRO 
may also notify the IRB/IEC on behalf of investigators, where permitted. An initial report 
followed promptly by a complete report will be forwarded to the IRB, or in accordance 
with the IRB policy.
9.8.2
Serious Adverse Event Follow-Up
The patient will be observed and monitored carefully until 
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∀
the event resolves, or
∀
the event/condition has stabilized (e.g., in the case of persistent impairment), or
∀
the event returns to baseline, if a baseline value is available.
The investigator and Medical Monitor will determine if additional follow-up is required.
Follow-up information relating to an SAE must be submitted to the regional designee as 
soon as additional data related to the event are available. All efforts must be taken to 
obtain follow-up information promptly. 
Follow-up information may consist of:
∀
A hospital discharge summary for patients who are hospitalized. If possible, the 
discharge summary should be obtained when it becomes available.
∀
A copy of the autopsy report, if a death occurs and an autopsy is performed, 
should be obtained if possible when it becomes available.
Any SAEs that are ongoing at Visit 13 (Month 60) or ET should be followed as described 
above and a visit should be scheduled 3 weeks after Visit 13 to assess the SAE. Data after 
the 3-weeks FU Visit should be recorded on the source documents and submitted to the 
CRO on a SAE report form. For ongoing SAEs, the investigator must submit follow-up 
SAE reports to the regional designee regarding the patient’s subsequent course until the 
case is closed.
9.9 Reporting of Serious Adverse Events that are also Endpoints in the Study
Primary efficacy endpoints in the study will not be reported to health authorities as SAEs 
to avoid unnecessary unblinding of efficacy endpoints that are also SAEs. Events 
identified as suspected endpoints will be reported on separate event form in the eCRF to 
support central adjudication. Clinical data reported as AEs/SAEs will also be reviewed 
for possible endpoint events.  The initial notification of a suspected efficacy endpoint 
should be sent within the same time frames as defined for SAEs (see above). Selected 
events (leading to discontinuation or resulting in a dose modification, new onset diabetes 
mellitus, TIA, PHL cases or bleeding-related events) will be reported as AE/SAEs.
In addition to the normal monitoring of the study, a DMC will review all endpoint data 
and selected AEs/SAEs. Information will be sent to the Executive Committee and 
regulatory authorities if the DMC expresses safety concerns that suggest that study 
conduct should be amended.


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9.10
Pregnancy 
Any pregnancy occurring during this study will be reported within 24 hours of 
notification of the investigator. The investigator will promptly notify the Medical 
Monitor about the pregnancy and complete a pregnancy report form. The pregnancy 
report form will be faxed to the Medical Monitor via the SAE fax number. If a patient
becomes pregnant during the study, she must discontinue taking IP, but will continue to 
be followed in the protocol. Her obstetrician should be made aware of her study 
participation. The investigator should request information from the patient and her 
obstetrician about the outcome of the pregnancy, including any possible fetal 
abnormalities and congenital defects. If a congenital abnormality is reported, then it 
should be recorded in the source documents and reported to the Medical Monitor as a 
Serious Adverse Event.
9.11
Overdose
Overdose is defined as the accidental or intentional ingestion of any dose of 
investigational product that is considered both excessive and medically important. Once 
an investigator decides that a particular occurrence is an overdose, it must be reported as 
a Serious Adverse Event. If an overdose is suspected, monitoring of vital functions as 
well as treatment as appropriate should be performed.
In this study, a dose of more than 8 g of Epanova® (>8 capsules) during one day
should be considered as an overdose.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the
Investigator or other site personnel inform appropriate AstraZeneca representatives
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all
relevant information is provided to the AstraZeneca Patient Safety data entry site.


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10 INVESTIGATOR OBLIGATIONS
10.1 Ethical and Regulatory Considerations
This study will be conducted in accordance with Good Clinical Practice (GCP) 
Guidelines, 21 CFR Parts 11, 50 Subparts A and B, 54, 56, and International Conference 
on Harmonisation (ICH) GCP E6(R1). 
10.2 Institutional Review Board/Independent Ethics Committee 
The PI will ensure that AstraZeneca or its representative approves any changes to the IC 
template prior to submission to the IRB/IEC. 
Should changes to the IC form become necessary during the study, the PI will ensure that 
the changes are approved by AstraZeneca or its representative prior to submission to the 
IRB/ IEC. Should changes to the study protocol become necessary, the PI will ensure that 
the protocol amendment is approved by the IRB/IEC prior to implementation. The PI will 
ensure that protocol administrative changes have been reviewed by the IRB/IEC.
Prior to submission to the IRB/IEC, the PI will ensure that AstraZeneca or its 
representative approves the IC form. The PI will ensure that an appropriately constituted 
IRB/ IEC, in compliance with the requirements of 21 CFR 56 in the US or ICH GCP E6 
elsewhere, reviews and approves the clinical study and IC form. IRB/IEC approval must 
refer to the study by exact protocol title, number, and amendment number (if applicable), 
identify the documents reviewed, and state the date of review.
The PI will ensure that AstraZeneca or its representative is provided with a copy of the 
IRB/IEC approval documents and a copy of the IRB/IEC-approved IC form before the 
study is initiated.
AstraZeneca or its representative must be copied on all correspondence, including 
submission documentation, initiated by the site to the IRB/IEC during the course of the 
study. The PI will ensure copies of all correspondence from the IRB/IEC, including 
approvals and revised IC forms are provided to AstraZeneca or its representative.
10.3 Informed Consent
A properly executed, written IC, in compliance with 21 CFR Part 56 and Health 
Insurance Portability and Accountability Act (HIPAA) authorization (where required), 
will be obtained from each patient prior to enrollment and the initiation of screening 
evaluations required by this protocol. A copy of the IC form planned for use will be


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reviewed by AstraZeneca or its representative for acceptability and submitted by or on 
behalf of the investigator, together with the protocol, to the IRB/IEC for review and 
approval prior to the start of the study. Consent forms will be written in language fully 
comprehensible to the prospective patient.
All revisions of the protocol must be reflected in the IC form, if applicable, and reviewed 
by the IRB/IEC. Patients must be made aware of those applicable changes in the protocol 
and must consent to participate in the revised protocol.
10.4 Patient Confidentiality
All communications, reports, and patient samples will be identified by site number, and a 
coded number and/or initials to maintain patient confidentiality. All records will be kept 
confidential to the extent permitted by law. If a waiver or authorization separate from the 
statement in the IC is required for permitting access to a patient’s medical records (e.g. 
HIPAA), the investigator will obtain such authorization prior to enrolling a patient in the 
study. The PI should keep a separate log of patients, codes, names, and addresses.
Documents which identify the patient by name (for example, the IC form) should be kept 
in strict confidence.
AstraZeneca and its business associates agree to keep all patient information confidential. 
Only coded, blinded data will be released. Data resulting from analyses will be entered 
into a database that is not accessible to the public. Patient data will be identified only by 
the patient screen number, randomization number and initials, and not by any other 
annotation or identifying information. 
AstraZeneca and its business associates will take every possible step to reduce the risk of 
releasing information to the public that would enable patients to be personally identified. 


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11 STUDY MONITORING
11.1 Clinical Monitoring
An initiation meeting will be conducted by the CRO or an approved representative. At 
this meeting the protocol, the procedure for completing the eCRFs, and pertinent aspects 
of the eCRFs will be reviewed with the PI and all study staff.
Monitoring visits will be conducted during the study. The PI will make a reasonable 
amount of time available to the CRA on reasonable notice to assist with monitoring.
At each visit, the CRA will review the eCRFs and source documents to ensure that all 
items have been completed and that the data provided are accurate and obtained in the 
manner specified in the monitoring plan.
11.2 Auditing Procedures
In addition to the monitoring visits outlined above, an investigational site may undergo a 
quality assurance audit. The CRO, its authorized representative, AstraZeneca
representatives or a regulatory agency such as the FDA or European Medicines Agency 
(EMA) may conduct the audit. If a regulatory agency requests an audit of the study site, 
the investigator is required to inform the CRO (and/or AstraZeneca) immediately.
11.3 Executive Steering Committee
The Executive Steering Committee will have scientific responsibility for the study. They 
will review study conduct and progress, consider recommendations from the DMC, and 
resolve any other study related issues. The committee will also review all proposed 
ancillary studies and any proposed publications. Executive Steering committee members 
will remain blinded to the study data. The roles and responsibilities of the Committee will 
be documented in a Study Charter.


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12 CHANGES TO THE PROTOCOL AND STUDY TERMINATION
12.1Protocol Amendment and Administrative Change
All changes to the protocol must be documented by amendments, or administrative 
changes where applicable, and the amended protocol must be signed by AstraZeneca or 
its representative and the investigators. The amended protocol and a revised IC form, if 
necessary, will be submitted to the IRB/IEC for approval. If the protocol modifications 
affect the eCRFs, they will also be revised and provided to the site.
12.2Termination of the Study
The Sponsor AstraZeneca reserves the right to terminate the study at any time. In 
terminating the study, AstraZeneca and the PI will ensure that adequate consideration is 
given to the protection of each patient’s interest.


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13 SOURCE DOCUMENTS, CASE REPORT FORMS AND RECORD 
RETENTION
13.1 Source Documents
The PI will complete and maintain source documents for each patient participating in the 
study. The source documents should contain all demographic and medical information, 
including laboratory data. The patient’s source documents file should also indicate that 
the patient is participating in the clinical study, referencing the study number and the IP.
All information required by the protocol should be documented in the source records. An 
explanation must be given for any omissions. Each evaluation recorded will be performed 
at the time specified in the protocol. 
13.2 Case Report Forms 
The study will use EDC and all data will be recorded on eCRFs, which will be designed 
by the CRO. All information on the eCRFs must be traceable back to the source 
documents. All information must be entered on the eCRF and made available as soon as 
possible after the patient’s visit, in order that the CRA may verify the validity and 
completeness of the data and permit prompt transmission of the data. The PI should 
review all eCRFs for completeness, accuracy, and legibility before the CRA reviews and 
collects the data.
13.3 Record Retention 
The PI will maintain adequate records so that the conduct of the study can be fully 
documented and monitored. Copies of protocols, eCRFs or CD(s) with PDF files of all 
eCRFs, as well as the audit trial, test result originals, all IP accountability records, 
correspondence, patient IC forms, and any other documents relevant to the conduct of the 
study will be kept on file by the PI. Study documents will not be destroyed. For 
regulatory inspections, it will be necessary to have access to complete study patient 
records, provided that patient confidentiality is maintained.
Per the Clinical Development Agreement between AstraZeneca and its representative, 
investigators must retain patients’ records for a period of 2 years after FDA approval or 
until written approval to destroy the documentation is provided by AstraZeneca. The 
documentation must be retained longer if so required by local law. Investigators must 
notify AstraZeneca and its representative, in writing, of changes in address, sales of 


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practices or site closures in order to make arrangements for the maintenance of study 
files.


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14 FINAL REPORT/PUBLICATION STATEMENT 
Any formal presentation or publication of data collected as a direct or indirect result of 
this study will be considered as a joint publication by the investigator(s) and 
AstraZeneca. In the case of multicenter studies, it is mandatory that the first publication 
be made based on the totality of data obtained from all centers, analyzed as stipulated in 
the protocol, and presented and interpreted as documented in the final CSR. The resulting 
publication will name PIs according to the policy of the chosen journal. Where it is not 
permitted for all PIs to be included as authors, the publication will acknowledge all PIs 
within the publication. 
Individual investigators may publish data arising from their own patients only after 
publication of the main manuscript from this study. The PI will provide AstraZeneca with 
copies of written publications (including abstracts and posters) in advance of submission. 
This review is to permit AstraZeneca to review the communication for accuracy (thus 
avoiding potential discrepancies with submissions to regulatory authorities), to verify that 
confidential information is not inadvertently divulged (including patent protection), to 
allow adequate input or supplementary information that may not have been available to 
the PI, and to allow establishment of co-authorship.
Investigators participating in multicenter studies must agree not to engage in 
presentations based on data gathered individually or by a subgroup of centers before 
publication of the first main publication, unless this has been agreed otherwise by all 
other investigators and AstraZeneca. However, in the event that no publication of the 
overall results has been submitted after approval of the CSR, investigators may publish 
results of one or more center’s patients to the same review as outlined above. 
AstraZeneca will circulate proposed multi-center publications to all PIs for review.
Data will be reviewed by all participating investigators prior to publication. AstraZeneca
will review all definitive publications, such as manuscripts and book chapters, and 
abstracts.


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37. Liu J, Sempos CT, Donahue RP, Dorn J, Trevisan M, Grundy SM. Non-high-
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44. Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA, Foster E, 
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45. Scott R, O’Brien R, Fulcher G, et al. Effects of fenofibrate treatment on 
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components of the metabolic syndrome: the Fenofibrate Intervention and Event 
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46. Goff DC Jr, Gerstein HC, Ginsberg HN, Cushman WC, Margolis KL, Byington 
RP, Buse JB, Genuth S, Probstfield JL, Simons-Morton DG; ACCORD Study 
Group. Prevention of cardiovascular disease in persons with type 2 diabetes 
mellitus: current knowledge and rationale for the Action to Control 
Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol. 2007 Jun 
18;99(12A):4i-20i. Epub 2007 Apr 12.
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Sakata T, Shimada K, Shirato K; Japan EPA lipid intervention study (JELIS) 
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hypercholesterolaemic patients (JELIS): a randomised open-label, blinded 
endpoint analysis. Lancet. 2007 Mar 31;369(9567):1090-8.
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Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, 
Sakata T, Shimada K, Shirato K; JELIS Investigators, Japan. Effects of EPA on 
coronary artery disease in hypercholesterolemic patients with multiple risk 
factors: sub-analysis of primary prevention cases from the Japan EPA Lipid 
Intervention Study (JELIS).Atherosclerosis. 2008 Sep;200(1):135-40.
50. Davidson MH, Stein EA, Bays HE, Maki KC, Doyle RT, Shalwitz RA, 
Ballantyne CM, Ginsberg HN; COMBination of prescription Omega-3 with 
Simvastatin (COMBOS) Investigators. Efficacy and tolerability of adding 


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prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in 
hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-
controlled study. Clin Ther. 2007 Jul;29(7):1354-67.
51. Maki KC, Dicklin MR, Davidson MH, Doyle RT, Ballantyne CM; COMBination 
of prescription Omega-3 with Simvastatin (COMBOS) Investigators. Baseline 
lipoprotein lipids and low-density lipoprotein cholesterol response to prescription 
omega-3 acid ethyl ester added to simvastatin therapy. Am J Cardiol. 2010 May 
15;105(10):1409-12.
52. Arondekar B, Samuel S, Blumenfeld I, Peskin B, LeBute M, Stone G, Alperin P. 
Long-Term Outcomes in Patients with Severe Hypertriglyceridemia —
Simulation Using the Archimedes Model. J Clin Lipidol. Abstracts May 2010; 4: 
229-30.
53. Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Lloyd-Jones DM, Blum 
CB, McBride P, Eckel RH, Schwartz JS, Goldberg AC, Shero ST, Gordon D, 
Smith Jr SC, Levy D, Watson K, Wilson PWF. 2013 ACC/AHA Guideline on the 
Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in 
Adults, Journal of the American College of Cardiology 2014;63(25 Pt B):288.
54. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop 
JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with 
hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N 
Engl J Med. 1995 Nov 16;333(20):1301-7.
55. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, 
Sourjina T, Peto R, Collins R, Simes R; Cholesterol Treatment Trialists' (CTT) 
Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective 
meta-analysis of data from 90,056 participants in 14 randomised trials of statins. 
Lancet. 2005 Oct 8;366(9493):1267-78. Epub 2005 Sep 27.
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DC Jr, Malozowski S, Margolis KL, Probstfield JL, Schnall A, Seaquist ER; 
Action to Control Cardiovascular Risk in Diabetes Investigators. Epidemiologic 
relationships between A1c and all-cause mortality during a median 3.4-year 
follow-up of glycemic treatment in the ACCORD trial. Diabetes Care. 2010 
May;33(5):983-90.
57. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, 
Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, 


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Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp 
RG; PROSPER study group. Pravastatin in elderly individuals at risk of vascular 
disease (PROSPER): a randomized controlled trial. PROspective Study of 
Pravastatin in the Elderly at Risk. Lancet. 2002;360:1623–1630.
58. Ridker PM, MacFadyen J, Libby P, Glynn RJ. Relation of baseline high-
sensitivity C-reactive protein level to cardiovascular outcomes with rosuvastatin 
in the Justification for Use of statins in Prevention: an Intervention Trial 
Evaluating Rosuvastatin (JUPITER). Am J Cardiol. 2010 Jul 15;106(2):204-9.
59. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of 
improved algorithms for the assessment of global cardiovascular risk in women: 
the Reynolds Risk Score. JAMA. 2007 Feb 14;297(6):611-9.
60. Ridker PM, Paynter NP, Rifai N, Gaziano JM, Cook NR. C-reactive protein and 
parental history improve global cardiovascular risk prediction: the Reynolds Risk 
Score for men. Circulation. 2008 Nov 25;118(22):2243-51.
61. Jain A, McClelland RL, Polak JF, Shea S, Burke GL, Bild DE, Watson KE, 
Budoff MJ, Liu K, Post WS, Folsom AR, Lima JA, Bluemke DA. Cardiovascular 
imaging for assessing cardiovascular risk in asymptomatic men versus women: 
the multi-ethnic study of atherosclerosis (MESA). Circ Cardiovasc Imaging. 2011 
Jan;4(1):8-15.
62. Olsson AG, Eriksson M, Johnson O, Kjellström T, Lanke J, Larsen ML, Pedersen 
T, Tikkanen MJ, Wiklund O; 3T Study Investigators. A 52-week, multicenter, 
randomized, parallel-group, double-blind, double-dummy study to assess the 
efficacy of atorvastatin and simvastatin in reaching low-density lipoprotein 
cholesterol and triglyceride targets: the treat-to-target (3T) study. Clin Ther. 2003 
Jan;25(1):119-38.
63. Schectman G, Patsches M, Sasse EA. Variability in cholesterol measurements: 
comparison of calculated and direct LDL cholesterol determinations. Clin Chem. 
1996 May;42(5):732-7.
64. Bookstein L, Gidding SS, Donovan M, Smith FA. Day-to-day variability of serum 
cholesterol, triglyceride, and high-density lipoprotein cholesterol levels. Impact 
on the assessment of risk according to the National Cholesterol Education 
Program guidelines. Arch Intern Med. 1990 Aug;150(8):1653-7.


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65. Guidance for Industry: Diabetes Mellitus — Evaluating cardiovascular risk in 
new antidiabetic therapies to treat type 2 diabetes. US Department of Health and 
Human Services, Food and Drug Administration, Center for Drug Evaluation and 
Research (CDER). December 2008; UCM071627. 
66. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, 
Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd 
J, Willerson JT, Glynn RJ; JUPITER Study Group. Rosuvastatin to prevent 
vascular events in men and women with elevated C-reactive protein. N Engl J 
Med. 2008 Nov 20;359(21):2195-207.
67. Fruchart JC, Sacks FM, Hermans MP, et al. The Residual Risk Reduction 
Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. 
Diab Vasc Dis Res 2008;5:319-35.
68. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL 
cholesterol with statin therapy in people at low risk of vascular disease: meta-
analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.
69. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in 
type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
70. Mora S, Wenger NK, Demicco DA, et al. Determinants of residual risk in 
secondary prevention patients treated with high- versus low-dose statin therapy: 
the Treating to New Targets (TNT) study. Circulation 2012;125:1979-87.
71. Secondary prevention by raising HDL cholesterol and reducing triglycerides in 
patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) 
study. Circulation 2000;102:21-7.
72. Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride 
and LDL cholesterol and HDL cholesterol concentrations on coronary heart 
disease risk in the Helsinki Heart Study. Implications for treatment. Circulation 
1992;85:37-45.
73. Asztalos BF, Collins D, Horvath KV, Bloomfield HE, Robins SJ, Schaefer EJ. 
Relation of gemfibrozil treatment and high-density lipoprotein subpopulation 
profile with cardiovascular events in the Veterans Affairs High-Density 
Lipoprotein Intervention Trial. Metabolism 2008;57:77-83.
74. Sasaki J, Yokoyama M, Matsuzaki M, et al. Relationship between coronary artery 
disease and non-HDL-C, and effect of highly purified EPA on the risk of coronary 


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artery disease in hypercholesterolemic patients treated with statins: sub-analysis 
of the Japan EPA Lipid Intervention Study (JELIS). J Atheroscler Thromb 
2012;19:194-204.
75. Tenenbaum A, Fisman EZ. Fibrates are an essential part of modern anti-
dyslipidemic arsenal: spotlight on atherogenic dyslipidemia and residual risk 
reduction. Cardiovasc Diabetol. 2012 Oct 11;11:125.
76. Degirolamo C, Rudel LL. Dietary monounsaturated fatty acids appear not to 
provide cardioprotection. Curr Atheroscler Rep. 2010 Nov;12(6):391-6.
77. Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of 
increasing polyunsaturated fat in place of saturated fat: a systematic review and 
meta-analysis of randomized controlled trials. PLoS Med. 2010 Mar 
23;7(3):e1000252.
78. Buckland G, Mayén AL, Agudo A, Travier N, Navarro C, Huerta JM, Chirlaque 
MD, Barricarte A, Ardanaz E, Moreno-Iribas C, Marin P, Quirós JR, Redondo 
ML, Amiano P, Dorronsoro M, Arriola L, Molina E, Sanchez MJ, Gonzalez CA. 
Olive oil intake and mortality within the Spanish population (EPIC-Spain). Am J 
Clin Nutr. 2012 Jul;96(1):142-9
79. Baum SJ. ANCHOR trial conclusions regarding the effects of pure 
eicosapentaenoic acid on low-density lipoprotein cholesterol. Am J Cardiol. 2013 
Feb 1;111(3):454-5.
80. Joseph W. Hogan1;∗; †, Jason Roy2; ‡ and Christina Korkontzelou1;  2004; 
23:1455–1497 (DOI: 10.1002/sim.1728).
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APPENDIX A: Therapeutic Lifestyle Changes Diet
The guidelines developed by the National Cholesterol Education Program recommend a 
multifaceted lifestyle approach to reduce the risk of coronary heart disease. (NIH 
Publication 01-3670, http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm). 
The recommended ranges of intake for specific dietary components are listed in the Table 
below.
Nutrient Composition of the Therapeutic Lifestyle Changes Diet
Nutrient
Recommended Intake
Total Fat
25-35% of total calories
Saturated Fatty Acids
<7% of total calories
Monounsaturated Fatty Acids
Up to 20% of total calories
Polyunsaturated Fatty Acids
Up to 10% of total calories
Carbohydrates
50-60% of total calories
Fiber
20-30 grams per day
Protein
Approx. 15% of total calories
Cholesterol
<200 mg per day
Total Calories
Balance energy intake and expenditure to 
maintain desirable body weight/prevent 
weight gain


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The principles of the TLC diet or equivalent are as follows:
1. Start by choosing a target calorie level that best suits the patient’s weight goals. 
2. Focus on eating lots of fruits, vegetables, whole grains, low-fat or nonfat dairy 
products, fish, and skin-off poultry. 
3. Cut saturated fat to less than 7 percent of daily calories, which means eating less 
high-fat dairy, such as butter, and eliminating fatty meats like salami. 
4. Consume no more than 200 milligrams of dietary cholesterol a day-the amount in 
about 2 ounces of cheese. 
5. Consider adding plant stanols or sterols and 10 to 25 grams of soluble fiber each 
day to further reduce LDL-C.  


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APPENDIX B: Actions Required in Cases of Combined Increase of 
Aminotransferase and Total Bilirubin Hy´s Law: 
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with Quintiles Medical Monitors, in review and 
assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria are 
met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the 
outcome of the review and assessment in line with standard safety reporting processes.
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit 
of Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the 
study following the start of study medication irrespective of an increase in Alkaline 
Phosphatase (ALP). 
Hy’s Law (HL)
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than 
the IMP, can be found to explain the combination of increases, eg, elevated ALP 
indicating cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. 
on the same day) the elevation in TBL, but there is no specified timeframe within which 
the elevations in transaminases and TBL must occur.


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Identification of potential Hy’s Law cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:
∀
ALT ≥ 3xULN
∀
AST ≥ 3xULN
∀
TBL ≥ 2xULN
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to Quintiles 
Medical Monitor). 
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:
∀
Notify the Quintiles Medical Monitor
∀
Request a repeat of the test (new blood draw) by the central laboratory
∀
Complete the appropriate unscheduled laboratory eCRF module(s) with 
the original local laboratory test result
When the identification criteria are met from central or local laboratory results the 
Investigator will without delay:
∀
Determine whether the patient meets PHL criteria by reviewing laboratory 
reports from all previous visits (including both central and local laboratory 
results)
The Investigator will without delay review each new laboratory report and if the 
identification criteria are met will:
∀
Notify the Quintiles Medical Monitor
∀
Determine whether the patient meets PHL criteria by reviewing laboratory 
reports from all previous visits
∀
Promptly enter the laboratory data into the laboratory eCRF


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Follow-up
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
∀
Inform Quintiles Medical Monitor representative that the patient has not 
met PHL criteria. Perform follow-up on subsequent laboratory results 
according to the guidance provided in the Clinical Study Protocol.
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:
∀
Determine whether PHL criteria were met at any study visit prior to 
starting study treatment
∀
Notify the Quintiles representative who will then inform Quintiles 
Medical Monitor.
The Quintiles Medical Monitor contacts the Investigator, to provide guidance, discuss 
and agree an approach for the study patients’ follow-up and the continuous review of 
data. Subsequent to this contact the Investigator will:
∀
Monitor the patient until liver biochemistry parameters and appropriate 
clinical symptoms and signs return to normal or baseline levels, or as long 
as medically indicated 
∀
Investigate the etiology of the event and perform diagnostic investigations 
as discussed with the Study Physician
∀
Complete the three Liver eCRF Modules as information becomes 
available 
∀
If at any time (in consultation with Quintiles Medical Monitor) the PHL 
case meets serious criteria, report it as an SAE using standard reporting 
procedures
Review and Assessment of potential Hy’s Law cases
The instructions in this Section should be followed for all cases where PHL criteria are 
met.
No later than 3 weeks after the biochemistry abnormality was initially detected, Quintiles 
Medical Monitor contacts the Investigator in order to review available data and agree on 
whether there is an alternative explanation for meeting PHL criteria other than DILI 


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caused by the IMP.  The Sponsor Medical Science Director and Global Safety Physician 
will also be involved in this review together with other subject matter experts as 
appropriate.
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE:
∀
If the alternative explanation is not an AE, record the alternative 
explanation on the appropriate eCRF
∀
If the alternative explanation is an AE/SAE, record the AE /SAE in the 
eCRF accordingly and follow this study´s standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:
∀
Report an SAE (report term ‘Hy’s Law’) according to this study´s 
standard processes. 
&
The ‘Medically Important’ serious criterion should be used if no other 
serious criteria apply
&
As there is no alternative explanation for the HL case, a causality 
assessment of ‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary 
to assess whether or not the case meets the criteria for HL, then it is assumed that there is 
no alternative explanation until such time as an informed decision can be made:
∀
Report an SAE (report term ‘Potential Hy’s Law’) applying serious 
criteria and causality assessment as per above
∀
Continue follow-up and review according to agreed plan.  Once the 
necessary supplementary information is obtained, repeat the review and 
assessment to determine whether HL criteria are met.  Update the SAE 
report according to the outcome of the review
This section is applicable to patients who meet PHL criteria on study treatment having 
previously met PHL criteria at a study visit prior to starting study treatment.


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At the first on study treatment occurrence of PHL criteria being met the Investigator will:
∀
Determine if there has been a significant change in the patients’ condition#
compared with the last visit where PHL criteria were met#
&
If there is no significant change no action is required
&
If there is a significant change notify the Quintiles representative, who will 
inform the Quintiles Medical Monitor, then follow the subsequent process 
described in Section “Potential Hy’s Law Criteria met” of this Appendix.
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in 
isolation or in combination, or a clinically relevant change in associated symptoms.  The 
determination of whether there has been a significant change will be at the discretion of 
the Investigator, this may be in consultation with the Study Physician if there is any 
uncertainty.
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:
http://www fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf


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APPENDIX C: Standardized Definitions for Endpoint Events in Cardiovascular 
Trials
A. Death – All Cause Death (classified as CV death or Non-CV Death)
B. Non-fatal MI
C. Non-fatal Stroke
D. Hospitalization for Unstable Angina
E. Coronary Revascularization – Elective/Urgent
F. Heart Failure
A. Death
I.
Cardiovascular Death
Cardiovascular death includes death resulting from: an acute MI, sudden cardiac death, 
death due to heart failure (HF), death due to stroke, death due to cardiovascular (CV) 
procedures, death due to CV hemorrhage, and death due to other CV causes.
CV mortality will be classified more specifically (MI, sudden cardiac death, etc.) as 
follows:
1. Death due to Acute Myocardial Infarction refers to a death by any cardiovascular 
mechanism (e.g., arrhythmia, sudden death, HF, stroke, pulmonary embolus, 
peripheral arterial disease) ≤30 days1 after a MI related to the immediate 
consequences of the MI, such as progressive HF or recalcitrant arrhythmia. There 
may be assessable mechanisms of cardiovascular death during this time period, but 
for simplicity, it will be considered a death due to MI.
Acute MI should be verified to the extent possible by the diagnostic criteria outlined 
for acute MI in this document or by autopsy findings showing recent MI or recent 
coronary thrombosis.
Death resulting from a procedure to treat a MI (percutaneous coronary intervention 
(PCI), coronary artery bypass graft surgery (CABG), or to treat a complication 
resulting from MI), should also be considered death due to acute MI.
Death resulting from an elective coronary procedure to treat myocardial ischemia 
(i.e., chronic stable angina) or death due to a MI that occurs as a direct consequence 
of a CV investigation/procedure/operation should be considered as death due to a CV 
procedure (see # 5 below).


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1 The 30-day cutoff is arbitrary.
2. Sudden Cardiac Death refers to death that occurs unexpectedly, not following an 
acute MI, and includes the following deaths:
a.
Death witnessed and occurring without new or worsening symptoms
b. Death witnessed within 60 minutes of the onset of new or worsening cardiac 
symptoms, unless the symptoms suggest acute MI
c.
Death witnessed and attributed to an identified arrhythmia (e.g., captured on 
an electrocardiographic (ECG) recording, witnessed on a monitor, or 
unwitnessed but found on implantable cardioverter-defibrillator review)
d. Death after unsuccessful resuscitation from cardiac arrest
e.
Death after successful resuscitation from cardiac arrest and without 
identification of a specific cardiac or non-cardiac etiology
f.
Unwitnessed death in a patient seen alive and clinically stable ≤ 24 hours prior 
to being found dead without any evidence supporting a specific non-
cardiovascular cause of death (information regarding the patient’s clinical 
status preceding death should be provided, if available)
General Considerations
Unless additional information suggests an alternate specific cause of death 
(e.g., Death due to Other Cardiovascular Causes), if a patient is seen alive ≤ 
24 hours of being found dead, sudden cardiac death (criterion 2f, above) 
should be recorded. For patients who were not observed alive within 24 hours 
of death, undetermined cause of death (see section III below) should be 
recorded (e.g., a patient found dead in bed, but who had not been seen by 
family for several days).
3. Death due to Heart Failure refers to death in association with clinically worsening 
symptoms and/or signs of heart failure regardless of HF etiology. Deaths due to heart 
failure can have various etiologies, including single or recurrent myocardial 
infarctions, ischemic or non-ischemic cardiomyopathy, hypertension, or valvular 
disease.
4. Death due to Stroke refers to death after a stroke that is either a direct consequence 
of the stroke or a complication of the stroke. Acute stroke should be verified to the 
extent possible by the diagnostic criteria outlined for stroke.
5. Death due to Cardiovascular Procedures refers to death caused by the immediate 
complications of a cardiac procedure.
6. Death due to Cardiovascular Hemorrhage refers to death related to hemorrhage 
such as a non-stroke intracranial hemorrhage, non-procedural or non-traumatic 
vascular rupture (e.g., aortic aneurysm), or hemorrhage causing cardiac tamponade.
7. Death due to Other Cardiovascular Causes refers to a CV death not included in the 
above categories but with a specific, known cause (e.g., pulmonary embolism or 
peripheral arterial disease)


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II.
Non-Cardiovascular Death
Non-cardiovascular death is defined as any death with a specific cause not thought to be 
CV in nature, as described above (section I). The following is a suggested list of non-CV 
causes of death:
∀
Pulmonary
∀
Renal
∀
Gastrointestinal
∀
Hepatobiliary
∀
Pancreatic
∀
Infection (includes sepsis)
∀
Inflammatory (e.g., systemic inflammatory response syndrome [SIRS]/ 
immune [including autoimmune])
∀
Hemorrhage that is neither cardiovascular bleeding nor a stroke
∀
Non-CV procedure or surgery
∀
Trauma
∀
Suicide
∀
Non-prescription drug reaction or overdose
∀
Prescription Drug Reaction or overdose
∀
Neurological (non-CV)
∀
Malignancy
∀
Other non-CV
III.
Undetermined Cause of Death
Undetermined Cause of Death refers to a death not attributable to one of the above 
categories of CV death or to a non-CV cause. Inability to classify the cause of death may 
be due to lack of information (e.g., the only available information is “patient died”) or 
when there is insufficient supporting information or detail to assign the cause of death. In 
general, the use of this category of death should be discouraged and should apply to a 
minimal number of patients. 
For this study, it will be assumed that all undetermined cases are included in the 
cardiovascular category (e.g., presumed cardiovascular death, specifically “death due to 
other cardiovascular causes”) since, in a CV population, it is the overwhelming likelihood 
in cases where data are missing or incomplete. 


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B. Non-fatal Myocardial Infarction 
Criteria for acute myocardial infarction
The term acute myocardial infarction (MI) should be used when there is evidence of 
myocardial necrosis in a clinical setting consistent with acute myocardial ischemia.
Under these conditions any one of the following criteria meets the diagnosis for MI:
∀
Detection of a rise and/or fall of cardiac biomarker values (preferably cardiac 
troponin (cTn)) with at least one value above the 99th percentile upper reference 
limit (URL) and with at least one of the following:
o
Symptoms of ischemia;
o
New or presumed new significant ST-T changes or new LBBB *;
o
Development of pathological Q waves in the ECG;
o
Imaging evidence of new loss of viable myocardium or new regional wall 
abnormality;
o
Identification of an intracoronary thrombus by angiography or autopsy.
*ECG manifestations of acute myocardial ischemia (in absence of left ventricular 
hypertrophy (LVH) and left bundle branch block (LBBB):

ST elevation: New ST elevation at the J point in two contiguous leads with the 
cut-points: ≥ 0.1 mV in all leads other than leads V2-V3 where the following 
cut-points apply: ≥ 0.2 mV in men ≥ 40 years (≥ 0.25 mV in men < 40 years) 
or ≥ 0.15 mV in women.

ST depression and T-wave changes: New horizontal or down-sloping ST 
depression > 0.05 mV in two contiguous leads and/or new T inversion > 0.1 
mV in two contiguous leads with prominent R wave or R/S ratio > 1.
For cardiac biomarkers, laboratories should report an upper reference limit (URL). If the 
99th percentile of the upper reference limit (URL) from the respective laboratory 
performing the assay is not available, then the URL for myocardial necrosis from the 
laboratory should be used. If the 99th percentile of the URL or the URL for myocardial 
necrosis is not available, the MI decision limit for the particular laboratory should be 
used as the URL. Laboratories can also report both the 99th percentile of the upper 
reference limit and the MI decision limit. Reference limits from the laboratory 
performing the assay are preferred over the manufacturer’s listed reference limits in an 
assay’s instructions for use. In general, troponins are preferred. CK-MB should be used if 
troponins are not available, and total CK may be used in the absence of CK-MB and 
troponin.


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Criteria for prior myocardial infarction
Any one of the following criteria meets the definition for prior MI:
∀
Pathologic Q waves with or without symptoms in the absence of non-ischemic 
causes.
∀
Imaging evidence of a region of loss of viable myocardium that is thinned and 
fails to contract, in the absence of a non-ischemic cause.
∀
Pathologic findings of a prior MI.
For each MI identified by the CEC, a Type of MI will be assigned using the following 
guidelines:
∀
Type 1 Spontaneous MI
Spontaneous MI related to atherosclerotic plaque rupture, ulceration, fissuring, 
erosion, or dissection with resulting intraluminal thrombus in one or more of the 
coronary arteries leading to decreased myocardial blood flow or distal platelet 
emboli with ensuing myocyte necrosis. The patient may have underlying severe 
CAD but on occasion non-obstructive or no CAD.
∀
Type 2 Myocardial Infarction secondary to an ischemic imbalance
In instances of myocardial injury with necrosis where a condition OTHER THAN 
CAD contributes to an imbalance between myocardial oxygen supply and/or 
demand, (e.g., coronary endothelial dysfunction, coronary artery spasm, coronary 
embolism, tachy-/brady-arrhythmias, anemia, respiratory failure, hypotension, 
and hypertension with or without left ventricular hypertrophy).
∀
Type 3 Myocardial infarction resulting in death when biomarker values are 
unavailable
Cardiac death with symptoms suggestive of myocardial ischemia and presumed 
new ischemic ECG changes or new LBBB, but death occurring before blood 
samples could be obtained, before cardiac biomarker values could increase, or in 
rare cases were not collected. Note: For this study, these will be classified as 
CV deaths.
∀
Type 4a Myocardial infarction related to percutaneous coronary intervention 
(PCI)
Percutaneous coronary intervention (PCI) related MI is arbitrarily defined by 
elevation of cTn values (>5 x 99th percentile URL) in patients with normal 
baseline values (< 99th percentile URL) or a rise of cTn values ≥20% if the 
baseline values are elevated and are stable or falling. In addition, either (i) 


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symptoms suggestive of myocardial ischemia, or (ii) new ischemic ECG changes 
or new LBBB, or (iii) angiographic loss of patency of a major coronary artery or a 
side branch or persistent slow or no-flow embolization, or (iv) imaging 
demonstration of new loss of viable myocardium or new regional wall motion 
abnormality are required.
∀
Type 4b Myocardial Infarction related to stent thrombosis
Myocardial infarction associated with stent thrombosis is detected by coronary 
angiography or autopsy in the setting of myocardial ischemia and with a rise 
and/or fall of cardiac biomarkers values with at least one value above the 99th 
percentile URL.
∀
Type 4c Myocardial Infarction related to PCI restenosis
Myocardial infarction related to PCI restenosis is defined as ≥50% stenosis at 
coronary angiography or a complex lesion associated with a rise and/or fall of cTn 
values >99th percentile URL and no other significant obstructive coronary artery 
disease (CAD) of greater severity following: (i) initially successful stent 
deployment, or (ii) dilation of a coronary artery stenosis with balloon angioplasty 
(<50%).
∀
Type 5 Myocardial Infarction related to coronary artery bypass grafting
(CABG)
Myocardial infarction associated with CABG is arbitrarily defined by elevation of 
cardiac biomarker values (>10 x 99th percentile URL) in patients with normal 
baseline cTn values (< 99th percentile URL) plus, either (i) new pathological Q 
waves or new LBBB, or (ii) angiographic documented new graft or new native 
coronary artery occlusion, or (iii) imaging evidence of new loss of viable 
myocardium or new regional wall motion abnormality.
C. Non-fatal Stroke 
Stroke is defined as an acute episode of focal or global neurological dysfunction, 
generally lasting more than 24 hours, caused by brain, spinal cord, or retinal injury as a 
result of hemorrhage or infarction. For each stroke identified by the CEC, the event will 
be further categorized using the following guidelines:


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A. Ischemic Stroke
Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal 
dysfunction caused by infarction of central nervous system tissue. Hemorrhage may 
be a consequence of ischemic stroke. In this situation, the stroke is an ischemic stroke 
with hemorrhagic transformation and not a hemorrhagic stroke.
B. Hemorrhagic Stroke
Hemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal 
dysfunction caused by intraparenchymal, intraventricular, or subarachnoid 
hemorrhage.
Note: Subdural hematomas are intracranial hemorrhagic events and NOT strokes.
C. Undetermined Stroke
Undetermined stroke is defined as an acute episode of focal or global neurologic 
dysfunction caused by presumed brain, spinal cord, or retinal vascular injury as a 
result of hemorrhage or infarction but with insufficient information to allow 
categorization as A or B.  In general, the use of this category of stroke should be 
discouraged and should apply to a minimal number of patients. 
For this study, it will be assumed that all undetermined cases are included in the 
hemorrhagic category since use of other omega-3 agents has been associated with an 
increase in bleeding risk.  A sensitivity analysis will be performed in which the 
undetermined strokes are included with the ischemic stroke category.
D. Disability Assessment for Patients Suffering a Stroke
The Modified Rankin Scale (mRS) will be used to assess patients who sustain a
stroke.
Scale
Disability
0
No symptoms at all
1
No significant disability despite symptoms; able to carry out all usual duties 
and activities
2
Slight disability; unable to carry out all previous activities, but able to look 
after own affairs without assistance
3
Moderate disability; requiring some help, but able to walk without 
assistance


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4
Moderately severe disability; unable to walk without assistance and unable
to attend to own bodily needs without assistance
5
Severe disability; bedridden, incontinent and requiring constant nursing care 
and attention
6
Dead
D. Hospitalization for Unstable Angina 
Hospitalization for Unstable Angina is defined as:
1. Ischemic discomfort (angina or symptoms thought to be equivalent) > 10 minutes in 
duration occurring:
∀
At rest, or
∀
In an increasing pattern with frequent episodes associated with progressively 
decreased exercise capacity.
AND
2. Prompting an unscheduled hospitalization within 24 hours of the most recent 
symptoms. Hospitalization is defined as an admission to an inpatient unit or a visit to 
an emergency department that results in at least a 24 hour stay (or a change in 
calendar date if the hospital admission or discharge times are not available).
AND
3. At least 1 of the following:
a.
New or worsening ST or T wave changes on resting ECG (in the absence of 
confounders such as LVH and LBBB)
∀
Transient ST elevation (duration < 20 minutes)
New ST elevation at the J point in two contiguous leads with the cut-
points: ≥ 0.1 mV in all leads other than leads V2-V3 where the 
following cut-points apply: ≥ 0.2 mV in men ≥ 40 years (≥ 0.25 mV in 
men < 40 years) or ≥ 0.15 mV in women.
∀
ST depression and T-wave changes
New horizontal or down-sloping ST depression ≥ 0.05 mV in 2 
contiguous leads; and/or new T inversion ≥ 0.3 mV in 2 contiguous 
leads.
b. Definite evidence of inducible myocardial ischemia as demonstrated by:
-
An early positive exercise stress test, defined as ST elevation or >2mm 
ST depression prior to 5 mets OR
-
stress echocardiography (reversible wall motion abnormality) OR


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-
myocardial scintigraphy (reversible perfusion defect), OR
-
MRI (myocardial perfusion deficit under pharmacologic stress).
AND believed to be responsible for the myocardial ischemic 
symptoms/signs.
c.
Angiographic evidence of new or worse ≥ 70% lesion and/or thrombus in an 
epicardial coronary artery that is believed to be responsible for the myocardial 
ischemic symptoms/signs.
d. Need for coronary revascularization procedure (PCI or CABG) for the 
presumed culprit lesion(s). This criterion would be fulfilled if 
revascularization was undertaken during the unscheduled hospitalization, or 
subsequent to transfer to another institution without interceding home 
discharge.
AND
4. Negative cardiac biomarkers and no evidence of acute MI.
General Considerations
1. Escalation of pharmacotherapy for ischemia, such as IV nitrates or increasing doses 
of ∋-blockers, should be considered supportive but not diagnostic of the diagnosis of 
unstable angina. However, a typical presentation and admission to the hospital with 
escalation of pharmacotherapy, without any of the additional findings listed under 
category 3 (above), would be insufficient to support classification as hospitalization 
for unstable angina.
2. If patients are admitted with suspected unstable angina, and subsequent testing 
reveals a non-cardiac or non-ischemic etiology, this event should not be recorded as 
hospitalization for unstable angina. Potential ischemic events meeting the criteria for 
myocardial infarction should not be adjudicated as unstable angina.
3. Planned hospitalization or rehospitalization for performance of an elective 
revascularization in patients who do not fulfill the criteria for unstable angina should 
not be considered a hospitalization for unstable angina. For example,
∀
Hospitalization of a patient with stable exertional angina for coronary 
angiography and PCI that is prompted by a positive outpatient stress test 
should not be considered hospitalization for unstable angina.


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∀
Rehospitalization of a patient meeting the criteria for unstable angina 
who was stabilized, discharged, and subsequently readmitted for 
revascularization, does not constitute a second hospitalization for unstable 
angina.
4. A patient who undergoes an elective catheterization where incidental coronary artery 
disease is found and who subsequently undergoes coronary revascularization will not 
be considered as meeting the hospitalization for unstable angina end point.
5. A patient who has UA and subsequently dies should be adjudicated as defined above 
(see Section I) to determined cause of death. 
E. Cardiac Revascularization Procedure
A cardiac (coronary) revascularization procedure is defined as either coronary artery 
bypass graft surgery (CABG) or a percutaneous coronary intervention (PCI) (e.g.,
angioplasty, coronary stenting). CABG is defined as the successful placement of at least 
one conduit with either a proximal and distal anastomosis or a distal anastomosis only.
PCI is defined as placement of an angioplasty guidewire, balloon, or other device (e.g., 
stent, atherectomy catheter brachytherapy delivery device, or thrombectomy catheter) 
into a native coronary artery or coronary artery bypass graft for the purpose of 
mechanical coronary revascularization. In the assessment of the severity of coronary 
lesions with the use of intravascular ultrasound, CFR, or FFR, insertion of a guide wire 
will NOT be considered PCI. Coronary Artery Bypass Graft surgeries and Percutaneous 
Coronary Interventions will be categorized into two distinct categories, elective and 
urgent:
a. Elective: The procedure can be performed on an outpatient basis or during a 
subsequent hospitalization without significant risk of myocardial infarction 
(MI) or death. For stable in-patients, the procedure is being performed during 
this hospitalization for convenience and ease of scheduling and NOT because 
the patient's clinical situation demands the procedure prior to discharge. 
b. Urgent: The procedure does not meet “elective” criteria. This encompasses all 
non-elective procedures including those of an urgent, emergent or salvage 
nature.
F. Heart Failure
A HF Event may consist of a hospitalization, as well as urgent outpatient visits. All 
events identified as being representative of HF will be sub-classified as 1) HF 
hospitalization or 2) urgent HF visit. In addition, all events identified as being 
representative of HF will be sub-classified as 1) new or 2) exacerbation of existing HF.


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I) A HF Hospitalization is defined as an event that meets ALL 5 of the following 
criteria:
1) The patient is admitted to the hospital with a primary diagnosis of HF
2) The patient’s length-of-stay in hospital extends for at least 24 hours (or a 
change in calendar date if the hospital admission and discharge times are 
unavailable)
3) The patient exhibits documented new or worsening symptoms due to HF on
presentation, including at least ONE of the following:
a. Dyspnea (dyspnea with exertion, dyspnea at rest, orthopnea, paroxysmal 
nocturnal dyspnea)
b. Decreased exercise tolerance
c. Fatigue
d. Other symptoms of worsened end-organ perfusion or volume overload
4) The patient has objective evidence of new or worsening HF, consisting of at 
least TWO physical examination findings OR one physical examination finding 
and at least ONE laboratory criterion, including:
a. Physical examination findings considered to be due to heart failure, 
including new or worsened:
i. Peripheral edema
ii. Increasing abdominal distention or ascites (in the absence of 
primary hepatic disease)
iii. Pulmonary rales/crackles/crepitations
iv. Increased jugular venous pressure and/or hepatojugular reflux
v. S3 gallop
vi. Clinically significant or rapid weight gain thought to be related 
to fluid retention
b. Laboratory evidence of new or worsening HF, if obtained within 24 
hours of presentation, including:
i. Increased B-type natriuretic peptide (BNP)/ N-terminal pro-BNP 
(NT-proBNP) concentrations consistent with decompensation of 


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heart failure (such as BNP > 500 pg/mL or NT-proBNP > 2,000 
pg/mL). In patients with chronically elevated natriuretic peptides, a 
significant increase should be noted above baseline.
ii. Radiological evidence of pulmonary congestion
iii. Non-invasive or invasive diagnostic evidence of clinically 
significant elevated left- or right-sided ventricular filling pressure 
or low cardiac output. For example, echocardiographic criteria 
could include: E/e’ > 15 or D-dominant pulmonary venous inflow 
pattern, plethoric inferior vena cava with minimal collapse on 
inspiration, or decreased left ventricular outflow tract (LVOT) 
minute stroke distance (time velocity integral (TVI)
OR
iv. Invasive diagnostic evidence with right heart catheterization 
showing a pulmonary capillary wedge pressure (pulmonary artery 
occlusion pressure) ≥ 18 mmHg, central venous pressure ≥ 12 
mmHg, or a cardiac index < 2.2 L/min/m2
Note: All results from diagnostic tests should be reported, if available, even if 
they do not meet the above criteria, because they provide important 
information for the adjudication of these events.
5) The patient receives initiation or intensification of treatment specifically for 
HF, including at least ONE of the following:
a. Augmentation in oral diuretic therapy
b. Intravenous diuretic, inotrope, or vasodilator therapy
c. Mechanical or surgical intervention, including:
i. Mechanical circulatory support (e.g., intra-aortic balloon pump, 
ventricular assist device)
ii. Mechanical fluid removal (e.g., ultrafiltration, hemofiltration, 
dialysis)
II) An Urgent HF Visit is defined as an event that meets all of the following:


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1) The patient has an urgent, unscheduled office/practice or emergency 
department visit for a primary diagnosis of HF, but not meeting the criteria for a 
HF hospitalization.
2) All signs and symptoms for HF hospitalization, i.e., symptoms, physical 
examination findings/laboratory evidence of new or worsening HF, (as indicated 
above) must be met.
3) The patient receives initiation or intensification of treatment specifically for 
HF, as detailed in the above section with the exception of oral diuretic therapy, 
which will not be sufficient.
Note: A HF event that results in death should be classified as a CV Death due to 
Heart Failure.
REFERENCES
1. Thygesen K, Alpert J, Jaffe A, Simoons M, Chaitman B, White, H. Third Universal 
definition of myocardial infarction. European Heart Journal Advance Access 
published Aug 24, 2012.
2. Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Stockbridge NL, 
Targum SL, Temple R; on behalf of the Standardized Data Collection for 
Cardiovascular Trials Initiative. Standardized Definitions for Cardiovascular and 
Stroke End Point Events in Clinical Trials. Draft Definitions for Testing Nov. 9, 
2012.


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APPENDIX D: 2013 ACC/AHA Guidelines for High-, Moderate- and Low-Intensity 
Statin Therapy
List of References:
Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Lloyd-Jones DM, Blum CB, 
McBride P, Eckel RH, Schwartz JS, Goldberg AC, Shero ST, Gordon D, Smith Jr SC, 
Levy D, Watson K, Wilson PWF. 2013 ACC/AHA Guideline on the Treatment of Blood 
Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, Journal of the 
American College of Cardiology 2014;63(25 Pt B):288.






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APPENDIX F : Additional Safety Information
Clinical Study Protocol Appendix F
Drug Substance
Epanova®
Study Code
D5881C00004
Edition Number
1
Date
May 2015
Appendix F
Additional Safety Information


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FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic 
failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the 
reasons for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or 
surgical operations planned before or during a study are not considered AEs if the illness 
or disease existed before the subject was enrolled in the study, provided that it did not 
deteriorate in an unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is 
serious in situations where important medical events may not be immediately life 
threatening or result in death, hospitalisation, disability or incapacity but may jeopardize 
the subject or may require medical intervention to prevent one or more outcomes listed in 
the definition of serious.  These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; 
medical judgement must be used.
∀
Angioedema not severe enough to require intubation but requiring iv 
hydrocortisone treatment
∀
Hepatotoxicity caused by paracetamol (acetaminophen) overdose 
requiring treatment with N-acetylcysteine
∀
Intensive treatment in an emergency room or at home for allergic 
bronchospasm
∀
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, 
etc) or convulsions that do not result in hospitalisation


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∀
Development of drug dependency or drug abuse


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A GUIDE TO INTERPRETING THE CAUSALITY QUESTION
When making an assessment of causality consider the following factors when deciding if 
there is a ‘reasonable possibility’ that an AE may have been caused by the drug.
∀
Time Course.  Exposure to suspect drug.  Has the subject actually received 
the suspect drug?  Did the AE occur in a reasonable temporal relationship 
to the administration of the suspect drug?
∀
Consistency with known drug profile.  Was the AE consistent with the 
previous knowledge of the suspect drug (pharmacology and toxicology) or 
drugs of the same pharmacological class? Or could the AE be anticipated 
from its pharmacological properties?
∀
De-challenge experience.  Did the AE resolve or improve on stopping or 
reducing the dose of the suspect drug?
∀
No alternative cause.  The AE cannot be reasonably explained by another 
aetiology such as the underlying disease, other drugs, other host or 
environmental factors.
∀
Re-challenge experience.  Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? AstraZeneca would not normally 
recommend or support a re-challenge.
∀
Laboratory tests.  A specific laboratory investigation (if performed) has 
confirmed the relationship.
In difficult cases, other factors could be considered such as:
∀
Is this a recognized feature of overdose of the drug?
∀
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence 
for a ‘reasonable possibility’ of a causal relationship for the individual case.  The 
expression ‘reasonable possibility’ of a causal relationship is meant to convey, in general, 
that there are facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in 
the case, it is likely that the event(s) will be assessed as ‘not related’.


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Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.


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APPENDIX G
Clinical Study Protocol Appendix G
Drug Substance
Epanova®
Study Code
D5881C00004
Edition Number
1
Date
May 2015
Appendix G
Pharmacogenetics Research –for the US only


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation or 
special term
Explanation
CSR
Clinical Study Report
DNA
Deoxyribonucleic acid
ECRF
Electronic Case Report Form
EDTA
Ethylenediaminetetraacetic acid
GWAS
Genome wide association studies
HR
Hazard Ratio
ICH
International Conference on Harmonisation
LDL-C
Low density lipoprotein-cholesterol
LIMS
Laboratory information management system
MI
Myocardial Infarction
PGx
Pharmacogenetics
SNP
Single Nucleotide Polymorphism


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Background and rationale
AstraZeneca intends to perform genetic research in the Epanova clinical development 
programme to explore how genetic variations may affect the clinical parameters 
associated with Epanova where appropriate.  Collection of DNA samples from 
populations with well described clinical characteristics may lead to improvements in the 
design and interpretation of clinical trials and, possibly, to genetically guided treatment 
strategies.
Genetic variation can contribute to an individual’s risk of adverse clinical outcomes as 
well as to their response to pharmacotherapy. Specifically, genetic polymorphisms can 
identify individuals at increased risk of adverse clinical outcomes, through known and yet 
to be discovered biological pathways. Genetic variants that identify patients at higher risk 
for thrombotic events might be used to tailor therapy. Patients at higher risk for adverse 
events will, by definition, enjoy a greater absolute risk reduction for a given relative risk 
reduction from a therapy and hence require a smaller number needed to treat to prevent 
an adverse event. Moreover, pathobiologically relevant genetic variants may identify a 
specific subset of patients who enjoy a larger relative risk reduction with a given 
pharmacotherapeutic intervention, and thus an even greater absolute risk reduction.
For this study, it has been decided to collect genetic samples from 2000 patients in the 
US only.
Genetic Research Objectives
The objective of this research is to collect and store DNA for exploratory research into 
genes/genetic variation that may influence response (i.e., distribution, safety, tolerability 
and efficacy) to omega-3 fatty acids and other cardiovascular medications and/or 
susceptibility to and/or prognosis of cardiovascular, metabolic and related diseases.


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genetic Research plan and procedures
Selection of genetic research population
Study selection record
It is estimated that 2000 subjects in US will be asked to participate in this genetic 
research.  Participation is voluntary and if a subject declines to participate there will be 
no penalty or loss of benefit.  The subject will not be excluded from any aspect of the 
main study.
Inclusion criteria
For inclusion in this genetic research, subjects must fulfill all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and:
∀
Provide informed consent for the genetic sampling and analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following:
∀
Previous allogeneic bone marrow transplant
∀
Non-leukocyte depleted whole blood transfusion in 120 days of genetic 
sample collection
Discontinuation of subjects from this genetic research
Specific reasons for discontinuing a subject from this genetic research are:
Withdrawal of consent for genetic research:  Subjects may withdraw from this genetic 
research at any time, independent of any decision concerning participation in other 
aspects of the main study.  Voluntary discontinuation will not prejudice further treatment.  
Procedures for discontinuation are outlined in Section 4.3 of the main Clinical Study 
Protocol.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the subjects at Visit 2.  
Although genotype is a stable parameter, early sample collection is preferred to avoid 
introducing bias through excluding patients who may withdraw due to an adverse event 
(AE), such patients would be important to include in any genetic analysis.  Only one 


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sample should be collected per subject for genetics during the study.  Samples will be 
collected, labelled, stored and shipped as detailed in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality.  Samples will be stored for a maximum of 
15 years from the date of last subject last visit, after which they will be destroyed.  DNA 
is a finite resource that is used up during analyses.  Samples will be stored and used until 
no further analyses are possible or the maximum storage time has been reached.
The samples and data for genetic analysis in this study will be single coded.  The link 
between the subject enrolment/randomisation code and the DNA number will be 
maintained and stored in a secure environment, with restricted access within the Clinical 
Genotyping Group Laboratory Information Management System (LIMS) at AstraZeneca.  
The link will be used to identify the relevant DNA samples for analysis, facilitate 
correlation of genotypic results with clinical data, allow regulatory audit and to trace 
samples for destruction in the case of withdrawal of consent.
Genotyping
The genetic research conducted may use a variety of genotyping methodologies as 
needed. For example, specific sections of DNA may be selected from areas of the 
genome (e.g., candidate genes) known to encode the drug target, drug metabolizing 
enzymes, and areas linked to the study disease or related cardiovascular or metabolic 
diseases as well as associated with mechanisms underlying adverse events. In addition, 
genome-wide scans involving large numbers of polymorphic markers (e.g., single 
nucleotide polymorphisms (SNPs)) located throughout the genome may be employed for 
discovery of novel genetic variants linked to outcomes of interest. Additional 
methodologies may be used, but only as related the genetic objective stated earlier.


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Ethical and Regulatory Requirements
The principles for ethical and regulatory requirements for the study, including this 
genetics research component, are outlined in Section 10.1 of the main Clinical Study 
Protocol.
Informed consent
The genetic component of this study is optional and the subject may participate in other 
components of the main study without participating in the genetic component.  To 
participate in the genetic component of the study the subject must sign and date both the 
consent form for the main study and the genetic component of the study.  Copies of both 
signed and dated consent forms must be given to the subject and the original filed at the 
study centre.  The principal investigator(s) is responsible for ensuring that consent is 
given freely and that the subject understands that they may freely discontinue from the 
genetic aspect of the study at any time.
Subject data protection
AstraZeneca will not provide individual genotype results to subjects, any insurance 
company, any employer, their family members, general physician or any other third 
party, unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the subject.  In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a subject.  For 
example, in the case of a medical emergency, an AstraZeneca Physician or an 
investigator might know a subject’s identity and also have access to his or her genetic 
data.  Also Regulatory authorities may require access to the relevant files, though the 
subject’s medical information and the genetic files would remain physically separate.


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Data Management
Any genotype data generated in this study will be stored in an appropriate secure system 
within AstraZeneca and/or third party contracted to work with AstraZeneca to analyze the 
samples.
The results from this genetic research may be reported in the CSR for the main study, or 
in a separate report as appropriate.
Some or all of the clinical datasets from the main study may be merged with the genetic 
data in a suitable secure environment separate from the clinical database.
Statistical Methods and determination of Sample Size
The number of subjects that will agree to participate in the genetic research is unknown.  
It is therefore not possible to establish whether sufficient data will be collected to allow a 
formal statistical evaluation or whether only descriptive statistics will be generated. 
If decided that the result will be part of the CSR, then a statistical analysis plan will be 
prepared and signed before un-blinding.  
All analyses for this Pharmacogenetics Research are exploratory and any p-value that is 
generated will be regarded as descriptive only. Analyses may be carried out to evaluate 
the degree of association between patient genotype (or haplotype) and selected 
phenotypes (e.g., outcomes). In addition to evaluating the main effects of the genotypes 
(haplotypes or alleles) on the selected phenotypes, the possibility of a treatment group by 
genotype (haplotype or allele) interaction will also be explored. 


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List of references
Kathiresan S, Voight BF, Purcell S, et al. Genome-wide association of early-onset 
myocardial infarction with single nucleotide polymorphisms and copy number variants. 
Nat Genet 2009;41(3):334-41.
Lanfear DE, Jones PG, Marsh S, Cresci S, McLeod HL, Spertus JA. Beta2-adrenergic 
receptor genotype and survival among patients receiving beta-blocker therapy after an 
acute coronary syndrome. JAMA 2005;294(12):1526-33.
Rossi GP, Maiolino G, Zanchetta M, et al. The T(-786)C endothelial nitric oxide synthase 
genotype predicts cardiovascular mortality in high-risk patients. J Am Coll Cardiol 
2006;48(6):1166-74.
Wheeler JG, Keavney BD, Watkins H, Collins R, Danesh J. Four paraoxonase gene 
polymorphisms in 11212 cases of coronary heart disease and 12786 controls: meta-
analysis of 43 studies. Lancet 2004;363(9410):689-95.

SAP_001.pdf: 
 
 
1 
Statistical Analysis Plan 
Study Code 
D5881C00004 
Edition Number 
Version 5.0 
Date 
22 April 2020 
A Long-Term Outcomes Study to Assess STatin Residual Risk Reduction 
with EpaNova in HiGh Cardiovascular Risk PatienTs with 
Hypertriglyceridemia (STRENGTH) 
 
 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
2 
 
 
 
 
 
 
A Long-Term Outcomes Study to Assess STatin Residual Risk Reduction 
with EpaNova in HiGh Cardiovascular Risk PatienTs with 
Hypertriglyceridemia (STRENGTH) 
 
Study Statistician 
 
 
 
 
, IQVIA 
 
20124 Milano 
Italy 
 
Date 
 
 
Redacted
Redacte Redact
Redacted


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
3 
 
 
 
 
 
 
A Long-Term Outcomes Study to Assess STatin Residual Risk Reduction 
with EpaNova in HiGh Cardiovascular Risk PatienTs with 
Hypertriglyceridemia (STRENGTH) 
 
Global Product Statistician 
 
 
Senior Statistician 
Biometrics, Late-stage Development, Cardiovascular, 
Renal and Metabolism, BioPharmaceuticals R&D  
AstraZeneca 
 
Date 
 
 
 
Redacted


Redacted


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
5 
TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ............................................................................................................................ 1 
SIGNATURE OF STUDY STATISTICIAN ........................................................................... 2 
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN .................................................... 3 
TABLE OF CONTENTS ......................................................................................................... 5 
LIST OF TABLES ................................................................................................................... 7 
LIST OF ABBREVIATIONS .................................................................................................. 8 
AMENDMENT HISTORY .................................................................................................... 10 
1. 
STUDY DETAILS ................................................................................................. 16 
1.1 
Study objectives ..................................................................................................... 16 
1.1.1 
Primary objective ................................................................................................... 16 
1.1.2 
Primary outcome measure ...................................................................................... 16 
1.1.3 
Secondary outcome measures ................................................................................ 16 
1.1.4 
Tertiary outcome measures .................................................................................... 17 
1.1.5 
Biomarker efficacy endpoints ................................................................................ 17 
1.1.6 
Safety assessments ................................................................................................. 18 
1.2 
Study design ........................................................................................................... 18 
1.3 
Number of patients ................................................................................................. 22 
2. 
ANALYSIS SETS ................................................................................................. 22 
2.1 
Definition of Analysis Sets .................................................................................... 22 
2.1.1 
Full Analysis Set (FAS) ......................................................................................... 22 
2.1.2 
Safety Analysis Set (SAF) ..................................................................................... 23 
2.2 
Deviations .............................................................................................................. 23 
3. 
PRIMARY AND SECONDARY VARIABLES ................................................... 24 
3.1 
Adjudication of clinical endpoints ......................................................................... 24 
3.2 
Baseline .................................................................................................................. 24 
3.3 
Efficacy variables ................................................................................................... 24 
3.3.1 
Reference start date and study day ......................................................................... 26 
3.3.2 
TTE calculation ...................................................................................................... 26 
3.3.3 
Primary efficacy variable ....................................................................................... 26 
3.3.4 
Secondary efficacy variables ................................................................................. 26 
3.3.5 
Tertiary outcome variables..................................................................................... 28 
3.3.6 
Biomarker endpoints .............................................................................................. 28 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
6 
3.4 
Safety variables ...................................................................................................... 29 
3.4.1 
Adverse Events ...................................................................................................... 29 
3.4.2 
Bleedings ................................................................................................................ 31 
3.4.3 
New onset of diabetes mellitus during the study ................................................... 32 
3.4.4 
Laboratory tests ...................................................................................................... 33 
3.4.5 
Vital signs .............................................................................................................. 33 
3.4.6 
Electrocardiogram (ECG) ...................................................................................... 33 
3.4.7 
Physical examination ............................................................................................. 34 
3.4.8 
Overdoses ............................................................................................................... 34 
3.5 
Additional variables ............................................................................................... 34 
3.5.1 
Demographic and other baseline characteristics .................................................... 34 
3.5.2 
Medical history ...................................................................................................... 35 
3.5.3 
Prior and concomitant medications ........................................................................ 35 
3.5.4 
Duration of exposure .............................................................................................. 36 
3.5.5 
Treatment compliance ............................................................................................ 36 
3.5.6 
End-of-Study (EOS) assessment ............................................................................ 37 
3.6 
Study Completers ................................................................................................... 37 
4. 
ANALYSIS METHODS ....................................................................................... 38 
4.1 
General principles .................................................................................................. 38 
4.1.1 
Study Periods ......................................................................................................... 38 
4.1.2 
Visit Window and retests ....................................................................................... 39 
4.1.3 
Common calculations ............................................................................................. 41 
4.1.4 
Imputation rules and missing data ......................................................................... 41 
4.1.5 
Patient disposition .................................................................................................. 44 
4.1.6 
Demographics and baseline characteristics............................................................ 44 
4.1.7 
Medical history ...................................................................................................... 44 
4.1.8 
Prior and concomitant medications ........................................................................ 45 
4.1.9 
Duration of exposure .............................................................................................. 45 
4.1.10 
Treatment compliance ............................................................................................ 45 
4.2 
Analysis of efficacy outcome measures ................................................................. 45 
4.2.1 
Primary efficacy ..................................................................................................... 45 
4.2.2 
Secondary outcome analyses ................................................................................. 51 
4.2.3 
Tertiary outcome analyses ..................................................................................... 52 
4.2.4 
Exploratory outcome measures .............................................................................. 54 
4.2.5 
Biomarkers Efficacy .............................................................................................. 54 
4.3 
Analysis of safety outcome measures .................................................................... 56 
4.3.1 
AEs ......................................................................................................................... 57 
4.3.2 
Bleedings ................................................................................................................ 58 
4.3.3 
New onset of diabetes mellitus during the study ................................................... 59 
4.3.4 
Laboratory Evaluations .......................................................................................... 59 
4.3.5 
ECG ........................................................................................................................ 61 
4.3.6 
Vital signs .............................................................................................................. 61 
4.3.7 
Physical examination ............................................................................................. 61 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
7 
4.3.8 
Overdoses ............................................................................................................... 62 
5. 
INTERIM ANALYSES ......................................................................................... 62 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL ............................................... 63 
7. 
REFERENCES ...................................................................................................... 66 
8. 
APPENDICES ....................................................................................................... 67 
APPENDIX 1 SUBGROUPS AND GEOGRAPHIC REGIONS ....................................... 67 
APPENDIX 2 LIST OF LABORATORY TESTS .............................................................. 70 
APPENDIX 3 STATISTICAL MODELS ........................................................................... 71 
Appendix 3.1 Cox proportional hazard model, Kaplan-Meier (KM) product-Limit 
method, event rates and hazard plots ..................................................................... 71 
Appendix 3.2 Analysis of covariance model ....................................................................... 73 
APPENDIX 4 TIMI BLEED CLASSIFICATIONS DERIVATION..................................... 74 
APPENDIX 5 PTS FOR TERTIARY OUTCOME ANALYSIS OF TOTAL 
THROMBOTIC EVENTS ..................................................................................... 78 
APPENDIX 6 PTS FOR CARDIOVASCULAR EVENTS ................................................ 82 
 
List of Tables 
 
Table 1 
Schedule of Procedure .............................................................................. 19 
Table 2 
Summary of time-to-events (TTE) endpoints ........................................... 25 
Table 3  
Analysis Visits by Visit Window ............................................................. 40 
Table 4 
Marked abnormality criteria ..................................................................... 61 
Table 5 
Interim Analysis Plan ............................................................................... 63 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
8 
LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
5-point MACE 
A composite MACE endpoint consisting of at least one of either 
cardiovascular death, non-fatal myocardial infarction, non-fatal 
stroke, emergent/elective coronary revascularization, or 
hospitalization for unstable angina 
AA 
arachidonic acid 
AE 
adverse event 
Apo B-100 
apolipoprotein B-100 
Apo C-III 
apolipoprotein C-III 
BILI 
Total bilirubin 
CEC 
Clinical Events Committee 
CI 
confidence interval 
CSP  
Clinical study protocol 
CSR 
Clinical study report 
CV 
cardiovascular 
CVD 
cardiovascular disease 
DBP 
diastolic blood pressure 
DHA 
docosahexaenoic acid 
DMC 
Data Monitoring Committee 
DPA 
docosapentaenoic acid 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end-of-study 
EOT 
end-of-treatment 
EPA 
eicosapentaenoic acid 
ET 
early termination 
FAS 
Full Analysis Set 
FPFV 
first patient first visit 
GFR 
glomerular filtration rate 
HDL-C 
high-density lipoprotein cholesterol 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
9 
Abbreviation or 
special term 
Explanation 
HGR 
Human Genetic Resources 
HR 
hazard ratio 
hs-CRP 
high-sensitivity C-reactive protein 
IP 
investigational product 
KM 
Kaplan-Meier 
LDL-C 
low-density lipoprotein cholesterol 
MA 
marked abnormality 
MACE 
major adverse cardiovascular events (cardiovascular death, 
non-fatal myocardial infarction, non-fatal stroke, emergent/elective 
coronary revascularization or hospitalization for unstable angina) 
MAR 
missing at random 
MedDRA  
Medical Dictionary for Regulatory Affairs 
NNT 
number needed to treat 
PHL 
potential Hy’s Law 
PIT 
probability integral transformation 
PT 
preferred term 
RBC 
red blood cells 
SAE 
serious adverse event 
SAF 
Safety 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SMQ 
Standardised MedDRA Queries 
SOC 
system organ class 
TC 
total cholesterol 
TG 
triglycerides 
TIA 
transient ischemic attack 
TIMI 
thrombolysis in myocardial infarction 
TTE 
time-to-event 
VLDL 
very low-density lipoprotein 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
10 
AMENDMENT HISTORY 
Date 
Brief description of change 
22nd Apr 2020 
1. Global product statistician updated. 
2. Amended list of abbreviations. 
3. In Section 1.1.5, clarified differences for high-sensitivity C-reactive 
protein analysis.  
4. In Section 2.2, disallowed used rather than prohibited and updated list 
of deviations.  
5. In Section 3.3, clarified how will be handled events with 
undetermined adjudication assessment. 
6. In Section 3.3.6, rectified timing of biomarker assessments.  
7. Section 3.4.1.8 deleted. 
8. In the bleeding event analysis, added a new category for bleeding 
event not categorizable due to missing data.  
9. Rectified starting point for HbA1c check in the definition of new 
onset of diabetes mellitus and added clarification about how to handle 
multiple signals of diabetes mellitus. 
10. MedDRA Dictionary and WHO-DD versions updated. 
11. In Section 3.4.8, changed definition of overdose.  
12. In Section 3.6, changed definition of study completers.  
13. Updated Table 3 and added in Section 4.1.2 details for visit name 
“Study terminated by sponsor”. 
14. Added more details in Section 4.1.4 for imputation rules on missing 
data and included bleeding events and new onset of diabetes mellitus. 
15. Deleted the last carried forward approach foreseen for Biomarkers, 
since no needed considering the windowing rules.  
16. In Section 4.1.10, added sensitivity analysis on treatment compliance.  
17. Amended Section 4.2.1.3.  
18. In Section 4.2.1.5, added a supplemental analysis with censoring at 
time of decision to early terminate the study and updated Section 6 
accordingly. 
19. In Section 4.2.3, amended the joint frailty model to be used for 
recurrent events analysis.  
20. In Section 4.3.2, added analysis for location of bleeding events.  
21. In Section 4.3.4, added details on how local laboratory data are used 
for the analysis and changed time period for reporting of Hy’s Law 
cases. 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
11 
Date 
Brief description of change 
24th  Sept 2019 
1. Rephrased objectives as in the CSP, in Section 1.1.1, 1.1.2 and 
1.1.3.2.  
2. Extended terms rather than abbreviations used for all endpoints and 
amended the list of abbreviations accordingly. 
3. Added to the list of abbreviations CSP, NNT and SMQ.  
4. Applied consistency in the reference to the dichotomous established 
cardiovascular disease at baseline variable.  
5. Amended Section 2.2 to be consistent with ICH E3 terminology on 
protocol deviation. Amended terminology for patients randomized 
more than once. 
6. Deleted Section on handling of patients randomized more than once. 
7. Added new Section 3.2 for definition of baseline.  
8. Clarified collection timing for biomarkers measures in Section 3.3.6 
9. Amended and clarified definition of completers in Section 3.6.  
10. Added multiple imputation scheme for the biomarker analyses in 
Section 4.1.4. 
11. Added imputation rules for missing/incomplete dates in Section 4.1.4.  
12. Amended definition of duration of exposure in Section 3.5.4. 
13. Amended definition of treatment compliance in Section 3.5.5. 
14. Added definition of study periods in Section 4.1.1. 
15. Moved description of the analysis of diabetes onset to Section 4.3.3 
and changed to time to event analysis. 
16. Removed redundancy in the description of safety variables in Section 
3.4 and added pregnancy test and overdoses. 
17. Removed terminology for treatment-emergent AEs and clarified 
timing for collection of AEs and SAEs. 
18. In Section 4.3.4 clarified that listing about abnormalities is based on 
MA criteria. 
19. Clarified that imputation rules for partial/missing dates will not be 
applied for listings in Section 3.4.1. 
20. Amended algorithm to identify AEs indicating diabetes in Section 
3.4.3 and removed Appendix 5.Amended terminology for premature 
discontinuation of study medication in Section 4.1.5. 
 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
12 
 
21. Amended modelling language for clarity in Section 4.2.1. 
22. Added additional estimates to be presented in the KM analysis in 
Section 4.2.1. 
23. Created separate Section 4.2.1.1 for diagnostic procedures for the 
primary efficacy model.  
24. Added to the diagnostic procedures for the primary efficacy model the 
Cox-Snell residual plot and the diagnostic plots of hazard 
proportionality assumption for all the covariates in Section 4.2.1.1. 
25. Moved the analysis of on-treatment MACE events to Section 4.2.4 for 
exploratory outcome measure. Added in Section 6 the corresponding 
deviation from the protocol. 
26. Added a permutation-based approach to assess homogeneity of 
treatment effect in the subgroups analysis for primary outcome in 
Section 4.2.1.4.  
27. In Section 4.2.5 changed analysis from MMRM to ANCOVA, 
reflected in a reference to PROC GLM rather than PROC MIXED, for 
all the biomarkers. Added Appendix 3.2. A for ANCOVA model 
description and clearly specified the natural log transformation for the 
outcome measures included. Added in Section 6 the corresponding 
deviation from the protocol. Clarified that high-sensitivity C-reactive 
protein will be analyzed as percent change from baseline to end of 
treatment. Added a last observation carried forward approach to the 
analysis and a multiple imputation scheme to asses impact of missing 
data. 
28. Clarified in Section 4.2.3 that the composite measure analysis will 
include all the events collected in the eCRF “Tertiary Endpoints” form 
and all those identified among the AEs collected. 
29. Extended the list of tertiary outcomes measures in Section 1.1.4 and 
3.3.5, and added corresponding analysis details in Section 4.2.3. 
30. Clarified that bleeds will be classified programmatically. Added 
Appendix 4 with corresponding algorithm. Added in Section 6 the 
corresponding deviation from the protocol. Moved analysis methods 
for bleedings into Section 4.3.2, amended censoring rule. Clarified 
that bleedings will not be adjudicated by CEC.  
31. Removed list of TFLs. 
32. Removed listings on vital signs, medical history, prior and 
concomitant medication and ECG in Section 3.4.5, 4.3.6, 4.1.7, 4.1.8, 
4.3.5.  
33. Added definition and analysis details for overdoses in Section 3.4.8 
and 4.3.8. 
34. Added TIA definition in Section 3.4.1.  
35. Added definition for AEs leading to dose reduction and IP interruption 
in Section 3.4.1.  
 
 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
13 
36. Added imputation rule for start and end date of study medication 
doses in Section 4.1.3. Also amended the last dose definition in 
Section 3.5.4 to consider also the “end date of study medication” from 
eCRF “Exposure” form. 
37. Moved Schedule of Procedure to Section 1.2. 
38. Moved Summary of time-to-event (TTE) endpoints to Section 3.3. 
39. Moved to Section 3.3.6 timing description for biomarkers collection.  
40. Amended wording for listing of safety variables in Section 3.4. 
41. Clarified timing of collection of AEs and SAEs in Section 4.3.1.  
42. Deleted definition of SAEs in Section 3.4.1.7. 
43. Added rule for imputation of partially missing or missing end date for 
AEs in Section 3.4.1.8. 
44. Added rule to identify patients without diabetes mellitus at baseline in 
Section 3.4.3. 
45. Added rule for analysis of laboratory test results reported as above or 
below the limit of quantification in Section 3.4.4. 
46. Clarified that Physical Examination data are not collected separately 
in Section 3.4.7. 
47. Removed from Section 3.5.1 safety variables and multiple risk factors.  
48. Moved Analysis Visits by Visit Window to Section 4.1.2. 
49. Clarified that prior and concomitant medication summaries will be 
reported separately and also for allowed and disallowed medications 
in Section 4.1.8. 
50. Clarified that data about administration of IP will be provided in 
listings in Section 4.1.9.  
51. Deleted analysis of compliance by visit.  
52. Added in Section 4.2.1.3 imputation rule for partially missing date of 
last contact. 
53. Removed Rosuvastatin subgroup from Section 4.2.1.4. 
54. Added in Section 4.3.1 summaries for on-treatment SAEs with event 
rates, on-treatment AEs with event rates. 
55. Added figures displaying maximum post baseline total bilirubin 
against maximum post baseline ALT and AST in Section 4.3.4. 
56. Added details for all subgroup variables in the Appendix 1. 
57. Amended Appendix 4 TIMI bleed classifications derivation. 
58. Added baseline estimated GFR and Ezetimibe treatment at baseline in 
Section 4.2.1.4. 
59. Time to all-cause death and corresponding subgroup analysis on 
patients with established cardiovascular disease at baseline added as 
key secondary measures. Added in Section 6 the corresponding 
deviation from the protocol. 
60. Added subgroup analyses in Section 4.3.1, 4.3.2 and 4.3.3.  
 


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14 
Date 
Brief description of change 
03rd July 2019 
1. Amended details for study statistician and global product statistician 
on signature page. 
2. Clarified how time to onset of fatal myocardial infarction and stroke is 
derived in Sections 3.3.3 and 3.3.4. 
3. Extended the list of secondary outcomes measures in the hierarchical 
testing to include subgroup analysis in Sections 1.1.3.1, 3.3.4 and 
4.2.2 and added to Changes from Protocol in Section 6. 
4. Added safety analysis of the patients with established cardiovascular 
disease at baseline to Section 3.4.1. 
5. Amended censoring language for clarity in Section 4.2.1.3. 


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15 
Date 
Brief description of change 
29th June 2018 
1. Added 5-point MACE and 3-point MACE definitions to abbreviations 
and referenced throughout document. 
2. Updated section 1.11 with explanation of endpoints. 
3. New section 1.1 on handling of patients randomized more than once in 
analysis added. 
4. Updated bleeding section with TIMI criteria in 3.4.2. 
5. Added section 3.4.3 on Diabetes onset during study. 
6. Updated the analysis visit windowing in section 4.1.3. 
7. Added reference to Hy's Law and marked abnormality outputs in 
section 0 and Hy’s Law in section 3.4. 
8. Updated the statistical methodology for Biomarker Analysis in section 
4.2.5. 
9. Added in a note on systemic thromboembolism in section 1.1.1. 
10. Added in biomarker efficacy and safety to Study Objectives in 
sections 1.1.5 and 1.1.6. 
11. Added PHL and TIA to acronyms. 
12. Updated text in PD section 2.2 to reflect that PDs will be identified 
prior to DBL but not necessarily all programmatically. 
13. Updated PD list in section 2.2. 
14. Added an additional summary on exposure in section 3.5.4. 
15. Removed multiple risk factors from model in section 4.2.1.4. 
16. Added Appendix 5 PTs for DIABETES ONSET DURING THE 
STUDY. 
17. Clarified SAF population in section 1.1.  
18. Refined censoring definition in section 4.2.1.3. 
19. Added assessments used in censoring definition. 
20. Clarified handling of deaths with undetermined cause in section 3.3. 
21. Added section 3.6 on study completers. 
22. Added derivation for handling multiple entries of same AE due to 
multiple hospitalizations in section 3.4.1.  
23. Clarified in section 4.2.5 that back-transformed data will be presented. 
24. Clarified in section 4.2.5 biomarkers are from plasma and RBC 
bioanalysis. 
25. Added Kaplan-Meier for time from first dose of bleed in section 4.3. 
26. Clarified AE summaries only include treatment-emergent AE in 
section 4.3.1. 
 
 
 


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16 
1. 
STUDY DETAILS 
1.1 
Study objectives 
1.1.1 
Primary objective 
The primary objective of this study is to evaluate the effectiveness of adding Epanova to statin 
therapy (with or without ezetimibe) for lowering MACE (cardiovascular death, non-fatal 
myocardial infarction, non-fatal stroke, emergent/elective coronary revascularization, or 
hospitalization for unstable angina) in high cardiovascular risk patients, with persistent 
hypertriglyceridemia and low high-density lipoprotein cholesterol. 
1.1.2 
Primary outcome measure 
The primary outcome measure is the time to the first occurrence of any of the components of 
the composite of MACE.  
1.1.3 
Secondary outcome measures 
1.1.3.1 
Key secondary outcome measures 
1. The composite measure of MACE that include the first occurrence of cardiovascular 
death, non-fatal myocardial infarction, non-fatal stroke, emergent/elective coronary 
revascularization, or hospitalization for unstable angina in the subgroup of patients 
with established cardiovascular disease at baseline. 
2. The composite measure of cardiovascular events that include the first occurrence of 
cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. 
3. The composite measure of cardiovascular events that include the first occurrence of 
cardiovascular death, non-fatal myocardial infarction and non-fatal stroke in the 
subgroup of patients with established cardiovascular disease at baseline. 
4. The composite measure of coronary events that include the first occurrence of cardiac 
death (including death due to acute myocardial infarction, sudden cardiac death and 
death due to cardiovascular procedures), non-fatal myocardial infarction, 
emergent/elective coronary revascularization, or hospitalization for unstable angina. 
5. The composite measure of coronary events that include the first occurrence of cardiac 
death (including death due to acute myocardial infarction, sudden cardiac death and 
death due to cardiovascular procedures), non-fatal myocardial infarction, 
emergent/elective coronary revascularization, or hospitalization for unstable angina in 
the subgroup of patients with established cardiovascular disease at baseline. 
6. Time to cardiovascular death. 
7. Time to cardiovascular death in the subgroup of patients with established 
cardiovascular disease at baseline. 
8. Time to all-cause death. 
9. Time to all-cause death in the subgroup of patients with established cardiovascular 
disease at baseline. 


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17 
1.1.3.2 
Other secondary outcome measures (not included in hierarchical testing 
procedure) 
Other secondary outcome measures are:  
x Emergent/elective coronary revascularization 
x Hospitalization for unstable angina 
x Fatal or non-fatal myocardial infarction 
x Non-fatal myocardial infarction 
x Fatal or non-fatal stroke 
x Non-fatal stroke 
1.1.4 
Tertiary outcome measures 
Tertiary outcome measures are:  
x The first occurrence of new onset atrial fibrillation. 
x The composite measure of total thrombotic events that include the first occurrence of 
documented coronary stent thrombosis, any systematic thromboembolism including 
arterial stent (except coronary) thrombosis or venous thromboembolism, i.e. deep vein 
thrombosis and/or pulmonary embolism. 
x First occurrence of a heart failure event.   
x The second, third, fourth, and total number occurrences of major cardiovascular events 
(primary and secondary outcome measures). 
x The first CV-related hospitalization. 
For an overall look of the study outcome measures, please refer to Table 2. The standardized 
definition for endpoint events in cardiovascular trials can be found in protocol Appendix C. 
1.1.5 
Biomarker efficacy endpoints 
Biomarker efficacy endpoints will evaluate differences in change from baseline (Month 0) to 
Month 12 (primarily) between placebo (corn oil) and Epanova treatments. 
In addition, biomarker data after Month 12 will be presented in a descriptive manner. 
Biomarker variables include non-high-density lipoprotein cholesterol, triglycerides, high-
density lipoprotein cholesterol, total cholesterol, very low density lipoprotein cholesterol, total 
cholesterol: high-density lipoprotein cholesterol ratio and calculated low density lipoprotein 


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cholesterol (in patients with triglycerides > 400 mg/dl low-density lipoprotein cholesterol will 
be directly measured), apolipoprotein B-100, apolipoprotein C-III, eicosapentaenoic acid , 
docosahexaenoic acid, docosapentaenoic acid and arachidonic acid in plasma and red blood 
cells, high-sensitivity C-reactive protein. 
1.1.6 
Safety assessments 
Safety assessments include adverse events, safety laboratory assessments, pregnancy tests and 
physical examinations. 
1.2 
Study design 
This study is a randomized, double-blind, placebo-controlled (corn oil), parallel group design 
that will enroll approximately 13,000 patients with hypertriglyceridemia and high risk for 
cardiovascular disease.  It includes up to 3 Screening visits followed by a double-blind 
treatment period of approximately 3-5 years as determined when the number of patients with 
5-point MACE outcomes is reached.  This is an event-driven study and approximate 1,600 
adjudicated primary outcome events are required.  The treatment arms are balanced 1:1, 
Epanova: Placebo (corn oil) on top of a background of standard care (statin therapy).  
It is estimated there are about 15 scheduled clinic visits, refer to Table 1 Schedule of 
Procedures.  There will be up to 3 Screening visits, depending on the need for repeated 
laboratory sample assessments or statin/ezetimibe adjustment.  During the Screening period, 
patients will maintain a stable diet, and after randomization, be willing to adhere to the 
National Cholesterol Education Program Therapeutic Lifestyle Changes or equivalent diet.  
Patients who meet all Inclusion Criteria and no Exclusion Criteria will be randomized.  The 
randomization visit will be Month 0 followed by 11 treatment visits at Months 3, 6, 12, 18, 24, 
30, 36, 42, 48, 54 and 60.  There will be a 3-week follow-up visit after an early termination 
(ET) visit for those patients who undergo early permanent investigational product (IP) 
discontinuation due to a serious adverse event (SAE).  
 
 


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19 
Table 1 
Schedule of Procedure 
Study Period 
Screening2 
Randomization and 
treatment 
EOT/ET 
EOT/ET 
Follow-up 
for SAE 
Visit1 
1 
1
a 
1b 
2 3 
4 
5 
6 – 12 
13 
14 
Month (±2 
weeks) 
 
 
 
0 3 
6 
12 
18, 24, 
30, 36, 
42, 48 
and 54 
6015 
3 weeks 
after 
EOT/ET 
for SAE17 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
X 
X 
 
 
 
 
 
 
Prior Medications X 
X 
X 
X 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
X 
 
X 
 
Clinical 
Assessments3 
X 
X 
X 
X X 
X 
X 
X 
X 
 
Fasting Lipid 
Panel4,5 
X 
X 
X 
X 
 
 
X1
3 
X13 
X13 
 
Hemoglobin A1c 
X 
 
 
X 
 
 
X1
3 
X13 
X13 
 
Eligibility 
Review 
X 
X 
X 
X 
 
 
 
 
 
 
hs-CRP 
X 
 
 
X 
 
 
 
 
X 
 
Serum 
Chemistry6 
X 
 
 
X 
 
 
X 
X7 
X7 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
Urine Pregnancy 
Test8 
X 
 
 
 
 
 
 
 
 
 
Fasting Plasma 
Glucose 
 
 
 
X 
 
 
X1
3 
X13 
X13 
 
Hematocrit 
 
 
 
 
 
 
X1
3 
X13 
X13 
 
ECG 
 
 
 
X 
 
 
 
 
 
 
Fasting Special 
Lipid Markers4,9 
 
 
 
X 
 
 
X 
 
X 
 
Plasma and RBC 
Fatty Acids4,10 
 
 
 
X 
 
 
X 
 
X10 
 
Fasting CV Risk 
Markers4,11 
 
 
 
X X 
 
 
 
 
 
Genetic sample14 
 
 
 
X 
 
 
 
 
 
 


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20 
Counseling on 
TLC or 
Equivalent Diet 
X 
 
 
 
 
 
 
 
 
 
AEs, 
Concomitant 
Medications and 
Endpoint 
Assessments12 
 
 
 
 
X 
X 
X 
X 
X16 
X18 
Telephone Calls12 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
Dispense IP 
 
 
 
X X 
X 
X 
X 
 
 
Assess IP 
Compliance 
 
 
 
 
X 
X 
X 
X 
X 
 
AE = adverse event;  
EOT = End of treatment; EOT is defined for patients who 1) permanently discontinue IP before the study has 
ended but agree for further follow-up assessments (on-site visits or telephone or via third party) until end of study 
2) complete Visit 12 (Month 60) and have not discontinued IP early; 
ET = Early Termination. ET is defined for patients who permanently discontinue IP before the study has ended 
and decide not to participate with any follow-up assessments (on-site visits or telephone or via third party); 
TSH = thyroid stimulating hormone;  
hs-CRP = high-sensitivity C-reactive protein;  
ECG = electrocardiogram;  
CV = cardiovascular;  
TLC = Therapeutic Lifestyle Changes;  
IP = Investigational Product.  
RBC= red blood cells 
1. If fasting is not normal routine clinical practice, informed consent should be obtained prior to 
request for fasting for the Screening visit. If this is the case, the Screening visit should be split 
into 2 separate visits with informed consent obtained and IWRS accessed to obtain the patient 
number at the initial visit; and all other procedures obtained at the subsequent visit. In the 
event that the Screening visit is split into 2 separate visits, the screening visit lab draw must be 
completed within 3 days.  At any subsequent visit, if the patient did not fast for the 
recommended 9-14 hours, the fasted lab may be drawn the next day. 
2. If at Visit 1 the patient’s TG, LDL-C, and HDL-C meet the inclusion criteria and the patient 
has been on a stable diet and has met all other inclusion criteria and none of the exclusion 
criteria the patient should return within 2 weeks for randomization at Visit 2.   
If at Visit 1 the patient requires an adjustment to their statin regimen and/or a washout of other 
excluded lipid medications, the patient should return 4-6 weeks later to have their lipids re-
drawn at Visit 1a. 
If at Visit 1 the patient does not require an adjustment to their statin regimen and/or a washout 
of other excluded lipid medications and either the patient’s TG and/or HDL-C are borderline: 
TG  >160 - 179 mg/dL (>1.81 – 2.02 mmol/L) or TG ≥500 and <575 mg/dL (>5.65 and <6.49 
mmol/L) and/or HDL-C ≤45 mg/dL (1.17 mmol/L) for men and ≤50 mg/dL (1.30 mmol/L) for 
women, the patient can return within 2 weeks later to have all lipids re-drawn at Visit 1a.  


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21 
If at Visit 1 the patient does not require an adjustment to their statin regimen and/or a washout 
of other excluded lipid medications, and TG and HDL-C values are outside of borderline 
boundaries, the patient is considered screen failed. 
The TG, LDL-C and HDL-C results from Visit 1a will be used to determine eligibility in the 
same way as for Visit 1.  If re-drawn TG and HDL-C values are again borderline (as above), 
lipids can be repeated once more at Visit 1b to determine eligibility. Note that all lipid 
parameters qualifying for randomization should be obtained from the same visit. 
The same process as for Visit 1a is applied for Visit 1b. If the TG, LDL-C and HDL-C criteria 
are not met after Visit 1b, the patient should be screen failed. 
Please note the possibility to rescreen in the some situations, please see protocol section 6.4  
3. Includes height (Visit 1 only), waist circumference and weight (Visit 1, 5, 7, 9, 11, 13 only), 
blood pressure, and heart rate.  
4. Fasting blood samples should be drawn after the recommended 9-14 hour fast. 
5. Lipid panel includes serum TG, TC, calculated LDL-C (in patients with triglycerides > 400 
mg/dl LDL-C will be directly measured), HDL-C, calculated non-HDL-C, VLDL-C and TC: 
HDL-C ratio. 
6. Serum chemistry includes creatine kinase, ALT, AST, total and direct bilirubin, and creatinine. 
Glomerular Filtration Rate (GFR) will be calculated only at Visits 1 and 5 
7. Only ALT, AST and bilirubin will be analyzed, and only at Visits 7, 9, 11 and 13. 
8. Females of childbearing potential only (see Exclusion No. 17). 
9. Special lipid markers include serum apolipoprotein B-100 (Apo B-100), and apolipoprotein C-
III (Apo C-III).  
10. Plasma and RBC fatty acids (EPA, DHA, DPA and AA) will be measured from the 
recommended 9-14 hour fasting samples. Note: Plasma and RBC assessments are performed 
only at Visits 2 and 5, or ET before Visit 5. 
11. Blood samples will be collected for future analyses on a subset of patients located in the US, 
of lipid fractions, inflammatory markers and other CV markers that may be identified during 
the course of the study. 
12. In addition to these scheduled procedures, a well-being phone call will be made every 6 
months (±2 weeks) starting after Visit 4 that will occur at Months 9, 15, 21, 27, 33, 39, 45, 51, 
and 57, except at scheduled visits, to question about adverse events, endpoint assessment, 
changes in medications and any major issues with the IP (losses or noncompliance). For 
further assessment of any identified potential or confirmed AE, a physical examination should 
be carried out if clinically appropriate. 
13. Fasting lipid panel, Hb A1c, fasting plasma glucose and hematocrit will be measured annually 
at Visits 5, 7, 9, 11 and 13. 
14. Genetic samples will be collected for future analysis on approximately 2000 patients in the 
US, see protocol Appendix F for details.The sample should preferably be taken at Visit 2. If 
for any reason the sample is not drawn at Visit 2, it may be taken at any visit until the last 
study visit. 
15. Patients who permanently discontinue taking IP for any reason will be asked to continue the 
regular study visits after the scheduled ET visit and (for permanent discontinuation of IP due 


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22 
to SAE) the 3-week Follow-up visit unless they withdraw consent for further participation and 
the use of their data. In this case, patient will be asked to provide written documentation (when 
possible) of withdrawal of consent and complete the ET Visit procedures only. If the patient is 
permanently discontinued from study medication and agrees to continue in the protocol, then 
the patient, if possible, should have regularly scheduled study visits.  
16. Patients who have early permanent discontinuation of IP due to an SAE and have an ET visit, 
will be required to schedule a 3-week Follow-up (Visit 14) to assess the SAE and concomitant 
medications. The patients should be asked to continue  the regular study visits as described 
above thereafter. 
17. Visit window is ±1 week for Visit 14 (ET/EOT Follow-up for SAE). 
18. At Follow-up Visit 14, other assessments from the procedures table may be performed upon 
investigator discretion to further evaluate the SAE causing ET or for SAE identified at EOT. 
 
1.3 
Number of patients 
This event-driven study is designed to have approximately 90% power to detect a 15% 
reduction in risk of primary efficacy 5-point MACE rate (hazard ratio [HR] = 0.85) for 
patients treated with Epanova when compared to placebo (corn oil), on top of a background of 
standard care (statin therapy).  With an overall type I error rate (alpha level) of 5%, a total of 
1,600 primary efficacy events are required for this study.   
The enrolment of patients with documented CVD will be ≥50% of all randomized patients; the 
enrolment of patients with risk factors only (primary prevention) will be less than 50% of all 
randomized patients; these proportions will be monitored via interactive web response system. 
Assuming total study duration of 4.5 years and a placebo (corn oil) event rate of 
approximately 4% per year, a sample size of 13,000 patients (6,500 per treatment arm) is 
required. 
2. 
ANALYSIS SETS 
2.1 
Definition of Analysis Sets 
2.1.1 
Full Analysis Set (FAS)  
The FAS will contain all patients who were randomized.  Patients will be analyzed according 
to the treatment arm to which they were randomized (not according to the treatment arm 
actually received). If randomized more than once, the enrolment code at first randomization 
will be included in the FAS. 
The notation of FAS will be used interchangeably with the notation of intent-to-treat 
population from the protocol, and this change is also documented in Section 6.  


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2.1.2 
Safety Analysis Set (SAF) 
The SAF will contain all randomized patients who received at least 1 dose of IP.  Patients will 
be analyzed according to their randomized treatment. Patients who are given treatment 
different to their randomized treatment will be listed in the protocol deviations summary. 
2.2 
Deviations 
As defined by ICH E3, protocol deviations are any change, divergence, or departure from the 
study design or procedures defined in the protocol. Important protocol deviations are those 
protocol deviations that may significantly impact the completeness, accuracy, and/or 
reliability of the study data or that may significantly affect a subject’s rights, safety, or 
wellbeing.  
All important protocol deviations will be summarized and listed by randomized treatment arm. 
Protocol deviations pertaining (but not limited) to the following categories are considered to 
be Important:  
x Patients who were randomized but did not meet inclusion and exclusion criteria. 
x Patients who received disallowed concomitant medications and dietary products. 
x Patients who either enrolled into the study more than once or enrolled into another 
interventional (pharmacologic agent or device - observational/non-interventional trial 
enrolment is permitted) clinical trial in parallel to this study. 
x Patients who received the wrong study treatment at any time during the study. 
x Patients who took < 80% of total scheduled study treatment whilst on study treatment. 
x Patients who become pregnant and for whom IP is not discontinued. 
x Patients with ALT or AST ≥ 3xULN and total bilirubin (BILI) ≥ 2xULN elevation 
(and in which the elevation in transaminases precedes or on the same day as the 
elevation in BILI) on or after the first dose of study medication for whom IP is not 
discontinued. 
x Patients who had no written informed consent provided. 
This list is not intended to be all-inclusive. Other protocol deviations may be identified as 
important by the study team during on-going review of the study prior to treatment 
unblinding. Important protocol deviations will be documented in a separate PD plan. 
FAS will be used for the primary analysis therefore protocol deviations will not imply 
exclusion from the analysis. No analysis on a Per-Protocol population is planned for this 
study. 


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3. 
PRIMARY AND SECONDARY VARIABLES 
3.1 
Adjudication of clinical endpoints 
An independent Clinical Events Committee (CEC) will systematically identify and adjudicate 
all components of the primary and secondary endpoints as well as the tertiary heart failure 
event endpoint.  Events will be analyzed per pre-specified definitions provided in a separate 
CEC charter and will be agreed upon by the CEC and the Executive Committee.  Standardized 
definitions for endpoint events are provided by the Standardized Data Collection for 
Cardiovascular Trials Initiative (CSP Appendix C: Standardized Definitions for Endpoint 
Events in Cardiovascular Trials).  
In this study, 5-point MACE is defined as a composite measure of cardiovascular death, non-
fatal myocardial infarction, non-fatal stroke, emergent/elective coronary revascularization and 
hospitalization for unstable angina.  Primary efficacy endpoints in the study will not be 
reported to health authorities as SAEs.  Events identified as suspected MACE-endpoints will 
be reported on a separate event form in the electronic case report form (eCRF) to support 
central adjudication.  Clinical data reported as adverse events (AEs)/SAEs will be reviewed 
for possible endpoint events. 
3.2 
Baseline 
Baseline is defined as the last non-missing measurement taken on or prior to date of 
randomization (including unscheduled assessments).  
3.3 
Efficacy variables 
The efficacy objectives will be evaluated using analysis of time from randomization to the 
first event, using only events positively adjudicated by CEC. Events with undetermined 
adjudication assessment will be considered as positively adjudicated. Deaths with 
undetermined cause will be counted as cardiovascular deaths for primary composite endpoint 
as well as all secondary endpoints involving cardiovascular death. Time will be calculated as 
the number of days plus 1 between the date of randomization and date of the first occurrence 
of the event, or, if no event has occurred, the date of censoring will be used.  Censoring rules 
are further described in Section 4.2.1.3. 
In order to facilitate describing various time-to-event (TTE) analyses the following table 
accounts for all endpoints. 
 


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Table 2 
Summary of time-to-events (TTE) endpoints  
Description 
Primary 
(MACE) 
Secondary  
Tertiary3  
KEY1  
Other (exploratory) 2 
cardiovascular death4 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
cardiac death5 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
non-fatal myocardial 
infarction 
X 
X X 
 
 
 
 
 
X 
 
 
 
 
 
 
myocardial infarction 
(fatal or non-fatal) 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
non-fatal stroke 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
stroke (fatal or non-
fatal) 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
emergent/elective 
coronary 
revascularization 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
hospitalization for 
unstable angina6 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
all-cause death 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
atrial fibrillation 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
coronary stent 
thrombosis 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
systematic 
thromboembolism7 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
venous 
thromboembolism/ 
pulmonary embolism 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
heart failure 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
CV-related 
hospitalization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1Note: Key secondary endpoints are those that are tested in a hierarchical order to preserve the alpha level. The 
Primary endpoint and all key secondary endpoints are also evaluated in the subgroup of patients with established 
cardiovascular disease at baseline. Those tests are also performed under Type I error control, see Section 3.3.4 
for the exact testing hierarchy. 
2Note: Other secondary endpoints are the individual components of the primary composite, which are not part of 
the hierarchical testing procedure and therefore should be regarded as exploratory. 
3Note: Tertiary endpoints are exploratory endpoints which do not consist of components of the primary. 
4Note: Cardiovascular death includes death resulting from: an acute myocardial infarction (fatal or non-fatal 
myocardial infarction), sudden cardiac death, death due to heart failure, death due to stroke, death due to 
cardiovascular procedures, death due to cardiovascular hemorrhage, and death due to other cardiovascular 
causes. Deaths with undetermined cause are included in the cardiovascular category. 
5Note: Cardiac death includes death resulting from: an acute myocardial infarction, sudden cardiac death, death 
due to cardiovascular procedures. 
6Note: The analysis date for the start of the hospitalization for unstable angina is the date that the patient was 
hospitalized for hospitalization for unstable angina 
7Note: Systemic thromboembolism includes arterial stent (except coronary) thrombosis 


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3.3.1 
Reference start date and study day 
Study Day will be calculated from the reference start date and will be used to show start/stop 
day of assessments and events.   
Reference start date is defined as the date of randomization, Day 1 is the day of 
randomization, and Day -1 is the day prior to the date of randomization.  
x If the date of the event is on or after the reference date then:  
Study Day = date of event – date of randomization + 1 day. 
x If the date of the event is prior to the reference date then:  
Study Day = date of event – date of randomization. 
When converting the number of days to other units, the following conversion factors will be 
used: 1 year = 365.25 days; 1 month = 30.4375 days. 
3.3.2 
TTE calculation 
Unless noted otherwise, the reference start day for TTE analysis will be based on the date of 
randomization:  
x TTE (months) = (date of event – date of randomization + 1 day)/30.4375 
3.3.3 
Primary efficacy variable 
The primary outcome measure is time to first occurrence of any component of the composite 
of 5-point MACE events (cardiovascular death, non-fatal myocardial infarction, non-fatal 
stroke, emergent/elective coronary revascularization or hospitalization for unstable angina; 
Table 2)   
An index myocardial infarction or stroke can lead to a death occurring at a later time point and 
therefore the time to event calculation for fatal myocardial infarctions and fatal strokes will be 
defined as follows: 
Time to event will be calculated as the time from date of randomization to the date on which 
the index event (myocardial infarction or stroke) leading to death happened, if occurring on a 
separate day than death. If death occurred on the same day, this is the fatal event date used to 
calculate time to event. 
3.3.4 
Secondary efficacy variables 
The key secondary variables, which will be tested in hierarchical order, are time-to the first 
occurrence of:  


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1. The composite measure of MACE that include the first occurrence of cardiovascular 
death, non-fatal myocardial infarction, non-fatal stroke, emergent/elective coronary 
revascularization, or hospitalization for unstable angina in the subgroup of patients 
with established cardiovascular disease at baseline. 
2. The composite measure of cardiovascular events that include the first occurrence of 
cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. 
3. The composite measure of cardiovascular events that include the first occurrence of 
cardiovascular death, non-fatal myocardial infarction and non-fatal stroke in the 
subgroup of patients with established cardiovascular disease at baseline. 
4. The composite measure of coronary events that include the first occurrence of cardiac 
death (including death due to acute myocardial infarction, sudden cardiac death and 
death due to cardiovascular procedures), non-fatal myocardial infarction, 
emergent/elective coronary revascularization, or hospitalization for unstable angina. 
5. The composite measure of coronary events that include the first occurrence of cardiac 
death (including death due to acute myocardial infarction, sudden cardiac death and 
death due to cardiovascular procedures), non-fatal myocardial infarction, 
emergent/elective coronary revascularization, or hospitalization for unstable angina in 
the subgroup of patients with established cardiovascular disease at baseline. 
6. Cardiovascular death. 
7. Cardiovascular death in the subgroup of patients with established cardiovascular 
disease at baseline. 
8. All-cause death. 
9. All-cause death in the subgroup of patients with established cardiovascular disease at 
baseline. 
Other secondary variables are time-to:  
x emergent/elective coronary revascularization 
x hospitalization for unstable angina 
x fatal or non-fatal myocardial infarction 
x non-fatal myocardial infarction 
x fatal or non-fatal stroke 
x non-fatal stroke  
Time to event calculations for fatal myocardial infarctions and strokes will be handled as 
detailed in Section 3.3.3.  
This applies to endpoints where myocardial infarctions and/or strokes are included. In 
analyses of time to cardiovascular death or time to death, the time to event calculation will use 
the actual death date. 
For an overall look of the secondary efficacy variables, please refer to Table 2. 


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3.3.5 
Tertiary outcome variables 
Tertiary variables include: 
x Time to first occurrence of new onset atrial fibrillation. 
x Time to the composite measure of total thrombotic events that include the first 
occurrence of documented coronary stent thrombosis, any systemic thromboembolism 
including arterial stent (except coronary) thrombosis or venous thromboembolism, i.e. 
deep vein thrombosis and/or pulmonary embolism. 
x Time to first occurrence of a heart failure event. 
x The second, third, fourth, and total number occurrences of major cardiovascular events 
(primary and secondary outcome measures). 
x The time to first CV-related hospitalization. 
CV-related hospitalization is defined as any hospitalization related to an adjudicated endpoint 
(MACE or heart failure) or a cardiovascular AE. A cardiovascular AE is defined by the list of 
Preferred Terms in Appendix 6. 
The time to hospitalization will be from randomization to admission according to the 
calculation in Section 3.3.2. If admission date is incomplete or missing, it will for purposes of 
analysis be imputed according to the following rules: 
x If the admission date is incomplete, the earliest possible date is compared to the AE 
onset date and the latest of these dates is imputed. The earliest possible date is defined 
as the first day of the month if only the day part of the admission date is missing or 
January 1st if both day and month are missing from the admission date. 
x If admission date is missing, the AE onset date is imputed. 
For an overall look of the tertiary efficacy variables, please refer to Table 2. 
3.3.6 
Biomarker endpoints 
Biomarker parameters include: 
x Non-high-density lipoprotein cholesterol, triglycerides and high-density lipoprotein 
cholesterol; 
x Total cholesterol, very low-density lipoprotein cholesterol, total cholesterol: high-
density lipoprotein cholesterol ratio and low-density lipoprotein cholesterol; 
x Apolipoprotein B-100 and apolipoprotein C-III; 


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x Eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid and arachidonic 
acid in plasma and red blood cells; 
x High-sensitivity C-reactive protein.  
Low-density lipoprotein cholesterol will be directly measured in patients with triglycerides > 
400 mg/dl. For the other patients it will be calculated. 
A fasting lipid panel including serum triglycerides, total cholesterol, low-density lipoprotein 
cholesterol, high-density lipoprotein cholesterol, calculated non-high-density lipoprotein 
cholesterol, very low-density lipoprotein cholesterol and total cholesterol: high-density 
lipoprotein cholesterol ratio will be measured at Analysis Visits 5 (Month 12), 7 (Month 24), 9 
(Month 36), 11 (Month 48), and 13 (Month 60 or end of study).  
The lipid biomarkers apolipoprotein B-100 and apolipoprotein C-III will be measured at 
Analysis Visit 5 (Month 12) and 13 (Month 60 or end of study). The fatty acids 
eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and arachidonic acid for 
both plasma and red blood cells will be measured at Analysis Visit 5 (Month 12) and at early 
termination visit if it occurs before Analysis Visit 5 (Month 12). High-sensitivity C-reactive 
protein will be measured at end of treatment. 
3.4 
Safety variables 
The safety variables that will be analyzed in the study are the following: 
x AEs that are considered serious, lead to discontinuation of IP or result in a dose 
modification, new onset diabetes mellitus (Section 3.4.3), TIA, PHL cases or bleeding-
related events (Section 3.4.2) 
x Laboratory tests as hematology and serum chemistry (Section 3.4.4)  
x Physical examinations (Section 3.4.7) and vital signs (Section 3.4.5); 
x Urine pregnancy test (Section 3.4.4);  
x Overdoses (Section 3.4.8). 
 
3.4.1 
 Adverse Events 
In this study, only AEs that are considered serious, lead to discontinuation of IP or result in 
a dose modification, overdose, new onset of diabetes mellitus, TIA, PHL cases or bleeding-
related events will be captured starting after randomization through the final visit. 
SAEs will be recorded at all visits for the patients who prematurely discontinue IP. Non 
serious AEs will be collected until the final visit but no more than 30 days after the last dose 
of IP. 
 


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3.4.1.1 
Severity 
Severity is classified as mild, moderate and severe.  A missing severity will be classified as 
severe in summary tables by severity.  If a patient reports the same AE more than once 
within that system organ class (SOC) and preferred term (PT), the AE with the worst case 
severity will be used in the corresponding severity summaries. 
3.4.1.2 
Relationship to study medications 
Relationship, as indicated by the Investigator, is classified as “not related”, “suspected” and 
“related”.  AEs reported by investigator as "suspected" or "related" to study medication are 
categorized as “related” for AE analyses.  AEs with a missing relationship will be regarded 
as “related” to study medication.  If a patient reports the same AE more than once within 
that SOC and PT, the AE with the worst case relationship to study medication will be used 
in the corresponding relationship summaries.  
3.4.1.3 
AEs leading to discontinuation of IP 
AEs leading to discontinuation of IP will be identified if the “action taken with study 
treatment” is “drug withdrawal” from eCRF AE page. 
3.4.1.4 
TIAs 
TIAs are those AEs with preferred term=” TRANSIENT ISCHAEMIC ATTACK”.  
3.4.1.5 
AEs leading to dose reduction 
AEs leading to dose reduction will be identified if the “action taken with study treatment” is 
“dose reduced” from eCRF AE page. 
3.4.1.6 
AEs leading to IP interruption 
AEs leading to IP interruption will be identified if the “action taken with study treatment” is 
“drug interrupted” from eCRF AE page. 
3.4.1.7 
SAE 
SAEs are those events recorded as “yes” to the question of “serious event” on the AE page of 
eCRF.  
Events that are related to the primary efficacy outcomes will not be reported as SAEs, 
including all cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal 
stroke, hospitalization for unstable angina, or events associated with emergent/elective 
emergent/elective coronary revascularization procedure. 
3.4.1.8 
Missing dates for AEs 
For AEs with a missing or partially missing onset date the following rules apply. 
o If only the day part of the AE onset date is missing and occurs in the same month 
and year as the date of randomization, the date of randomization will be used as the 


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onset date of the AE.  Otherwise, the first day of the month will be used to 
complete the onset date of the AE.  
o If the day and month parts of the AE onset date are missing and occur in the same 
year as the date of randomization, the date of randomization will be used as the 
onset date of the AE.  Otherwise, January 1 will be used to complete the onset date 
of the AE. 
o If the AE onset date is completely missing, the date of randomization will be used 
as the onset date of the AE. 
For AEs with a missing or partially missing end date the following rules apply. 
o If only the day part of the AE end date is missing and occurs in the same 
month and year as the date of last contact, the date of last contact will be 
used as the AE end date. Otherwise, the last day of the month will be used 
to complete the AE end date. 
o If the day and month parts of the AE end date are missing and occur in the 
same year as the date of last contact, the date of last contact will be used as 
the AE end date.  Otherwise, December 31 will be used to complete the AE 
end date. 
o If the AE end date is completely missing, the date of last contact will be 
used as the AE end date.  
Missing or partially missing onset date or end date will be imputed only for analysis purpose 
but will remain as missing or partially missing in patient listings. 
3.4.2 
Bleedings 
The investigator will report any blood loss in the eCRF and the bleedings will be classified 
according to the thrombolysis in myocardial infarction (TIMI) non-coronary artery bypass 
graft bleeding definitions (Mehran et al. 2011): major, minor, requiring medical attention or 
minimal.  
Major 
-Any intracranial bleeding (excluding microhemorrhages) 
-Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥ 5 g/dL (0.78 
mmol/L) 
-Fatal bleeding (bleeding that directly results in death within 7 days) 
Minor 
-Clinically overt (including imaging), resulting in hemoglobin drop of 3 to <5 g/dL 


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Requiring medical attention 
-Any overt sign of hemorrhage that meets one of the following criteria and does not meet 
criteria for a major or minor bleeding event, as defined above 
-Requiring intervention (medical practitioner-guided medical or surgical treatment to stop or 
treat bleeding, including temporarily or permanently discontinuing or changing the dose of a 
medication or study drug) 
-Leading to or prolonging hospitalization 
-Prompting evaluation (leading to an unscheduled visit to a healthcare professional and 
diagnostic testing, either laboratory or imaging) 
Minimal 
-Any overt bleeding event that does not meet any criteria above. 
The bleeds are categorized into the classifications programmatically. The rule set for these 
classifications based on the data within the Bleed eCRF form can be found in Appendix 4. If 
the available data are not enough to determine the TIMI bleed classification, the bleeding 
event will be reported as “Bleeding event not categorizable due to missing data”. A summary 
of bleeds location will be included to allow a better evaluation of uncategorized events.  
3.4.3 
New onset of diabetes mellitus during the study 
New onset of diabetes mellitus during the study is identified programmatically among patients 
without HbA1c >= 6.5% (48 mmol/mol) at the last measurement on or before the first dose of 
study medication and without medical history or AE with start date before the first dose of 
study medication indicating diabetes. The preferred terms to be used are those included in the 
SMQ Hyperglycaemia/new onset diabetes mellitus (narrow scope). 
New onset of diabetes mellitus during the study is identified according to at least one of the 
following criteria 
x AE with start date on or after the first dose of study medication and indicating 
diabetes. The preferred terms to be used are those included in the SMQ 
Hyperglycaemia/new onset diabetes mellitus (narrow scope) 
x Two consecutive values of fasting plasma glucose of ≥7mM (126 mg/dL) on or 
after the first dose of study medication 
x Two consecutive values of HbA1c ≥6.5% (48 mmol/mol) on or after the first 
dose of study medication 
If more than one of the above criteria are met, the earliest date among the onset date of the 
earliest AE indicating diabetes, the date of the earliest fasting plasma glucose of ≥7mM (126 


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mg/dL) confirmed by a consecutive result and the date of the earliest HbA1c  ≥6.5% (48 
mmol/mol) confirmed by a consecutive result will be considered as the onset date of the event 
of new onset of diabetes mellitus.  
MedDRA dictionary 22.1 and corresponding SMQ will be used. 
3.4.4 
Laboratory tests 
Laboratory tests include hematology, serum chemistry, urine pregnancy data, refer to 
Appendix 2.   
Quantitative laboratory measurements will be compared with the relevant laboratory reference 
ranges and categorized as low, normal or high. 
If a laboratory test is reported as above or below the limit of quantification (i.e., result 
includes operator >, ≥, <, or ≤), the limit of quantification will be used for analysis. The result 
with the operator will be reported in listings. 
Urine pregnancy tests, conducted only on women of childbearing potential, will be collected 
only once during Screening and will be analyzed by the site and recorded in the eCRF.   
3.4.5 
Vital signs 
Height (cm) is measured only once at Visit 1.   
The following measurements will be collected at multiple clinic visits: 
x Sitting systolic blood pressure (SBP, mmHg) and diastolic blood pressure (DBP, 
mmHg) 
There will be 3 blood pressure measurements, to be taken after at least 3 minutes of 
seated rest.  The 1st measurement will be ignored.  The average of the last 2 
measurements will be collected through eCRF and will be presented in summary 
tables. 
x Sitting heart rate (beats/minute) 
x Waist circumference (cm)  
x Weight (kg). 
3.4.6 
Electrocardiogram (ECG) 
A 12-lead ECG will be performed after patient has been supine at rest for at least 5 minutes at 
Visit 2.  Any clinically significant finding observed at Visit 2 will be included in the Medical 
History. 
The following baseline ECG parameters will be captured. 
x Heart rate (beats/minute) 


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x PQ interval (msec) 
x RR interval (msec) 
x QRS interval (msec) 
x QT interval with Bazett’s correction (msec) 
x Clinical significance: normal, clinically non-significant abnormal and clinically 
significant abnormal. 
3.4.7 
Physical examination  
A physical examination consisting of an evaluation of the head, neck, eyes, ears, nose, throat, 
chest, heart, lungs, abdomen, skin, extremities, and the neurological and musculoskeletal 
systems will be performed at Visit 1 and Visits 5 as well as on Visit 13/end-of-treatment/ET. 
The results of the Physical Examinations are not collected separately. Any clinically 
significant finding observed up to and including Visit 2 will be considered Medical History. 
Any new or worsened clinically significant finding observed after Visit 2 through Visit 
13/EOT/ET will be considered an adverse event. 
3.4.8 
Overdoses 
A dose of more than 8 g of IP (>8 capsules) during one day should be considered as an 
overdose and must be reported as a SAE. Overdoses will be identified using the appropriate 
flag “Occurred with overdose” in the eCRF “Adverse Events” form. 
3.5 
Additional variables 
3.5.1 
Demographic and other baseline characteristics 
The following demographic and patient baseline characteristics will be reported for this study: 
x Age (years) = (date of randomization - date of birth+1)/365.25, rounded down to 
the nearest integer; 
x Sex: male and female; 
x Race: American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or other Pacific Islanders, White, and Others; 
x Ethnicity (US residents only): Hispanic or Latino, not Hispanic or Latino, Not 
Reported, and Unknown; 
x Established cardiovascular disease at baseline: 
o Yes: patients that meet 1 or more of the atherosclerotic cardiovascular disease 
criteria as defined in Inclusion Criteria 3a; 


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o No:  patient that do not meet any of the Inclusion Criteria 3a. 
x Region: Asia, Australia & New Zealand, Europe, Latin America and North 
America.   
3.5.2 
Medical history 
Medical history conditions are defined as those conditions which stopped on or prior to the 
date of randomization at Visit 2, or were ongoing at the time of randomization.  
3.5.3 
Prior and concomitant medications 
Prior medications are those medications taken by the patient during the 4 weeks before Visit 1 
or during Screening and stopped on or prior to the date of randomization at Visit 2. 
Concomitant medications are medications, other than IP, that were ongoing at the date of 
randomization at Visit 2 or started or stopped by the patient after the date of randomization at 
Visit 2.  If it is not possible to define the medication to be prior or concomitant, the 
medication will be classified by the worst case; i.e. concomitant. 
3.5.3.1 
Missing dates for medications 
For medications with a missing or partially missing start date the following rules apply. 
o If only the day part of the medication start date is missing and occurs in the 
same month and year as the date of randomization, the date of randomization 
will be used as the start date of the medication.  Otherwise, the first day of the 
month will be used to complete the start date of the medication.  
o If the day and month parts of the medication start date are missing and occur 
in the same year as the date of randomization, the date of randomization will 
be used as the start date of the medication.  Otherwise, January 1 will be used 
to complete the start date of the medication. 
o If the medication start date is completely missing, the date of randomization 
will be used as the start date of the medication. 
For medications with a missing or partially missing end date the following rules apply. 
o If only the day part of the medication end date is missing and occurs in the 
same month and year as the date of last study contact, the date of last study 
contact will be used as the end date of the medication.  Otherwise, the last day 
of the month will be used to complete the end date of the medication.  
o If the day and month parts of the medication end date are missing and occur in 
the same year as the date of last study contact, the date of last study contact 


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will be used as the end date of the medication.  Otherwise, December 31 will 
be used to complete the end date of the medication.  
o If the medication end date is completely missing, the medication will be 
assumed as ongoing. 
The end date should remain null for medications that are ongoing. 
3.5.4 
Duration of exposure  
Duration of exposure to study medication will be based on the first and last dose date:   
x Duration of exposure (months) = (date of last dose – date of first dose + 1 
day)/30.4375.  
Date of first dose will be taken from the first “start date of study medication” from eCRF 
“Exposure” form.  Date of last dose will be the latest of the “date of last dose” from eCRF 
“Disposition – Treatment” form or the “end date of study medication” from eCRF “Exposure” 
form.  Intermittent missed doses will not be taken into consideration. 
An additional summary will be produced that will account for interruptions. 
For this summary, duration of exposure will be based on the first and last dose date for each 
period without treatment interruption: 
Duration of exposure (months) = ∑(end date of study medication – start date of study 
medication + 1)/30.4375 
The “start/end date of study medication” for each period without treatment interruption will be 
taken from eCRF “Exposure” form. 
3.5.5 
Treatment compliance 
Study medications will be administered in a double-blinded fashion, 4 grams once daily.  If 
the patient has intolerability symptoms with study drug dose of 4 g/day, a dose reduction may 
be required. A temporary stop of study treatment may be necessary if symptoms persist 
despite dose reduction.  
Derivation of compliance will be based on the number of capsules dispensed and returned as 
reported in the eCRF “Drug Accountability” form and on the prescribed dose as collected in 
the eCRF “Exposure” form.   
Compliance will be calculated as the number of capsules taken divided by the prescribed 
number of capsules that were expected to be taken considering interruptions and dose 
reductions. This value is expressed as a percentage on per-patient basis first, then summarized 
overall. 
The number of capsules taken is derived as the total number dispensed – total returned. 


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The prescribed number of capsules is the number that would have been taken, considering  
interruptions and dose reductions.  For patients with no treatment interruption and no dose 
reduction, the prescribed number of capsules is derived as (last dose date – first dose date + 1 
day) x 4 capsules per day.  
In case of treatment interruption, any day of treatment interruption will be subtracted from the 
difference (last dose date – first dose date + 1 day). Since as per CSP only temporary 
interruptions which last 7 or more sequential days should be reported, shorter interruptions are 
missed and will not been considered in this compliance algorithm. For this reason, 
underestimates of compliance might be possible.  
In case of dose reduction, the period between first dose date and last dose date + 1 day will be 
fragmented in multiple segments each with a corresponding prescribed dose. Dose reduction 
start date will be the day of dose reduction as collected in the eCRF “Exposure” form. Dose 
reduction end date will be the date of the following change in prescribed dose as collected in 
the eCRF “Exposure” form. If there are no further change in prescribed dose, then the last 
dose prescribed will be considered as prescribed until end of treatment. 
Once defined the start and stop date of each segment, the prescribed number of capsules for 
each segment is derived as (stop date of segment– start date of segment) x number of capsules 
per day as prescribed in the segment. The prescribed number of capsules is derived as the sum 
of the prescribed dose at each segment. 
Study medications will be dispensed in bottles; each bottle contains 60 capsules, unless noted 
otherwise.  Only full bottles will be dispensed each time.   
3.5.6 
End-of-Study (EOS) assessment  
Patients who discontinue IP but agree to participate with any follow-up assessments (visit or 
telephone) will undergo the ET visit, and the 3-week Follow-up visit for discontinuation from 
an SAE if applicable and brought in for an EOS visit at study completion.  Unless otherwise 
specified, EOS assessment is defined as the last non-missing measurement for an event of 
interest, after baseline but on or prior to the latest of ET visit or EOS visit (including 
unscheduled assessments).   
3.6 
Study Completers 
To properly describe the completeness of follow-up of primary outcome measure, the 
following completer categories are defined:  
x Patients with complete follow-up of primary outcome measure (i.e. first MACE event) 
This category includes all patients considered as under complete observation for 
primary outcome measure collection. This includes all patients except those who 
discontinued the study prior to observing a MACE event for other reasons than death 
or study terminated by sponsor. 


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x Patients with complete follow-up of total MACE events (first and subsequent MACE 
events) 
This category includes all patients considered as under complete observation for total 
MACE events. This is a subset of category 1 excluding patients dying during the study 
and patients who discontinued the study at any time during the study except those who 
discontinued the study due to the study being terminated by the sponsor.  
x Patients who complete study schedule 
This category includes all patients completing their EOT visit at their planned Month 
60 visit prior to the date of early study termination by the sponsor.. 
Patients with premature IP discontinuation who have consented to follow-up only through 
medical records will be considered as under observation for endpoint collection but are not 
considered as having completed study schedule. 
4. 
ANALYSIS METHODS 
4.1 
General principles 
For qualitative variables, the population size (N for sample size and n for number of patients 
with available data) and the percentage (of available data) for each class of the variable will be 
presented.  Quantitative variables will be summarized using descriptive statistics, unless 
otherwise stated, including n, mean, standard deviation, Q1, median, Q3, minimum, and 
maximum values as appropriate.  Median will be presented in conjunction with Q1 and Q3.  
Categorical variables will be summarized as the number of patients and percentages.  All 
summaries will be based on all randomized patients apart from safety summaries that will be 
based on all patients who had taken at least one dose of IP; hence missing values will also be 
reported as a separate level.  Unless noted otherwise, percentages will be based on the count 
of patients with missing and non-missing values, and will be presented as 0 in case of zero 
counts.  Extra measurements (such as unscheduled or repeated assessments) will not be 
included in the descriptive statistics, unless otherwise specified, but will be included in patient 
listings.   
The default significance level will be 5%; confidence intervals (CIs) will be 95% and all tests 
will be two-sided, unless otherwise specified in the description of the analyses.  P-values will 
be presented with 3 decimal places.  P-values will be presented as <0.001 if less than 0.001 or 
>0.999 if greater than 0.999 before rounding.  No multiplicity adjustments will be made to the 
confidence intervals as they will be interpreted descriptively and used as measures of 
precision. 
All summaries and analyses will be conducted using at least SAS® 9.4.  
4.1.1 
Study Periods 
The following periods are defined in the study:  


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x Screening period: This period starts on Screening Visit 1 date and ends prior to the 
start of treatment period. 
x Treatment period: This period starts on date of randomization and ends on the EOT 
visit either at Month 60 or at study closure. For patients who permanently discontinue 
IP before study has ended and decide not to participate with any follow-up assessments 
this period ends at the ET visit. 
x Follow-up period: This period is defined for those patients who undergo early 
permanent IP discontinuation due to a SAE and starts after the EOT/ET visit and ends 
3 weeks after Visit 14 (Follow-Up visit for SAE). 
4.1.2 
Visit Window and retests 
Summary tables will be presented by analysis visit (Table 3) defined based on the number of 
days from randomization.   
The following conventions will apply:  
x For summaries at a patient level, all values should be included, regardless of whether 
they appear in a corresponding visit based summary, when deriving a patient level 
statistic such as a maximum. 
x The time windows should be exhaustive so that data recorded at any time point has the 
potential to be summarized. Inclusion within the time window should be based on the 
actual date and not the intended date of the visit. 
x All scheduled and unscheduled visit data have the potential to be included in the 
summaries. 
x The window for the visits following baseline will be constructed in such a way that the 
upper limit of the interval falls half way between the two visits (the lower limit of the 
first post-baseline visit will be Day 2). If an even number of days exists between two 
consecutive visits then the upper limit will be taken as the midpoint value minus 1 day.   
x Data collected after the first dose of IP and up to the date of the last dose of IP + 10 
days will be considered on-treatment. 
x For visit based summaries 
o If there is more than one value per patient within a time window then the 
closest value to the scheduled visit date should be summarized, or the later, in 
the event the values are equidistant from the target visit day. In the event that 
two or more values are located on the same side of the target day at the same 
date and time and are the closest to the target day, the mean of the values 
should be summarized. Note: in summaries of extreme values all on-treatment 
post baseline values collected are used including those collected at unscheduled 
visits regardless of whether the value is closest to the target visit day. 
o Analysis visits will be defined based on the planned schedule for each 
parameter as defined in Table 3. 


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For laboratory assessments, the date of sample collection rather than the date of the visit will 
be considered.  
Table 3  
Analysis Visits by Visit Window 
Analysis Visit 
Nominal day 
Lower 
bound (day) 
Upper bound 
(day) 
Plasma and Red Blood Cells Fatty Acids 
Baseline 
1 
 
 
Month 12 
360 
2 
Last study day 
Special Lipid Markers 
Baseline 
1 
 
 
Month 12 
360 
2 
1080 
Month 60 
1800 
1081 
Last study day 
Liver Function Tests, Lipid Panel, HBA1c, Fasting Plasma Glucose, 
Hematocrit, Hemoglobin, Height, Weight, Waist Circumference 
Baseline 
1 
 
 
Month 12 
360 
2 
540 
Month 24 
720 
541 
900 
Month 36 
1080 
901 
1260 
Month 48 
1440 
1261 
1620 
Month 60 
1800 
1621 
Last study day 
Creatinine, Creatine Kinase, Glomerular Filtration Rate 
Baseline 
1 
 
 
Month 12 
360 
2 
Last study day 
high-sensitivity C-Reactive Protein 
Baseline 
1 
 
 
Month 60 
1800 
2 
Last study day 
Diastolic and Systolic Blood Pressure, Heart Rate 
Baseline 
1 
 
 
Month 3 
90 
2 
135 
Month 6 
180 
136 
270 
Month 12 
360 
271 
450 
Month 18 
540 
451 
630 
Month 24 
720 
631 
810 
Month 30 
900 
811 
990 
Month 36 
1080 
991 
1170 
Month 42 
1260 
1171 
1350 
Month 48 
1440 
1351 
1530 
Month 54 
1620 
1531 
1710 


Statistical Analysis Plan  
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Month 60 
1800 
1711 
Last study day 
 
Due to the early termination of the study, and that safety laboratory assessments are presented 
for on and off treatment, many patients will be off treatment at their final visit. As many of 
these values will be affected due to a study level decision, these visits will be analyzed 
separately to the visit windows with the visit name “Study terminated by sponsor” to 
minimize the impact of the study termination on the presentation of the safety laboratories 
(hematology and serum chemistry). 
4.1.3 
Common calculations 
For quantitative measurements, change from baseline to “Time X” will be calculated as:  
x Test Value at Time X – Baseline Value. 
Percent change from baseline to “Time X” will be calculated as: 
x (Test Value at Time X – Baseline Value)/Baseline Value × 100%. 
If baseline is not available, the change from baseline and percent change from baseline will 
not be calculated and will remain missing.   
4.1.4 
Imputation rules and missing data 
Date of last dose will be the latest of the “date of last dose” from eCRF “Disposition – 
Treatment” form or the “end date of study medication” from eCRF “Exposure” form.  
For doses with missing or partially missing start or stop dates the following algorithm will be 
applied starting from the imputation of missing or partially missing date of start of first dose 
and date of stop of last dose. 
The first dose start date will be imputed according to the following rules: 
x If only the day part of the start date is missing and occurs in the same month and year 
as the date of randomization, the date of randomization will be used as the start date of 
the dose. Otherwise, the first day of the month will be used to complete the start date 
of the dose. 
x If the start date is completely missing, the date of randomization will be used as the 
start date of the dose. 
The last dose stop date will be imputed according to the following rules:  
x If only the day part of the end date is missing and occurs in the same month and year 
as the earliest of the date of the informed consent to continue participation in the trial 
after permanent IP discontinuation and last study contact, the earliest of the date of the 
informed consent to continue participation in the trial after permanent IP 


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discontinuation and last study contact will be used as the end date of the dose.  
Otherwise, the last day of the month will be used to complete the end date of the dose.  
x If the end date is completely missing, the earliest of the date of the informed consent to 
continue participation in the trial after permanent IP discontinuation and last study 
contact will be used as the end date of the dose. 
For all other dates of start or stop of doses missing or partially missing the imputation 
algorithm will start imputing the end dates and subsequently the start dates according to the 
following rules. 
x If only the day part of the end date is missing and occurs in the same month and year 
as the start date of the following dose, the start date of the following dose - 1 will be 
used as the end date of the dose. If only the day part of the end date is missing and 
occurs in the same month and year as the start date of the following dose and the start 
date of the following dose is partial, the 14th day of the month will be used as end date 
of the dose. If the end date is missing, the date before the start of the consecutive dose 
will be used as end date of the dose. If the end date is missing and the date of the 
consecutive dose is partial, then the 14th day of the month and year of the consecutive 
dose will be used as end date of the dose. Otherwise, the last day of the month will be 
used to complete the end date of the dose.  
x If only the day part of the start date is missing and occurs in the same month and year 
as the end date of the previous dose (also considering imputed dates), the end date of 
the previous dose + 1 will be used as the start date of the dose.  Otherwise, the first day 
of the month will be used to complete the start date of the dose. 
x If both the stop date and the start date of consecutive doses are missing, then the stop 
date will be imputed to fall half way between the start date of the same dose and the 
stop date of the following dose. If an even number of days exists between the start date 
of the same dose and the stop date of the following dose, then the stop date will be 
taken as the midpoint value minus 1 day. 
Missing or partially missing dose date will be imputed only for analysis purpose but will 
remain as missing or partially missing in patient listings. 
For deaths with a missing or partially missing date the following rules apply. 
x If only the day part of the death date is missing and occurs in the same month and year 
as the date of last contact, the date of last contact will be used as the death date.  
Otherwise, the first day of the month will be used to complete the death date.  
x If the day and month parts of the death date are missing and occur in the same year as 
the date of last contact, the date of last contact will be used as the death date.  
Otherwise, January 1 will be used to complete the death date. 


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x If the death date is completely missing, the date of last contact will be used as the 
death date. 
For all other efficacy events (i.e. myocardial infarction, stroke, emergent/elective coronary 
revascularization, hospitalization for unstable angina, atrial fibrillation, heart failure) with a 
missing or partially missing date of onset the following rules apply. 
x If only the day part of the onset date is missing and occurs in the same month and year 
as the date of randomization, the date of randomization will be used as the onset date.  
Otherwise, the first day of the month will be used to complete the onset date.  
x If the day and month parts of the onset date are missing and occur in the same year as 
the date of randomization, the date of randomization will be used as the onset date.  
Otherwise, January 1 will be used to complete the onset date. 
x If the onset date is completely missing, the date of randomization will be used as the 
onset date. 
For bleeding events with a missing or partially missing date of onset the following rules apply. 
x If only the day part of the onset date is missing and occurs in the same month and year 
as the date of first dose, the date of first dose will be used as the onset date.  
Otherwise, the first day of the month will be used to complete the onset date.  
x If the day and month parts of the onset date are missing and occur in the same year as 
the date of first dose, the date of first dose will be used as the onset date.  Otherwise, 
January 1 will be used to complete the onset date. 
x If the onset date is completely missing, the date of first dose will be used as the onset 
date. 
For new onset of diabetes mellitus with a missing or partially missing date of onset the 
following rules apply. 
x If only the day part of the onset date is missing and occurs in the same month and year 
as the date of first dose, the date of first dose will be used as the onset date.  
Otherwise, the first day of the month will be used to complete the onset date.  
x If the day and month parts of the onset date are missing and occur in the same year as 
the date of first dose, the date of first dose will be used as the onset date. Otherwise, 
January 1 will be used to complete the onset date. 
x If the onset date is completely missing, the date of first dose will be used as the onset 
date. 


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Missing or partially missing death or event dates will be imputed only for analysis purpose but 
will remain as missing or partially missing in patient listings.  
For the analyses of the change from baseline to Analysis Visit 5 (Month 12) of all biomarkers 
except high-sensitivity C-reactive protein, for patients who have discontinued IP prematurely 
during the first year, prior to the Visit 5 (Month 12), the measurement from the ET visit will 
be included in the analysis as Analysis Visit 5 (Month 12) measurement, as per windowing 
rules specified in Section 4.1.2. 
The impact of further missing data on the biomarker analyses will be assessed in a sensitivity 
analysis based on a multiple imputation scheme under a missing at random (MAR) 
missingness assumption. A measurement will be imputed for patients whose Analysis Visit 5 
(Month 12) measurement is missing or off treatment, including cases where patients have 
never started treatment with study medication, prematurely discontinued treatment with study 
medication, lost to follow-up, dead prior to Analysis Visit 5 (Month 12), or cases of spurious 
missing measurements. For high-sensitivity C-reactive protein imputation will occur on the 
missing values at end of treatment rather than at Analysis Visit 5 (Month 12). Further details 
are provided in Section 4.2.5. 
For AEs with a missing or partially missing onset date or end date the rules as specified in 
Section 3.4.1 will be applied.  
For prior and concomitant medications with a missing or partially missing onset date the rules 
as specified in Section 3.5.3 will be applied. 
4.1.5 
Patient disposition 
The number of patients enrolled (i.e., provided signatures to the informed consent form for the 
study), randomized, took study medication after randomization, completed/ prematurely 
discontinued from the treatment with associated reasons for premature discontinuation, 
completed/withdrew from the study (by the categories defined in Section 3.6) with associated 
reasons for early withdrawal will be summarized by treatment arm and overall based on the 
FAS.    
Additionally, the number of patients randomized by site, country and region will be 
summarized by treatment arm and overall based on FAS.  Similarly, a summary of patients by 
populations will also be presented based on FAS. All disposition data will also be listed. 
4.1.6 
Demographics and baseline characteristics 
Demographics and baseline characteristics will be summarized for FAS by treatment arm and 
overall. All demographics and baseline characteristics will be provided in listings.  
4.1.7 
Medical history 
Medical history information will be presented for FAS and coded using MedDRA dictionary 
22.1. 


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Medical history will be summarized as the number and percentage of patients by MedDRA 
SOC and PT, a patient will be counted only once within each SOC and PT.  Medical history 
will be sorted by SOC in alphabetical order, and PTs will be sorted by decreasing frequency 
by the total number of patients within each SOC. 
4.1.8 
Prior and concomitant medications 
Medications will be presented for FAS and coded using version WHODD-
WHOGLOBAL_201909_B3 of World Health Organization Drug Dictionary (WHO-DD). 
Medications will be summarized as the number and percentage of patients by World Health 
Organization (WHO) class name and PT; a patient will be counted only once within each 
WHO class name and PT.  Medications will be sorted by WHO class name in alphabetical 
order, and PTs will be sorted by decreasing frequency of the total number of patients within 
each WHO class name. Separate summaries will be provided for prior medications and 
concomitant medications. Concomitant medications will be presented by allowed and 
disallowed medications. Disallowed medications are defined in Section 7.4 of CSP.  
4.1.9 
Duration of exposure 
Duration of exposure to study medication, in months, will be presented for SAF.  Summary 
statistics for duration of exposure will be presented by treatment arm. All data about 
administration of IP will be provided in a listing.     
4.1.10 
Treatment compliance  
Treatment compliance will be presented descriptively for SAF. A sensitivity analysis will be 
performed setting equal to 0 all the derived compliance that are calculated to be negative and 
are due to data issues in the drug accountability data that can’t be resolved before the database 
lock. In addition, overall compliance rate will be summarized as the number and percentages 
of patients by treatment arm with categories of “<80%”, “>= 80% -- <120%” and “>=120%”.  
4.2 
Analysis of efficacy outcome measures 
Unless otherwise specified, efficacy analyses will be based on FAS, using events adjudicated 
by CEC.  The analysis for all TTE endpoints will be performed using the Cox proportional 
hazards model.  The HR, 95% CI for HR and Wald test p-value comparing the treatment arms 
of Epanova versus placebo (corn oil) will be presented.  Kaplan-Meier (KM) estimates for all 
TTE endpoints will be calculated and plotted. All data collected for the primary outcome 
measure, key secondary, other secondary, and tertiary outcome measures will be presented in 
listings. 
4.2.1 
Primary efficacy 
The primary outcome measure is time in months from randomization to first occurrence of 
any component of the composite of MACE events (cardiovascular death, non-fatal myocardial 
infarction, non-fatal stroke, emergent/elective coronary revascularization, or hospitalization 


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for unstable angina).  The primary outcome will be analyzed based on FAS using adjudicated 
events.   
Time-to-event analysis will be implemented using a Cox proportional hazards model (refer to 
Appendix 3.1.A).  The proportional factor of the hazard will be modelled as a function of 
treatment (Epanova vs. placebo), established cardiovascular disease at baseline (yes/no), and 
region.  A patient will be included in the established cardiovascular disease group if they 
satisfy Inclusion criteria 3a alone or in conjunction with primary prevention criteria (Inclusion 
criteria 3b and/or 3c), otherwise they will be considered without established cardiovascular 
disease at baselines. Region will be defined as in Appendix 1 as a categorical variable.   
The HR, 95% CI for HR, and Wald test p-value comparing the treatment arms of Epanova 
versus placebo will be presented.  The event rate will be estimated as the ratio between the 
number of events and the time at risk in patient-years and will be presented as events per 100 
patient-years at risk. 
KM product-limit method (refer to Appendix 3.1.F) will be used to illustrate event 
probabilities in the treatment arms. The cumulative number of patients with an event, the 
number at risk, the Kaplan-Meier event probability, and a 95% CI for the event probability 
will be provided at 3-month intervals for the first year and every 6 months thereafter. The 
difference in cumulative incidence and corresponding number needed to treat (NNT; defined 
as the inverse of that difference) will be presented.   
KM estimates of the cumulative proportion of patients with events will be calculated and 
plotted per treatment group, with the number of patients at risk indicated below the plot at 
specific time points. In addition, all KM curves will be truncated at a time just prior to when 
<10% of the randomized population is in the risk set in both groups for the primary analysis.  
4.2.1.1 
Model Diagnostics 
A Cox-Snell residual plot will be provided to help assess the overall model fit (refer to 
Appendix 3.1.C). 
The Cox-model relies on the assumption of a proportional hazard for the treatment effect and 
the other covariates included in the model. To investigate the reasonability of this assumption 
assessments will be performed. Results will be discussed in the light of these results.   
To assess the assumption of proportional hazards the following will be provided: 
x A plot of Schoenfeld residuals will be provided for the treatment effect. This plot will 
include a locally smoothed curve which will be added to the plot of Schoenfeld 
residuals to better assess any apparent trend. A flat line around 0 indicates that the 
model covariate does not vary over time and the proportional hazard assumptions 
holds for that covariate (refer to Appendix 3.1.D). 
x A Log cumulative hazard plot will be provided for the treatment effect. This will be 
performed by plotting the Log of the negative log of the KM survival function 


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estimates against the log of survival time. This will be visually inspected to assess the 
proportionality assumption.  
x These checks will be performed for the treatment effect but also for the other 
covariates included in the model: established cardiovascular disease at baseline 
(yes/no) and region.  
 
4.2.1.2 
Sensitivity analysis of primary outcome measure 
To assess the validity of the assumption of proportional hazards, a sensitivity analysis will be 
performed including a time dependent covariate (adding a treatment-by-time interaction term) 
and testing for treatment effect heterogeneity over time (not under Type I error control), to 
assess the extent to which this represents random variation. The treatment-by-time interaction 
term will consider time as a categorical variable for each year. The time-dependent HRs for 
each 1 year of follow-up with 95% confidence bands will be tabulated and plotted in a forest 
plot. If a lack of proportionality is evident, the HR from the primary analysis can still be 
meaningfully interpreted as an average HR over time unless there is extensive crossing of the 
survival curves.  
4.2.1.3 
Censoring rules for all outcome measures and vital status 
For the analysis of the primary and all key secondary endpoints, except for the analyses of 
time to cardiovascular death and time to all-cause death, patients will be censored at the 
earliest of withdrawal of consent date and last study contact. Complete endpoint information 
will be pursued with every effort for all patients regardless of their study medication status, 
unless they exercise their right to withdraw consent. Patients who have a non-fatal event will 
continue study follow-up. Any event observed after the earliest of withdrawal of consent date 
and last study contact will not be included in the analysis. 
Last study contact is defined as the latest of the dates of assessments contributing to an 
opportunity to assess as to whether the patient has had every component of the endpoint being 
analyzed. 
The dates of assessments that will be used include, but are not limited to,  
x Date of randomization 
x Start and end dates of dosing 
x Date of collection of laboratory evaluations 
x Date of vital sign testing 
x Date of physical examinations 
x Date of ECG 
x Start and end dates of concomitant medications 
x Start and end dates of hospitalization   
x Start and end dates of AE 
x Start and end dates of bleeding event 
x Date of event (if not endpoint of interest) 


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x Date of telephone communication with patient or a designated third party on behalf of 
the patient, such as hospital or immediate family 
x Date of end of treatment visit or early termination visit 
x Date of consent withdrawn 
x Date of death (if not endpoint of interest and if not reported on vital status form only) 
If the last contact date is partially missing or missing, this partially missing or missing date 
will be imputed to the earliest possible date. The imputed last contact date should not be 
earlier than any of the dates considered in the derivation of the last contact.  
Because data on vital status (dead or alive) is consistently pursued for all patients, including 
those potentially lost to follow up or withdrawn from the study, the analysis of time to all-
cause death will utilize data which extends even beyond last study contact and withdrawal of 
consent date. For the analysis of time to all-cause death, patients who have not had the event 
in question will be censored at the latest of the date of last study contact and last date known 
to be alive. 
All deaths, including those recorded at the time of vital status assessment, will be adjudicated. 
Because undetermined deaths will be assumed to be cardiovascular, the analysis of time to 
cardiovascular death as a single outcome measure will utilize data which extends beyond last 
study contact and withdrawal of consent date. For the analysis of time to cardiovascular death, 
patients will be censored at the latest of the date of last study contact, last date known to be 
alive, and date of non-cardiovascular death. 
Censoring in China 
As Human Genetic Resources (HGR) approval in China was lost on 31st January 2020 it is 
only possible to capture an extremely limited amount of data for patients at Chinese sites after 
this date. Investigators will only be able to enter event data, SAE data and vital status 
information. 
Due to this limitation there is the possibility that events prior to January 31st will fall after last 
contact date when defined as above. Therefore, if using the definition above the last contact 
date falls before January 31st 2020, but there is no evidence that a patient has left the study 
prior to that date, then January 31st 2020 will be set as last contact date. A patient has 
evidence of leaving the study if there is a study disposition date of completion or 
discontinuation, or a performed Visit 13/EOS/ET date before 31st January 2020. 
The number of events in each component that contribute to each of the composite endpoints 
will be presented. To assess the impact of the above censoring rule, particularly due to 
possible censored events in China, the number of events in each component that would have 
contributed to each of the composite endpoints if there was no censoring will also be 
presented. 


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4.2.1.4 
Subgroup analyses of the primary outcome measure 
Subgroup analyses will be performed to evaluate variation of treatment effect, as well as a test 
of interaction with treatment for each subgroup variable. Subgroup analyses for the following 
variables will be performed, and their corresponding subgroup categories are defined in 
Appendix 1:  
x age, 
x diabetes at baseline (yes/no), 
x sex, 
x race group (Asian, Black, Caucasian and Other),  
x BMI at baseline,  
x Region,  
x established cardiovascular disease at baseline (yes for patients that meet 1 or 
more of the atherosclerotic CVD criteria as defined in Inclusion Criteria 3a/no 
otherwise), 
x high-intensity statin vs other statin treatment at baseline, 
x Ezetimibe treatment at baseline,  
x baseline estimated GFR, 
x baseline high-sensitivity C-reactive protein, 
x baseline non-high-density lipoprotein cholesterol, 
x baseline triglycerides, 
x baseline very low-density lipoprotein, 
x baseline apolipoprotein C-III. 
 
For all subgroup analyses, apart from those performed on the subgroups of Region and 
established cardiovascular disease at baseline, the proportional factor of the hazard in the Cox 
model will be modelled as a function of treatment (Epanova vs. placebo), established 
cardiovascular disease at baseline (yes/no), Region, level for the subgroup of interest and 
treatment by the subgroup of interest interaction. 
For the subgroup analysis performed by Region, the proportional factor of the hazard will be 
modelled as a function of treatment, established cardiovascular disease status at baseline, 
Region and treatment by Region interaction. 
For the subgroup analysis performed by established cardiovascular disease status at baseline, 
the proportional factor of the hazard will be modelled as a function of treatment, Region, 
established cardiovascular disease status at baseline and treatment by established 
cardiovascular disease status at baseline interaction. 
In addition to the result tabulation described in Section 4.2.1, the p-value of the interaction test 
will be presented, and forest plots displaying hazard ratio and 95% confidence interval for the 
comparisons of Epanova vs. placebo for each subgroup will be presented.  P-values will be 
unadjusted for multiple comparisons and will be regarded as descriptive only. 


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A permutation-based approach will be applied for assessing the expected variability of 
observed effect in subgroups under an assumption of effect homogeneity. This approach 
simulates N number of study replicates under the assumption of effect homogeneity and is 
based on the SEAMOS method described in Dane et al. 2019. This will guide interpretation of 
subgroup results by putting the subgroup effects in context. Specifically, it provides a 
comparison with the extreme subgroup results that are expected under the null hypothesis of 
treatment homogeneity. 
Each simulated study replicate is derived through a random permutation of the rows of the 
matrix containing subgroup factors as columns where a row uniquely corresponds to a patient. 
By permutation of the aforementioned subgroup matrix, the observed outcome and treatment 
allocation are retained, thereby ensuring that the overall treatment effect and correlation 
between subgroups are constant across replicates. For each such study replicate, the data is re-
analyzed, rendering N multiple subgroup analyses. Within each study replicate, the subgroup-
deviation from the overall result is calculated for each subgroup as a z-score defined as the 
difference between the subgroup estimate and the overall estimate, normalized with the 
standard error for the subgroup estimate. The overall estimate is defined as the treatment 
effect from the primary efficacy analysis. This renders an i-th reference distribution for the i-
th ordered subgroup effect; here, the i corresponds to the ordering of the subgroups in z-score 
scale. 
Observed z-scores, will be presented similar to a forest plot where a 90% probability interval 
of extreme effects is overlaid to help identify potential heterogeneous results. The probability 
interval is derived from the reference distributions of the most extreme subgroup effects in 
each replication. The lower limit is defined as the 5th percentile of the minimum z-scores, and 
the upper limit is defined as the 95th percentile of the maximum z-scores, from each 
replication.  
The above approach will be implemented with N=2000. 
4.2.1.5 
Supplemental analysis with censoring at time of decision to early terminate the 
study 
On January 13, 2020, based on the recommendations of the DMC meeting held on January 8, 
2020, the decision to early terminate the study has been communicated to the sites. The 
communication included the instructions that patients should stop study medication. 
In order to assess the treatment effect without any bias due to this decision, a supplemental 
analysis on the primary and key secondary endpoint will be performed, with a censoring date 
of 13 January 2020. Only events occurring on or before this date will be included in the 
analysis, and subjects with a censoring date after this date will be censored on the 13 January 
2020.  
The analyses will be performed on the primary and key secondary endpoints and with the 
same criteria of the main analysis. Results from the Cox proportional hazards model will be 


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presented. KM product-limit method will be used to illustrate event probabilities in the 
treatment arms. 
4.2.2 
Secondary outcome analyses 
If the primary endpoint objective is met (2-sided p-value <0.05; Section 5), the secondary 
outcomes will be evaluated hierarchically at an overall alpha of 0.05 for each comparison, 
sequentially in order to control the family wise error rate at 0.05.  Once a key secondary 
endpoint is not met at alpha 0.05, all subsequent comparisons will be considered exploratory 
with nominal p-values.  If the study is stopped at any time prior to the accrual of the stipulated 
1,600 primary (MACE) events then the testing thresholds are detailed in Section 5. 
Key secondary outcome measures (tested at D=0.05, conditional on success of the primary 
outcome) include:  
1. The composite measure of MACE that include the first occurrence of cardiovascular 
death, non-fatal myocardial infarction, non-fatal stroke, emergent/elective coronary 
revascularization, or hospitalization for unstable angina in the subgroup of patients 
with established cardiovascular disease at baseline. 
2. The composite measure of cardiovascular events that include the first occurrence of 
cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. 
3. The composite measure of cardiovascular events that include the first occurrence of 
cardiovascular death, non-fatal myocardial infarction and non-fatal stroke in the 
subgroup of patients with established cardiovascular disease at baseline. 
4. The composite measure of coronary events that include the first occurrence of cardiac 
death (including death due to acute myocardial infarction, sudden cardiac death and 
death due to cardiovascular procedures), non-fatal myocardial infarction, 
emergent/elective coronary revascularization, or hospitalization for unstable angina. 
5. The composite measure of coronary events that include the first occurrence of cardiac 
death (including death due to acute myocardial infarction, sudden cardiac death and 
death due to cardiovascular procedures), non-fatal myocardial infarction, 
emergent/elective coronary revascularization, or hospitalization for unstable angina in 
the subgroup of patients with established cardiovascular disease at baseline. 
6. Time to cardiovascular death. 
7. Time to cardiovascular death in the subgroup of patients with established 
cardiovascular disease at baseline. 
8. Time to all-cause death. 
9. Time to all-cause death in the subgroup of patients with established cardiovascular 
disease at baseline. 
The test of effect in the subgroup of patients with established cardiovascular disease at 
baseline will be performed from a model with interaction between the variables of established 
cardiovascular disease status at baseline and treatment in addition to the effects included in the 
primary analysis. The HR in the subgroup will be derived from the linear combination of the 
estimated effects of the treatment and interaction between treatment and established 


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cardiovascular disease status at baseline. This will be presented together with the 95% CI for 
HR and the Wald test p-value comparing the treatment arms of Epanova versus placebo in the 
subgroup of patients with established cardiovascular disease at baseline. 
The effect of Epanova on other secondary outcome measures will also be assessed for the 
subgroup of patients with established cardiovascular disease at baseline but will not be under 
Type I error control. A Kaplan Meier Curve and the difference in cumulative incidence and 
corresponding NNT will be presented for the primary and key secondary outcome measures in 
the subgroup of patients with established cardiovascular disease at baseline.  
Consistency of effect in pre-specified subgroups will be investigated within the subgroup of 
patients with established cardiovascular disease at baseline (for subgroups specified in Section 
4). This will be done by fitting the Cox regression model with subgroup and treatment-by-
subgroup effect described in Section 4.2.1.4 to the data in the subgroup of patients with 
established cardiovascular disease at baseline. Results will be presented as described in that 
section.  
Other secondary outcome measures (evaluated using nominal p-values; NOT part of the 
hierarchical testing sequence and are exploratory) include time to:  
x emergent/elective coronary revascularization 
x hospitalization for unstable angina 
x fatal or non-fatal myocardial infarction 
x non-fatal myocardial infarction 
x fatal or non-fatal stroke  
x non-fatal stroke. 
The other secondary outcome measures will be analyzed the same as outlined above for the 
primary outcome measures in Section 4.2.1.   
4.2.3 
Tertiary outcome analyses 
The tertiary outcome measures will include: 
x Time to first occurrence of new onset atrial fibrillation. 
x Time to first occurrence of the composite measure of total thrombotic events that 
include the first occurrence of documented coronary stent thrombosis, any systemic 
thromboembolism including arterial stent thrombosis (except coronary) or venous 
thromboembolism, i.e. deep vein thrombosis and/or pulmonary embolism. 
x Time to first occurrence of a heart failure event. 
x Second, third, fourth, and total number occurrences of major cardiovascular events 
(primary and key secondary outcome measures).  


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x The time to first CV-related hospitalization. 
Time to tertiary outcome measures will be analyzed the same as outlined above for the 
primary outcome measure in Section 4.2.1.  The analysis of the tertiary outcomes will be 
considered observational only.  
For the time to first occurrence of the composite measure of total thrombotic events the 
analysis will include all the venous thromboembolisms, pulmonary embolism and confirmed 
stent thrombosis collected in the eCRF “Tertiary Endpoints” form and all the AEs identified 
using the PTs as reported in Appendix 5. 
Exploratory analysis of the occurrence of all events occurring within patients during follow-up 
(i.e., first and subsequent events), will be made for the primary and key secondary outcome 
measures, ie MACE events, cardiovascular events and coronary events. In these analyses, 
events occurring on the same date will be counted as one event and non-fatal events occurring 
on the same date as cardiovascular/coronary death will be counted as a 
cardiovascular/coronary death. The analyses will use the same censoring rules as in the 
primary outcome analyses. Bar plots showing the distribution of number of events per patient 
will also be presented. 
The Nelson-Aalen estimator of the mean cumulative function will be used to illustrate the 
average cumulative number of events per patient over the study follow-up time per treatment 
arm (Nelson 2003). 
The average number of events during follow-up will be modelled using Negative binomial 
regression using the log link function with log follow-up time as offset and including 
treatment, established cardiovascular disease status at baseline, and region as covariates. Rate 
ratios (RRs) and 95% CIs for the RRs comparing event rates between the treatment arms will 
be calculated. The Negative binomial regression models will be implemented using the SAS 
GENMOD procedure. 
In addition, Cox proportional hazards models modified for the analysis of recurrent events 
will be used to model time until an event, in models including treatment, established 
cardiovascular disease status at baseline, and region.  
The Andersen-Gill Cox model, which applies a counting process formulation of follow-up 
time, will be used to estimate HRs for events by treatment arms (Anderson and Gill 1982).  
The Wei-Lin-Weissfeld Cox regression model, modified for the analysis of recurring and 
terminal events by Li and Lagakos (Wei and Lin 1989, Li and Lagakos 1997, Scenario II), 
will be used to estimate HRs for the 1st, 2nd, 3rd, and 4th event.  
Both the Andersen-Gill and Wei-Lin-Weissfeld Cox models will utilize robust sandwich 
estimator for the regression coefficient standard errors, to adjust for dependencies between 
event times within the same individual (Lin and Wei 1989). Both Cox models will be 
implemented using the SAS PHREG procedure. 


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To account for informative censoring from death, joint frailty models will be used to estimate 
HRs for recurring events.  This analysis will be carried out for MACE events, cardiovascular 
events and coronary events. Estimation will be based on the %JointFrailty SAS macro 
(Toenges and Jahn-Eimermacher 2020). The model will assume a gamma distributed frailty 
term and a Weibull baseline hazard functions. The estimation of the model will be based on 
the Probability Integral Transformation (PIT) method. Adaptive Gaussian quadrature will be 
applied as superior to non-adaptive quadrature when associated with the PIT method (Toenges 
and Jahn-Eimermacher 2020). The NLMIXED procedure selects the appropriate number of 
quadrature points based on the evaluation of the log likelihood at the starting values of the 
parameters.  
Additional sensitivity analyses for the total event analysis include descriptive analyses of IP 
discontinuations after time at event (i.e. number and percentages of patients with first, 
second and third event), analyses counting all events including those occurring on the same 
date and analyses of Cox models with and without robust standard errors. 
4.2.4 
Exploratory outcome measures 
The primary outcome measure will be repeated for on-treatment MACE events using FAS, 
where on-treatment MACE events are defined as the first occurrence of MACE components 
that started on or after the date of first dose of study medication and on or prior to the 
permanent discontinuation of study medication + 10 days.  Patients who do not have an event 
that satisfies this criterion will be censored on the earliest between date of permanent 
discontinuation of study medication +11 days and the censoring date or the randomization 
date if the patient never started study medication. 
An exploratory analysis of time to first occurrence of fatal myocardial infarction and sudden 
cardiac death will be performed. The exploratory outcome measure will be analyzed as 
outlined above for the primary outcome measure in Section 4.2.1.  The analysis will be 
considered observational only.  
4.2.5 
Biomarkers Efficacy 
The analysis of biomarkers, except for high-sensitivity C-reactive protein, will focus on the 
differences between Epanova versus placebo (corn oil) in the Analysis Visit 5 (Month 12) 
measurement expressed as a percentage of the baseline measurement. High-sensitivity C-
reactive protein will be analyzed similarly but for the end of treatment measurement in place 
of the Analysis Visit 5 (month 12) measurement. This analysis will assess the effect of IP on 
biomarkers, and hence only data from samples collected up to the date of the last dose of IP + 
10 days will be included in the analysis. 
The following fasting lipid biomarkers will be included in the analysis: serum triglycerides, 
total cholesterol, low-density lipoprotein cholesterol (in patients with triglycerides > 400 
mg/dl low-density lipoprotein cholesterol will be directly measured), high-density lipoprotein 
cholesterol, calculated non-high-density lipoprotein cholesterol, very low-density lipoprotein 
cholesterol and total cholesterol: high-density lipoprotein cholesterol ratio.  


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The following additional fasting biomarkers will be included in the analysis: apolipoprotein 
B-100, apolipoprotein C-III, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic 
acid, and arachidonic acid for both plasma and red blood cells and high-sensitivity C-reactive 
protein.  
Analysis of covariance (refer to Appendix 3.2.A) will be used to model percent change from 
baseline as a function of treatment group as a main effect and baseline as a covariate.   
The dependent variable will be the natural log of the Analysis Visit 5 (Month 12) 
measurement expressed as a % of the baseline measurement, i.e.  ቀͳͲͲ ڄ
୷భమ
୷బቁ, where ଵଶ and 
଴ are the measurements at Analysis Visit 5 (Month 12) (or end of treatment for high-
sensitivity C-reactive protein) and baseline, respectively. This transform will be applied to 
improve the normality of residuals.  The measurement at baseline in logarithmic scale will be 
used as covariate in addition to the treatment group.  
 LSMeans, the difference in LSMeans between the two treatment arms and, 95% CIs will be 
provided on the back-transformed scale. LSMeans and difference in LSMeans on the back-
transformed scale are estimates for Geometric Means and Geometric Mean Ratios 
respectively. P-values will be also provided from the ANCOVA model. The model will be 
implemented using SAS® PROC GLM.  
For patients who have discontinued IP prematurely during the first year, prior to Analysis 
Visit 5 (Month 12), the result for the assessment done at the Early Termination (ET) visit will 
be carried forward to Analysis Visit 5 (Month 12) and will be included in the analysis in place 
of the missing measurement at Analysis Visit 5 (Month 12). 
In addition, for quantitative biomarkers, descriptive statistics will be presented for baseline 
and percent change from baseline to each post-baseline visit. 
4.2.5.1 
Multiple Imputation scheme 
To assess the impact of further missing data on the effect of Epanova in biomarker 
parameters, a sensitivity analysis will be performed. The sensitivity analysis will be based on 
a Multiple Imputation scheme under a MAR missingness assumption. 
The sensitivity analysis will assess the treatment effect of Epanova on biomarker parameters 
in the hypothetical situation that the patients had continued with treatment and had their 
Analysis Visit 5 (Month 12) measurement as planned.  
Hence, a measurement will be imputed for patients whose Analysis Visit 5 (Month 12) 
measurement are missing or off treatment, including cases where patients have never started 
treatment with study drug, prematurely discontinued treatment with study drug, lost to follow-
up, dead prior to the Analysis Visit 5 (Month 12), or cases of spurious missing measurements.  
For patients with missing data at the Analysis Visit 5 (Month 12), data will be imputed in a 
multiple imputation scheme in a two-step fashion for each biomarker variable: 


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Step 1: The imputation scheme will impute missing values from a model with parameters 
(β*,σ*) where (β*,σ*)  are drawn from the posterior distribution of the parameters (Ⱦ෠, ߪො) from 
a regression model of the existing Analysis Visit 5 (Month 12) measurements (O'Kelly 
and Ratitch 2014). β represents the regression effects and σ the covariance. This regression 
model will have the natural logarithm of the Analysis Visit 5 (Month 12) measurements as the 
dependent variable. Explanatory variables will be treatment and the natural logarithm of the 
baseline value. In addition, the dichotomous variable for any occurrence of SAE or MACE 
event during the first year from randomization will be added as an effect thought to explain 
the missingness mechanism. The seed for this imputation will be 3275. 
Note: Step 1 will result in M datasets without missing values at Analysis Visit 5 (Month 12) 
for patients with a non-missing baseline value, except for patients who had both baseline and 
Analysis Visit 5 (Month 12) measurement missing. These patients will not have had any 
imputed measurements. 
Step2: The ANCOVA modelled, as described for the biomarker analysis, is performed for 
each of the M datasets. This will result in M estimates of the LS means and LS mean 
differences.  
Finally, the M LS-mean and LS-mean differences are pooled according to Rubin’s Rules. This 
will be performed in SAS using PROC MIANALYZE (O'Kelly and Ratitch 2014). 
The above description of the MAR sensitivity analysis using Multiple Imputation will be 
implemented with M=1000 imputations. 
This sensitivity analysis will be performed for all biomarker variables and will thus be 
modified for high-sensitivity C-reactive protein to impute missing values at end of treatment 
rather than at Analysis Visit 5 (Month 12). 
4.3 
Analysis of safety outcome measures 
All outputs for safety outcomes will be based on SAF.  
Exposure to study medications, AEs/SAEs, bleedings, new onset of diabetes mellitus during 
the study, clinical laboratory data and vital signs will be summarized per treatment arm using 
descriptive statistics.   
Subgroup analyses will be performed on SAEs, AEs leading to discontinuation of IP, new 
onsets of diabetes mellitus during the study and bleedings. Subgroup analyses for the 
following variables will be performed. Their corresponding subgroup categories are defined in 
Appendix 1. 
x age, 
x sex, 
x race group,  
x Region,  


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x established cardiovascular disease at baseline (yes for patients that meet 1 or 
more of the atherosclerotic CVD criteria as defined in Inclusion Criteria 3a/no 
otherwise). 
4.3.1 
AEs 
AEs will be coded using MedDRA dictionary 22.1. 
AE summaries will only include AEs with onset date on or after the day of first dose of study 
medication. Non-serious AEs with onset date more than 30 days after the last dose of study 
medication will not be included. All SAEs will be included. 
x Overall summaries of AEs will include the following categories: any AE, any AE with 
outcome of death, any SAE, any AE related to study medication, any AE leading to 
discontinuation of IP, dose reduction or dose interruption.   
x Incidence of AEs will be presented by SOC and PT, also broken down further by 
maximum severity, relationship to study medications, AEs leading to discontinuation 
of IP; AEs with outcome of death and SAE.  
x Both a separate summary of on-treatment AEs and on-treatment SAEs will be 
provided, i.e. with onset up to the date of the last dose of IP + 10 days.  
The event rate per 100 patient years at risk will be included in these summaries, where 
the event rate per 100 patient years at risk is calculated as:  
ݐ݋ݐ݈ܽ݊ݑܾ݉݁ݎ݋݂݌ܽݐ݅݁݊ݐݏݓ݅ݐ݄ܽݐ݈݁ܽݏݐ݋݊݁݁ݒ݁݊ݐ
ݐ݋ݐ݈ܽ݊ݑܾ݉݁ݎ݋݂݌ܽݐ݅݁݊ݐݕ݁ܽݎݏܽݐݎ݅ݏ݇
כ ͳͲͲ 
The total number of patients at risk is calculated as the sum of [(date of last dose +10 
days)- date of first dose+1]/365.25 
x All AE data will be presented in AE listings.  Selected AE data will be listed for AEs 
with outcome of death, AEs leading to discontinuation of IP, dose reduction or dose 
interruption, TIAs and SAEs.    
x Safety in the subgroup of patients with established cardiovascular disease at baseline 
will be assessed by a tabulation of SAEs by SOC and PT by treatment group for 
subgroup of patients with established cardiovascular disease at baseline in the SAF. 
x Incidence of SAEs and AEs leading to discontinuation of IP, overall and broken down 
by severity, will be presented by age category, sex, race group and Region. Separate 
tables by age category, sex, race group and Region will be presented on the subgroup 
of patients with established cardiovascular disease at baseline. 
 


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4.3.2 
Bleedings 
Bleedings will not be adjudicated by CEC. Bleedings as collected in the eCRF “Bleed” form 
will be included in the analysis. 
The bleedings will be classified according to the thrombolysis in myocardial infarction (TIMI) 
non-coronary artery bypass graft bleeding definitions (Mehran et al. 2011): major, minor, 
requiring medical attention or minimal. 
Only bleeding events with an onset on or after the first dose of study medication will be 
included in analyses. 
Time from first dose to first bleeding will be computed as TTE (months) = (date of event – 
date of first dose + 1 day)/30.4375 
Time from first dose to first bleeding will be presented by a Kaplan-Meier summary and 
figure.  
Patients will be censored in this TTE analysis at last date of potential assessment for bleeds, 
defined as latest of:  
x Start and End Dates of AE 
x Start and End Dates of Dosing 
x Date of Hemoglobin or Hematocrit Lab Results 
x Start and End Date of Hospitalization 
x Recorded Scheduled Visit 
If the last date of potential assessment for bleeds is partially missing or missing, this partially 
missing or missing date will be imputed to the earliest possible date (as outlined in Section 
4.1.4). 
Bleedings events will be also presented in listings and tabulations by treatment arm and 
SOC/PT, per TIMI bleeding category.  
In addition, location of the bleeding events will be presented in listings and tabulated by 
treatment arm per TIMI bleeding category.  
Results will be presented overall and by age category, sex, race group and Region. Separate 
tables by age category, sex, race group and Region will be presented on the subgroup of 
patients with established cardiovascular disease at baseline. 
Complete information on the programmatic bleeding determination is available in Appendix 
4.   


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4.3.3 
New onset of diabetes mellitus during the study 
Number of patients with new onset of diabetes mellitus during the study will be presented by 
treatment group. Only diabetes onset on or after the first dose of study medication will be 
included in the analysis. Results by type of diabetes onset will be also reported.  
Time from first dose to first diabetes onset will be computed as TTE (months) = (date of event 
– date of first dose + 1 day)/30.4375 
Time from first dose to first diabetes onset will be presented by a Kaplan-Meier summary and 
figure. The log-rank test will be applied to test treatment difference. Patients will be censored 
in this TTE analysis at last date of potential assessment for diabetes, defined as latest of:  
x Start and End Dates of AE 
x Start and End Dates of Dosing 
x Date of HbA1c or Plasma Glucose Lab Results 
x Start and End Date of Hospitalization 
x Recorded Scheduled Visit. 
If the last date of potential assessment for diabetes is partially missing or missing, this 
partially missing or missing date will be imputed to the earliest possible date (as outlined in 
Section 4.1.4). 
Results will be presented overall and by age category, sex, race group and Region. Separate 
tables by age category, sex, race group and Region will be presented on the subgroup of 
patients with established cardiovascular disease at baseline. 
New onset of diabetes mellitus during the study will be also presented in listings. 
4.3.4 
Laboratory Evaluations 
Results from the central laboratory will be included in the reporting of this study for 
hematology and serum chemistry. In case of a bleeding event or an AE with potential elevated 
liver enzymes, results from local laboratories might be collected in the eCRF in the form 
“Bleed” (hematocrit and hemoglobin) and “Liver Lab Values” (AST, ALT, total bilirubin and 
alkaline phosphatase). These values are included in the safety laboratory analyses as detailed 
in Appendix 2. All longitudinal laboratory data will be analyzed by analysis visit as in Table 
3.  A complete list of laboratory tests is available in Appendix 2.      
The following summaries and listings will be provided for laboratory data: 
x Summary of baseline and change from baseline by visit (for quantitative measurements 
in hematology (hematocrit and HbA1c), serum chemistry (except alkaline 


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phosphatase), lipid data, special lipid markers, Plasma and red blood cells Fatty 
Acids). 
x Shifts from baseline to post-baseline by visit (based on assessments relative to normal 
range in hematology (hematocrit and HbA1c), serum chemistry (except alkaline 
phosphatase), lipid data, special lipid markers, Plasma and red blood cells Fatty 
Acids). 
x A listing of patients who potentially met Hy's laws criteria (ALT or AST≥3xULN and 
total bilirubin (BILI) ≥2xULN elevation, and in which the elevation in transaminases 
precedes or is on the same day as the elevation in BILI.) on or after the first dose of 
study medication will be presented by treatment group for Safety analysis set. Figures 
displaying maximum total bilirubin on or after the first dose of study medication 
against maximum ALT and AST on or after the first dose of study medication will also 
be produced. 
x Number and percentage of patients meeting predefined criteria for marked 
abnormalities at any time during treatment will be provided. A laboratory value is 
considered a marked abnormality (MA) if it is outside the pre-defined criteria for 
marked abnormality (Table 4).  If both the baseline and on-treatment values of a 
parameter are beyond the same MA limit for the parameter, then the on-treatment 
value will be considered a MA only if it is more extreme (farther from the limit) than 
was the baseline value.  If the baseline value is beyond the low MA limit, and the post-
baseline value is beyond the high MA limit (or vice-versa), then the post-baseline 
value will be considered a MA.   
x For a patient with at least 1 abnormal assessment meeting predefined criteria for 
marked abnormalities, all values for those laboratory tests with at least one abnormal 
assessment will be listed.   
x Urine pregnancy tests, conducted only on women of childbearing potential, will be 
collected only once during Screening and will be analyzed by the site.  All pregnancy 
test data will be listed.   
 
 
 
 
 
 


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Table 4 
Marked abnormality criteria 
 
Clinical laboratory 
variables 
Units 
Low 
High 
CLINICAL CHEMISTRY 
(Serum or Plasma) 
 
 
 
Alanine 
Aminotransferase 
(ALT) 
U/L 
 
>3X ULN 
>5X ULN 
>10X ULN 
>20X ULN 
Aspartate 
Aminotransferase 
(AST) 
U/L 
 
>3X ULN 
>5X ULN 
>10X ULN 
>20X ULN 
Bilirubin, Total 
mg/dL 
 
> 2X ULN if PreRx > ULN; 
> 3X ULN if PreRx > ULN 
Creatinine 
mg/dL 
 
Absolute Value >2.5 mg/dL 
(221 μmol/L) 
Fasting blood glucose 
(Plasma) 
mg/dL 
<50 mg/dL 
(<2.8 mmol/L) 
> 350 mg/dL㸦>19.4mmol/L㸧 
Creatine Kinase 
U/L 
 
>5X ULN 
 
4.3.5 
ECG  
Any clinically significant ECG findings observed at Visit 2 will be included in the Medical 
History.  
4.3.6 
Vital signs 
A summary table of baseline and change from baseline will be provided for SBP, DBP and 
heart rate, waist circumference and weight.  All vital sign data will be provided in listings. 
4.3.7 
Physical examination  
Any clinically significant finding observed up to and including Visit 2 will be reported under 
Medical History.  Any new or worsened clinically significant finding observed after Visits 2 
through Visit 13/EOS/ET will be reported in the AE panel. 
No separate summary tables or listings will be provided for physical examination data.  


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4.3.8 
Overdoses 
Overdoses will be listed along with key patient information. Time from start of treatment to 
overdose (days), time from last dose prior to overdose start date (days)", outcome and action 
taken (with IP) will be also reported.  
5. 
INTERIM ANALYSES 
Accrual of a total of 1,600 5-point MACE (primary efficacy) events is required to have 
approximately 90% power for this study (refer to Section 1.4).  The study is designed to 
continue until this number of events has accrued.  However, 2 interim analyses of the primary 
endpoint are planned and the study may be recommended for termination by the DMC early if 
the stopping rule for superiority or futility is met.  The Executive Steering Committee and the 
Sponsor will decide whether or not to enforce the DMC´s recommendation. 
A group sequential design will be used to preserve the overall type I error probability of 0.05. 
Planned interim analyses on 5-point MACE will be performed around the time when 50% 
(800) of adjudicated MACEs have occurred, and again when 75% (1,200) of adjudicated 
MACEs have occurred.  The final analysis is scheduled when at least 1,600 adjudicated 
MACEs have occurred.  The group sequential superiority boundaries (absolute value of z-
score) for the 1st and 2nd interim analyses are 3.719.  Boundaries (absolute value of z-score) 
for futility at the 1st and 2nd interim look are 0.3085 and 1.2375, respectively.  The 
significance threshold (z-score) for the final analysis is 1.9602, which correspond to a nominal 
p-value of 0.025.  CI for the main Primary analysis on MACE will be constructed at the 95% 
level.  All thresholds are constructed accounting for DMC recommendations for stopping for 
efficacy are “non-binding” in the sense of necessary but not sufficient. 
Superiority boundaries are defined based on Haybittle-Peto rule.  Specifically, this uses a 1-
sided p-value threshold held constant at 0.0001 for each look prior to final.  The final 
comparison will be carried out at a 2-sided alpha of 0.05.  Futility boundaries are based on 
Lan-DeMets alpha spending function that approximates an O’Brien-Fleming boundary in the 
setting of this particular study.  Details on the thresholds for stopping can be seen in Table 5.  
Corresponding thresholds in the hazard-ratio and the p-value scales are also presented. If the 
study is stopped for either futility or superiority patients will be brought in for their final visit 
and assessed for further events.  
 
 
 
 


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Table 5 
Interim Analysis Plan 
 
Interim 
analysis 
Number of adjudicated 
Events (%) 
Approximate 
Time from 
FPFV (months)a 
Boundaries (z-scale)b 
Superiority 
Futility 
1 
800 (50%) 
32 
ܾܽݏሺݖ௢௕௦ሻ
൐͵ǡ͹ͳͻ 
ܾܽݏሺݖ௢௕௦ሻ
൏Ͳǡ͵Ͳͺͷ 
ܪܴ௖൏Ͳǡ7682 
ܪܴ௖൐Ͳǡͻ͹ͺͷ 
݌൏ͲǡͲͲͲʹd 
݌൐Ͳǡ͹ͷ͹ͺd 
 
 
 
 
 
2 
1,200 (75%) 
43 
ܾܽݏሺݖ௢௕௦ሻ
൐͵ǡ͹ͳͻ 
ܾܽݏሺݖ௢௕௦ሻ
൏ͳǡʹ͵͹ͷ 
ܪܴ௖൏ͲǡͺͲ͸͵ 
ܪܴ௖൐Ͳǡͻ͵ͳʹ 
݌൏ͲǡͲͲͲʹd 
݌൐Ͳǡʹͳ͸d 
 
 
 
 
 
Final 
1,600 (100%) 
54 
ܾܽݏሺݖ௢௕௦ሻ൐ͳǡͻ͸Ͳʹ 
ܪܴ൏ͲǡͻͲ͸Ͷ 
݌൏ͲǡͲͷ 
FPFV = First Patient First Visit; abs = absolute value. 
a Based on simulations of 10000 trials 
b Non-binding boundaries 
cHR = hazard ratio 
d2-sided 
6. 
CHANGES OF ANALYSIS FROM PROTOCOL 
 Only the following documented changes are made at the time analysis. 
x For consistency purpose with other Epanova studies, FAS is used in this SAP 
interchangeably with the notation of intent-to-treat population from the protocol.  The 
definition of these 2 populations remains the same for the study. 
x To show treatment effect in the specific subgroup of patients with established 
cardiovascular disease at baseline over both primary and key secondary efficacy 
outcome measures, analyses of these outcome measures in this subgroup have been 
added to the hierarchical testing sequence found in Sections 1.1.3, 3.3.4 and 4.2.2. 


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x The second, third, fourth, and total number occurrences of major cardiovascular events 
(primary and secondary outcome measures) and the time to first CV-related 
hospitalization have been added as tertiary outcomes for completeness of analysis. 
x The CSP includes as covariate in the Cox proportional hazards model for the time to 
event analysis the multiple risk factors without established cardiovascular disease at 
baseline. However due to constraints on the data collection this ordering of patients is 
not applicable. Hence, this covariate which characterizes only the patients without 
established cardiovascular disease at baseline has been removed from the model. 
x In this SAP, the analysis of on-treatment MACE events is not referred as a sensitivity 
analysis, since it does not assess the impact of deviations from model assumptions on 
results, but instead answers another research question. It has therefore presented as an 
analysis on exploratory outcome measure.  
x The CSP states that “the analysis of biomarkers (e.g. lipids or other biomarkers) will 
be based on the differences in change from baseline (Month 0) to Month 12 
(primarily), between placebo (corn oil) and Epanova treatments.”. As high-sensitivity 
C-reactive protein is not recorded at Month 12, but only at end of treatment, the 
planned analysis of difference from baseline to Month 12 is not possible for this 
parameter. Hence, the analysis will focus on the difference from baseline to end of 
treatment. 
An MMRM analysis is stated as the planned approach to assess the impact of 
treatment on biomarker parameters. However, the biomarkers are not repeatedly 
measured between Baseline and Month 12. It is only by including measurements after 
Month 12 that it could be an MMRM analysis model. If missingness will mainly be 
monotone, the patients with missing values at month 12 will also have missing data at 
all subsequent visits. Thus, the analysis will be only based on the patients with values 
at Month 12, which will only provide an unbiased estimate under MCAR missingness. 
Because of these issues, the analysis model has been changed from MMRM to 
ANCOVA, for all biomarker variables.  
As it is indicated in the CSP that missingness may not be under MCAR but under 
MAR and that this will be investigated, a sensitivity analysis utilizing MI under MAR 
assumption will be added. 
 It has been more clearly stated that this analysis will be performed “on-treatment” and 
therefore that measurements after premature discontinuation of study medication will 
not be included. 
This SAP also specifies the type of transformation that will be applied to the 
biomarker measure. Based on assessment on data from previous trials, it was deemed 
that the natural log of 100 + % change from baseline would be sufficient to meet the 
normality assumption. 
 
x This SAP clarifies that the bleeding classifications are not directly collected on the 
Bleed eCRF form and therefore all bleeds will have to be categorized into the 
classifications programmatically. The rule set for these classifications based on the 
data within the Bleed eCRF form have been specified in Appendix 4. In this section 


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the SAP clarifies that also hematocrit values will be considered along with hemoglobin 
values.  
x In this SAP time to all-cause death has been changed into a key secondary measure, 
along with the corresponding subgroup analysis on patients with established 
cardiovascular disease at baseline. 
x Due to the decision to early terminate the study, a supplemental analysis has been 
added to assess any bias on the primary and key secondary endpoints caused by data 
collected after this decision being communicated to the sites.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7. 
REFERENCES 
Andersen PK 1982. Gill RD. Cox’s regression model for counting processes: A large sample 
study. Ann Statist 10(4):1100-1120.  
Cox DR, Snell EJ 1968. A general definition of residuals. Journal of the Royal Statistical 
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Dane A, Spencer A, Rosenkranz G, Lipkovich I, Parke T 2019. Subgroup Analysis and 
Interpretation for Phase 3 Confirmatory Trials: White paper of the EFSPI/PSI Working Group 
on Subgroup Analysis. Pharmaceutical Statistics, 18(2), 126-139. 
Grambsch PM, Therneau, TM 1994. Proportional hazards tests and diagnostics based on 
weighted residuals. Biometrika 81 (3): 515-526. 
Kay R 1977. Proportional hazard regression models and the analysis of censored survival data. 
Journal of the Royal Statistical Society Series C (Applied Statistics) 26: 227-237. 
Klein JP, Moeschberger ML 1997. Survival Analysis: Techniques for Censored and Truncated 
Data. Springer 
Mehran R et al. 2011. Standardized Bleeding Definitions for Cardiovascular Clinical Trials. A 
Consensus Report From the Bleeding Academic Research Consortium. Circulation, 2011, 
123: 2736-2747.) 
Li QH, Lagakos SW 1997. Use of the Wei-Lin-Weissfeld method for the analysis of a 
recurring and a terminating event. Stat Med 16:925-940. 
Lin DY, Wei LJ 1989. The Robust Inference for the Cox Proportional Hazards Model. J Am 
Stat 84: 1074-1078. 
O'Kelly M,  Ratitch B 2014. Clinical trials with missing data: a guide for practitioners. John 
Wiley & Sons. 
Rondeau V 2007. Joint frailty models for recurring events and death using maximum 
penalized likelihood estimation: application on cancer events. Biostatistics 8:708-21. 
Rondeau V, Mazroui Y and Gonzalez JR 2012. An R package for the analysis of correlated 
survival data with frailty models using penalized likelihood estimation or parametric 
estimation.  J. Stat. Softw 47:1-28. 
Toenges G, Jahn-Eimermacher A 2019. Computational issues in fitting joint frailty models for 
recurrent events with an associated terminal event. Computer Methods and Programs in 
Biomedicine 188:105259. 
Wei LJ, Lin DY, Weissfeld L 1989. Regression analysis of multivariate incomplete failure 
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67 
8. 
APPENDICES 
APPENDIX 1 
SUBGROUPS AND GEOGRAPHIC REGIONS  
Age at baseline (years) 
<65,  
≥65 to ≤75 
>75 
Sex 
Female 
Male 
Race group 
Asian 
Black 
Caucasian 
Other 
BMI (kg/m2) 
<30 
 ≥ 30 
Region 
Country 
Asia 
CHINA (MAINLAND) 
 
JAPAN 
 
SOUTH KOREA 
 
TAIWAN 
 
SOUTH AFRICA 
Australia & New Zealand 
AUSTRALIA 
 
NEW ZEALAND 
Europe 
BELGIUM 
 
CZECH REP 
 
DENMARK 
 
ESTONIA 
 
HUNGARY 
 
ITALY 
 
LITHUANIA 
 
NETHERLANDS 
 
POLAND 
 
RUSSIA 
 
UK 
 
UKRAINE 
Latin America 
MEXICO 
North America 
CANADA 
 
USA 
Diabetes at baseline 
 
Yes  
(patients with history of 
diabetes mellitus at baseline 
or with baseline HbA1c >= 


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6.5% (48 mmol/mol)) 
No  
(patients without history of 
diabetes mellitus at baseline 
and without baseline HbA1c 
>= 6.5% (48 mmol/mol)) 
Established cardiovascular 
disease at baseline 
Yes  
(patients that meet 1 or more 
of the atherosclerotic CVD 
criteria as defined in 
Inclusion Criteria 3a) 
No  
(patients that do not meet 
any of the atherosclerotic 
CVD criteria as defined in 
Inclusion Criteria 3a) 
High-intensity statin 
 
Yes  
(patients with an ongoing 
treatment with rosuvastatin 
>= 20 mg or atorvastatin >= 
40 mg once daily at the 
randomization visit.) 
No 
(patients without an ongoing 
treatment with rosuvastatin 
>= 20 mg or atorvastatin >= 
40 mg once daily at the 
randomization visit.) 
 
Ezetimibe treatment 
Yes  
(patients with an ongoing 
treatment with Ezetimibe at 
the randomization visit.) 
No 
(patients without an ongoing 
treatment with Ezetimibe at 
the randomization visit.) 
Baseline estimated GFR 
<60 mL/min/1.73 m2 
>= 60 mL/min/1.73 m2 
Baseline high-sensitivity C-
reactive protein 
<0.2 mg/dL (<2 mg/L) 
>=0.2 mg/dL (>=2 mg/L) 
Baseline non-high-density 
lipoprotein cholesterol  
<3.62 mmol/L (<140 mg/dL) 
>=3.62 mmol/L (>=140 
mg/dL) 
<3.387 mmol/L (<300 


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Baseline triglycerides 
mg/dL) 
>=3.387 mmol/L (>=300 
mg/dL) 
Baseline very low-density 
lipoprotein 
<P25 
 
≥P25 and <P50 
 
≥P50 and <P75 
 
≥P75 
Baseline apolipoprotein C III 
<P25 
 
≥P25 and <P50 
 
≥P50 and <P75 
 
≥P75 
 
 


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APPENDIX 2 
LIST OF LABORATORY TESTS 
Category 
Laboratory Tests 
Hematology 
Hematocrit 
Hemoglobin A1c (Hb A1c) 
Hemoglobin* 
Serum Chemistry 
Creatine Kinase 
Alanine Aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Total and Direct Bilirubin 
Creatinine 
Alkaline phosphatase (ALP)** 
Glomerular Filtration Rate (GFR) 
high-sensitivity C-reactive protein 
Plasma Glucose 
Pregnancy Test 
Urine Pregnancy Test 
Lipid Panel 
Triglycerides 
Total cholesterol 
Low-density lipoprotein cholesterol 
High-density lipoprotein cholesterol 
non-high-density lipoprotein cholesterol 
Very low-density lipoprotein cholesterol 
Total cholesterol: high-density lipoprotein cholesterol ratio 
Special Lipid Markers 
Apolipoprotein B-100 
Apolipoprotein C-III 
Plasma and red blood cells Fatty 
Acids 
Eicosapentaenoic acid 
 
Docosahexaenoic acid 
 
Docosapentaenoic acid 
 
Arachidonic acid 
* Hemoglobin values are collected on eCRF Bleeds form only and are analyzed by local 
laboratories. They will be included in the algorithm to classify bleeding events and will be listed, 
but not included in the summary statistics of laboratory evaluations.  
** Alkaline phosphatase values are collected on eCRF Liver Lab form only and are analyzed by 
local laboratories. They will be included in the analysis to identify Hy’s Law cases and will be 
listed, but not included in the summary statistics of laboratory evaluations.  


 
 
71 
APPENDIX 3 
STATISTICAL MODELS 
Appendix 3.1 
Cox proportional hazard model, Kaplan-Meier (KM) 
product-Limit method, event rates and hazard plots 
A. 
Model description 
The Cox proportional hazard model is given by 
ࢎሺ࢚ሻൌࢎ૙ሺ࢚ሻή ࢋ࢞࢖ሺࢄࢼሻ, 
where ࢎሺ࢚ሻ is the hazard function at time t; ࢎ૙ሺ࢚ሻ is the baseline hazard function, X is the 
vector of explanatory variables and E is vector of regression parameters to be estimated.   
The hazard ratio, 95% CI for the hazard ratio, and Wald test p-value comparing the 
treatment arms of Epanova versus placebo (corn oil) will be presented.   
B.  
Implementation 
The Cox proportional hazards model will be implemented in SAS, PROC PHREG. Ties will 
be handled using Breslow’s method, which is the default setting in PROC PHREG. 
C.  
Cox-Snell residuals 
Cox-Snell residuals will be used to assess the overall fit of the Cox proportional hazard 
model as proposed by Kay (1977) who applied the methods in Cox and Snell (1968) to 
derive the residuals for the proportional hazards regression model. 
Suppose a proportional hazards model  
ࢎሺ࢚ሻൌࢎ૙ሺ࢚ሻή ࢋ࢞࢖ሺࢄࢼሻ, 
where ࢎሺ࢚ሻ is the hazard function at time t; ࢎ૙ሺ࢚ሻ is the baseline hazard function, X is the 
vector of explanatory variables and E is vector of regression parameters to be estimated.   
The Cox-Snell residual for the j-th observation is defined as: 
࢘࢐ൌࡴ
̰
૙ሺࢀ࢐ሻࢋ࢞࢖ሺ෍࢈࢑࢞࢐࢑
࢖
࢑ୀ૚
ሻǡ ࢐ൌ૚ǡ Ǥ Ǥ Ǥ ǡ ࢔Ǥ 
Where ࢈ൌሺ࢈૚ǡ Ǥ Ǥ Ǥ ǡ ࢈࢖ሻ are the maximum likelihood estimates of ࢼ from the postulated 
model, ࡴ
̰
૙ሺ࢚ሻ is the Breslow’s estimate of baseline cumulative hazard function at time t and 
ࢀ࢐ is the observed death time for subject j. 
If the model is correct and the ࢈’s are close to the true values of ࢼ then the ࢘࢐ should look 
like a censored sample from a unit exponential distribution. 
To check whether the ࢘࢐’s behave as a sample from a unit exponential, we compute the 
Nelson-Aalen estimator of the cumulative hazard rate of the ࢘࢐’s. If the unit exponential fits 
the data then this estimator should be approximately equal to the cumulative hazard rate of 
the unit exponential ࡴࡱሺ࢚ሻൌ࢚. Thus, a plot of the estimated cumulative hazard rate of 


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the࢘࢐’s, ࡴ࢘൫࢘࢐൯ versus ࢘࢐ should be a straight line through the origin (Klein and 
Moeschberger 1997). Any large departure means that the model is lack of fit otherwise the 
model is adequate. 
D. 
Plot of Schöenfeld residuals (Grambsch and Therneau 1994) 
The Cox proportional hazards model is assuming the hazard functions are proportional and 
remained constant over time between treatment arms and other covariates included in the 
model.  A popular method for evaluating the proportional hazards assumption is to examine 
the Schöenfeld residuals.  Grambsch and Therneau (1994) show that a scaled version of the 
Schöenfeld residuals at time k for a particular covariate p will approximate the change in the 
regression coefficient at time k: 
ࡱ൫ࡿ࢑࢖൯൅ࢼ෡࢖ൎࢼ࢐ሺ࢚࢑ሻ 
Where ࡿ࢑࢖ is the scaled Schöenfeld residual for covariate p at time k; βp is the time-
invariant coefficient, and ࢼ࢐ሺ࢚࢑ሻ is the time-variant coefficient.  In other words, the mean of 
Schöenfeld residual for coefficient βp at time k estimates the changes in the coefficient at 
time k.  Thus, if the mean is 0 across the time that suggests the coefficient βp does not vary 
over time and the proportional hazards assumptions holds for covariate p.   
Considering the relationship with time may not be linear, so time will be transformed onto 
logarithm scale.  Visual inspection of the Schöenfeld residual plot will be made to see if the 
mean value of Schöenfeld residuals departs from 0.  This plot will include a locally 
smoothed curve which will be added to the plot of Schoenfeld to better assess any apparent 
trend. Departure from 0 indicates the coefficient varies from time and the proportional 
hazards assumption does not hold. 
E. 
Test of Treatment-by-time interaction terms 
Treatment-by-time interaction term will be included into the model to test if the treatment 
effect of Epanova is time-dependent.  A statistically significant interaction indicates the 
assumption of proportional hazards between the 2 treatment arms does not hold. If a 
departure from the proportional hazards assumption is detected then this analysis will also 
serve as a sensitivity analysis of the primary treatment effect.    
F. 
Model description 
The KM estimator is a nonparametric estimator of the survival function ࡿሺ࢚ሻ: 
ࡿ෡ሺ࢚ሻൌෑ૚െ
ࢊ࢐
࢔࢐
࢚࢐ஸ࢚
 
where ࢊ࢐ is the number of individuals who experience the event at time ࢚࢐ and ࢔࢐ is the 
number of individuals who have not yet experienced the event at time ࢚࢐ and are therefore 
still at risk. 
G.  
Log-cumulative hazard plots 
Log-cumulative hazard plots will be created by plotting the log of the negative log of the 
KM survival function estimates against the log of the survival time. A visual inspection will 


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be made using the log-cumulative hazard plots method to see if the proportional hazards 
assumption between the two treatment arms is appropriate. Under proportional hazard 
assumption the lines should be approximately parallel with constant vertical separation. 
H. 
Event Rates 
Event rates at specific times (e.g. yearly, etc.) will be expressed as the number of patients 
who have had an event divided by the exposure (in e.g. patient-years) of those at risk of 
having the same type of event.   
 
Appendix 3.2 
Analysis of covariance model 
A. 
Model description 
The analysis of covariance (ANCOVA) model is given by 
࢟࢏ൌࢄࢼ൅ࢋ࢏, 
where ࢟࢏ is the outcome score for the ith patient, X is the vector of explanatory variables, E 
is vector of regression parameters to be estimated and ࢋ࢏is the residual for the ith patient, 
assumed to be normally distributed with mean zero.   
The LS Means are computed as ࡸכ ࢼ where ࡸ is the hypothesis matrix, ࢼ is defined as 
ࢍ࢏࢔࢜ሺࢄᇱࢄሻכ ࢄԢࢅ. 
The hypothesis matrixࡸ is composed by row vectors each corresponding to a single 
hypothesis.  
The row vector of the least square mean for a given effect has all the ࡸ࢏ corresponding to 
continuous covariates set to their mean value, the ࡸ࢏ corresponding to the given level of the 
effect of interest equal to 1,  the ࡸ࢏  corresponding to other levels of the effect of interest 
equal to 0, and all ࡸ࢏ corresponding to other categorical effects equal to  
ଵ
௝ , where j is the 
number of levels of each effect. 
The standard error of ࡸכ ࢼ is defined as ඥࡸכ ࢍ࢏࢔࢜ሺࢄᇱࢄሻכ ࡸᇱכ ࣌૛, where ࢍ࢏࢔࢜ is the 
generalized inverse and the variance of residuals ࣌૛ is estimated by the mean square error. 
 
 


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APPENDIX 4 TIMI BLEED CLASSIFICATIONS DERIVATION 
Major: 
At least one of: 
x Any intracranial bleeding (excluding microhemorrhages) 
Defined as Location = “INTRACRANIAL” or “SUBDURAL HEMATOMA” 
x Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥ 5 
g/dL (0.78 mmol/L) 
Defined as  
a) The difference between prior hemoglobin and any hemoglobin record associated 
with the bleeding event is >= 50 [prior to transfusion] (The SI unit for hemoglobin is 
g/L, so after applying the conversion factor the criteria becomes >= 50 g/L) or the 
difference between prior hematocrit and any hematocrit record associated with the 
bleeding event is >=15%. 
and 
b) Clinically overt signs defined as: 
x CT, MRI, Ultrasound, Endoscopy or “Other Bleeding Procedure” was performed  
and/or 
x If one of the following is checked on the BLEED CRF fields that ask investigators to 
“Select all items that are relevant to this bleed” 
a) required laboratory evaluation is checked OR 
b) required surgical treatment is checked OR 
c) required transfusion is checked OR 
d) required medication change is checked OR 
e) compression or nasal packing is checked OR 
f) tamponade is checked OR 
g) drainage is checked OR 
h) hemostasis of bleeding vessel is checked 
and/or 
x Required a transfusion of the following type: 
a) blood unit is checked OR 
b) re-infuse shed blood is checked OR 
c) platelets is checked OR 


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d) FFP is checked OR 
e) R-factor VIIa is checked OR 
f) cryoprecipitate  is checked OR  
g)  other procoagulant factors is checked 
and/or 
Action Taken with Study treatment (from AE CRF) is “DOSE REDUCED” or “DRUG 
INTERRUPTED”. 
x Fatal bleeding (bleeding that directly results in death within 7 days) 
Defined as Outcome on Bleed eCRF ticked as “FATAL” and end date is within (and 
including) 7 days from start date. 
If end date of bleed is missing assume worst case scenario that patient satisfies this criterion. 
Minor: 
x Clinically overt (including imaging), resulting in hemoglobin drop of 3 to <5 g/dL 
Same definition as in Major for Clinically overt signs (with an additional possible sign of 
“Required imaging to look for bleeding” is checked), however for minor bleeds  
hemoglobin/hematocrit drop is defined as: 
 
a) The difference between prior hemoglobin and any hemoglobin record associated 
with the bleeding event is >= 30 and < 50 [prior to transfusion] (The SI unit for 
hemoglobin is g/L, so after applying the conversion factor the criteria becomes >= 
30 and <50 g/L) or 
b) the difference between prior hematocrit and any hematocrit record associated with 
the bleeding event is >=10% and <15% 
 
Requiring medical attention: 
Any overt sign of hemorrhage that meets one of the following criteria and does not meet 
criteria for a major or minor bleeding event, as defined above 
At least one of:  
x Requiring intervention (medical practitioner-guided medical or surgical treatment to 
stop or treat bleeding, including temporarily or permanently discontinuing or 
changing the dose of a medication or study drug) 
Defined as any intervention of: "MEDICATION CHANGE", "SURGICAL OR 
RADIOLOGY TREATMENT" or a transfusion of any type  
and/or 


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Action Taken with Study treatment (from AE CRF) is “DOSE REDUCED” or “DRUG 
INTERRUPTED”. 
x Leading to or prolonging hospitalization 
Defined as Hospitalization ticked as YES or there is a hospitalization date on the 
corresponding AE CRF for the patient 
x Prompting evaluation (leading to an unscheduled visit to a healthcare professional 
and diagnostic testing, either laboratory or imaging) 
Defined as any evaluation by "HEALTHCARE PROFESSIONAL” has been performed. 
 
Minimal: 
All other bleeding events that are not classified in any of the above categories. 
If the available data are not enough to determine the hemoglobin/hematocrit drop and 
consequently the TIMI bleed classification, the bleeding event will be reported as “Bleeding 
event not categorizable due to missing data”. The location of the bleeding event as collected in 
the eCRF will be tabulated and listed if available to help provide additional information to 
those reviewing the Clinical Study Report (CSR) and manuscripts. 
 
Rules for calculating Hemoglobin/Hematocrit in relation to BLEED event 
x All bleed events requiring laboratory evaluation must have a minimum of 2 entries if 
hemoglobin/hematocrit were evaluated. One entry must be prior to the onset of the 
bleeding event and the second value taken during the assessment of the event. 
NOTE: The hemoglobin/hematocrit value used prior to the start of the bleed event may be 
taken from medical records prior to the subject’s participation in the study. The initial entry 
should be the most recent hemoglobin/hematocrit analysis prior to the current bleed. 
x Any hemoglobin/hematocrit record associated with the bleeding event is defined as a 
record that occurs during the start date of the bleed to the end date of the bleed. If 
multiple records exist, then the record with the lowest result will be used. 
The prior hemoglobin/hematocrit record is defined as the latest record prior to the bleeding 
event being classified that is independent of another bleed. This record can include the 
hemoglobin/hematocrit result from the discharge of the patient due to a previous bleed. If no 
hemoglobin/hematocrit result is available after the first bleeding the hemoglobin/hematocrit 
result prior to the previous bleed can be considered as the prior value if there is a minimum 
time of two months (61 days) between the events.  
x If data between prior and bleed event labs is a mixture of hemoglobin and hematocrit 
the following rules will be utilized: 
o If prior is hemoglobin but bleed event is hematocrit then divide the 


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hematocrit (%) by 3 to calculate hemoglobin (g/dL) equivalent. 
o If prior is hematocrit but bleed event is hemoglobin then divide the prior 
hematocrit (%) by 3 to calculate hemoglobin (g/dL) equivalent  
If the above stated rules are not enough to compute the drop, for example where the 
hemoglobin/ hematocrit result during the bleed is missing or there are no the hemoglobin/ 
hematocrit result prior to the bleed and independent of another bleed, the drop will be 
assumed missing.  
 
 
 
 


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APPENDIX 5 
PTS FOR TERTIARY OUTCOME ANALYSIS OF 
TOTAL THROMBOTIC EVENTS 
The PTs for tertiary outcome analysis of total thrombotic events are given in the table below 
from MedDRA SMQs Embolic and thrombotic events, arterial and Embolic and thrombotic 
events, vessel type unspecified and mixed arterial and venous. 
 
From Embolic and thrombotic events, arterial (MedDRA SMQ) 
 
Amaurosis 
Amaurosis fugax 
Angioplasty 
Aortic embolus 
Aortic thrombosis 
Arterial angioplasty 
Arterial bypass occlusion 
Arterial bypass thrombosis 
Arterial graft 
Arterial stent insertion 
Arterial thrombosis 
Atherosclerotic plaque rupture 
Blindness transient 
Brachiocephalic artery occlusion 
Coeliac artery occlusion 
Embolia cutis medicamentosa 
Embolism arterial 
Femoral artery embolism 
Hepatic artery embolism 
Hepatic artery occlusion 
Hepatic artery thrombosis 
Hypothenar hammer syndrome 
Iliac artery embolism 
Iliac artery occlusion 
Leriche syndrome 
Mesenteric arterial occlusion 
Mesenteric arteriosclerosis 
Mesenteric artery embolism 
Mesenteric artery stenosis 
Mesenteric artery stent insertion 
Mesenteric artery thrombosis 
Ophthalmic artery thrombosis 
Penile artery occlusion 


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Peripheral arterial occlusive disease 
Peripheral arterial reocclusion 
Peripheral artery angioplasty 
Peripheral artery occlusion 
Peripheral artery thrombosis 
Peripheral embolism 
Peripheral endarterectomy 
Popliteal artery entrapment syndrome 
Profundaplasty 
Pulmonary artery occlusion 
Pulmonary artery therapeutic procedure 
Pulmonary artery thrombosis 
Pulmonary endarterectomy 
Pulmonary tumour thrombotic microangiopathy 
Renal artery angioplasty 
Renal artery occlusion 
Renal artery thrombosis 
Renal embolism 
Retinal artery embolism 
Retinal artery occlusion 
Retinal artery thrombosis 
Spinal artery embolism 
Spinal artery thrombosis 
Splenic artery thrombosis 
Splenic embolism 
Subclavian artery embolism 
Subclavian artery occlusion 
Subclavian artery thrombosis 
Thromboembolectomy 
Thrombotic microangiopathy 
Thrombotic thrombocytopenic purpura 
Truncus coeliacus thrombosis 
Vascular pseudoaneurysm thrombosis 
Visual acuity reduced transiently 
 
From Embolic and thrombotic events, vessel type unspecified and mixed arterial and venous 
(MedDRA SMQ) 
 
Administration site thrombosis 
Adrenal thrombosis 
Angiogram peripheral abnormal 
Application site thrombosis 


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Arteriovenous fistula occlusion 
Arteriovenous fistula thrombosis 
Arteriovenous graft thrombosis 
Artificial blood vessel occlusion 
Bone infarction 
Catheter site thrombosis 
Choroidal infarction 
Device embolisation 
Device occlusion 
Device related thrombosis 
Embolic pneumonia 
Embolism 
Eye infarction 
Graft thrombosis 
Haemorrhagic adrenal infarction 
Haemorrhagic infarction 
Hepatic infarction 
Hepatic vascular thrombosis 
Implant site thrombosis 
Incision site vessel occlusion 
Infarction 
Infusion site thrombosis 
Injection site thrombosis 
Inner ear infarction 
Instillation site thrombosis 
Intestinal infarction 
Medical device site thrombosis 
Mesenteric vascular insufficiency 
Mesenteric vascular occlusion 
Microembolism 
Optic nerve infarction 
Pancreatic infarction 
Paradoxical embolism 
Paraneoplastic thrombosis 
Paresis 
Pituitary infarction 
Placental infarction 
Postpartum thrombosis 
Prosthetic cardiac valve thrombosis 
Prosthetic vessel implantation 
Renal infarct 
Renal vascular thrombosis 


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Retinal infarction 
Retinal vascular thrombosis 
Shunt occlusion 
Shunt thrombosis 
Splenic infarction 
Splenic thrombosis 
Stoma site thrombosis 
Surgical vascular shunt 
Testicular infarction 
Thrombectomy 
Thromboangiitis obliterans 
Thrombolysis 
Thrombosis 
Thrombosis in device 
Thrombosis mesenteric vessel 
Thyroid infarction 
Tumour embolism 
Tumour thrombectomy 
Tumour thrombosis 
Vaccination site thrombosis 
Vascular access site thrombosis 
Vascular device occlusion 
Vascular graft occlusion 
Vascular graft thrombosis 
Vascular stent occlusion 
Vascular stent thrombosis 
Vessel puncture site occlusion 
Vessel puncture site thrombosis 
 
 
 
 


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APPENDIX 6 
PTS FOR CARDIOVASCULAR EVENTS 
The PTs for cardiovascular events are given in the table below. 
 
Acute cardiac event 
Acute Coronary Syndrome 
Altered state of consciousness 
Amaurosis 
Amaurosis fugax 
Aneurysm 
Aneurysm repair 
Aneurysm ruptured 
Angina pectoris 
Angina unstable 
Anginal Equivalent 
Angiogram abnormal 
Angiogram cerebral abnormal 
Angiogram peripheral abnormal 
Angioplasty 
Anomalous atrioventricular excitation 
Aortic aneurysm 
Aortic aneurysm repair 
Aortic aneurysm rupture 
Aortic arteriosclerosis 
Aortic bypass 
Aortic calcification 
Aortic dilatation 
Aortic disorder 
Aortic dissection 
Aortic dissection rupture 
Aortic elongation 
Aortic embolus 
Aortic intramural haematoma 
Aortic necrosis 
Aortic occlusion 
Aortic rupture 
Aortic stenosis 
Aortic stent insertion 
Aortic surgery 
Aortic thrombosis 
Aortic valve calcification 
Aortic valve disease 


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Aphasia 
Apparent death 
Apparent death 
Apparent life threatening event 
Arterial bypass operation 
Arterial insufficiency 
Arterial occlusive disease 
Arterial repair 
Arterial restenosis 
Arterial spasm 
Arterial stenosis 
Arterial stent insertion 
Arterial therapeutic procedure 
Arterial thrombosis 
Arteriogram abnormal 
Arteriogram carotid abnormal 
Arteriogram coronary abnormal 
Arteriosclerosis coronary artery 
Arteriospasm coronary 
Artery dissection 
Artificial heart implant 
Ataxia 
Atherectomy 
Atherosclerotic plaque rupture 
Atrial appendage closure 
Atrioventricular block 
Atrioventricular block complete 
Atrioventricular dissociation 
Balance disorder 
Balint's syndrome 
Basal ganglia haematoma 
Basal ganglia haemorrhage 
Basal ganglia infarction 
Basal ganglia stroke 
Basilar artery aneurysm 
Basilar artery occlusion 
Basilar artery perforation 
Basilar artery stenosis 
Basilar artery thrombosis 
Blindness transient 
Blood creatine phosphokinase abnormal 
Blood creatine phosphokinase increased 


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Blood creatine phosphokinase MB abnormal 
Blood creatine phosphokinase MB increased 
Brain death 
Brain herniation 
Brain natriuretic peptide abnormal 
Brain natriuretic peptide increased 
Brain oedema 
Brain operation 
Brain stem haemorrhage 
Brain stem infarction 
Brain stem ischaemia 
Brain stem microhaemorrhage 
Brain stem stroke 
Brain stem syndrome 
Brain stem thrombosis 
Cardiac aneurysm repair 
Cardiac arrest 
Cardiac asthma 
Cardiac complication associated with device 
Cardiac death 
Cardiac discomfort 
Cardiac disorder 
Cardiac dysfunction 
Cardiac enzymes increased 
Cardiac failure 
Cardiac failure acute 
Cardiac failure chronic 
Cardiac failure congestive 
Cardiac failure high output 
Cardiac fibrillation 
Cardiac index decreased 
Cardiac massage 
Cardiac operation 
Cardiac output decreased 
Cardiac perforation 
Cardiac procedure complication 
Cardiac stress test abnormal 
Cardiac tamponade 
Cardiac valve rupture 
Cardiac ventricular disorder 
Cardiac ventriculogram abnormal 
Cardiac ventriculogram left abnormal 


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Cardiac ventriculogram right abnormal 
Cardiogenic shock 
Cardiomegaly 
Cardiomyopathy 
Cardiomyopathy acute 
Cardiomyopathy alcoholic 
Cardioplegia 
Cardiopulmonary bypass 
Cardiopulmonary failure 
Cardio-respiratory arrest 
Cardio-respiratory distress 
Cardiovascular insufficiency 
Carotid aneurysm rupture 
Carotid angioplasty 
Carotid arterial embolus 
Carotid arteriosclerosis 
Carotid artery aneurysm 
Carotid artery bypass 
Carotid artery disease 
Carotid artery dissection 
Carotid artery dolicheoctasia 
Carotid artery insufficiency 
Carotid artery occlusion 
Carotid artery perforation 
Carotid artery restenosis 
Carotid artery stenosis 
Carotid artery stent insertion 
Carotid artery stent removal 
Carotid artery thrombosis 
Carotid endarterectomy 
Carotid revascularisation 
Catheterisation cardiac abnormal 
Central nervous system haemorrhage 
Central venous pressure increased 
Cerebral venous sinus thrombosis 
Cerebellar artery occlusion 
Cerebellar artery thrombosis 
Cerebellar ataxia 
Cerebellar embolism 
Cerebellar haematoma 
Cerebellar haemorrhage 
Cerebellar infarction 


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Cerebellar ischaemia 
Cerebellar microhaemorrhage 
Cerebellar syndrome 
Cerebral aneurysm perforation 
Cerebral arteriosclerosis 
Cerebral arteriovenous malformation haemorrhagic 
Cerebral arteritis 
Cerebral artery embolism 
Cerebral artery occlusion 
Cerebral artery stenosis 
Cerebral artery thrombosis 
Cerebral ataxia 
Cerebral capillary telangiectasia 
Cerebral circulatory failure 
Cerebral disorder 
Cerebral gas embolism 
Cerebral haematoma 
Cerebral haemorrhage 
Cerebral haemorrhage traumatic 
Cerebral hyperperfusion syndrome 
Cerebral hypoperfusion 
Cerebral infarction 
Cerebral ischaemia 
Cerebral microangiopathy 
Cerebral microembolism 
Cerebral microhaemorrhage 
Cerebral reperfusion injury 
Cerebral revascularisation 
Cerebral septic infarct 
Cerebral small vessel ischaemic disease 
Cerebral thrombosis 
Cerebral vascular occlusion 
Cerebral vasoconstriction 
Cerebral venous thrombosis 
Cerebral ventricle dilatation 
Cerebral ventricular rupture 
Cerebrospinal thrombotic tamponade 
Cerebrovascular accident 
Cerebrovascular arteriovenous malformation 
Cerebrovascular disorder 
Cerebrovascular insufficiency 
Cerebrovascular operation 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
87 
Cerebrovascular spasm 
Cerebrovascular stenosis 
Charcot-Bouchard microaneurysms 
Chest discomfort 
Chest pain 
Cheyne-Stokes respiration 
Chronic left ventricular failure 
Chronic right ventricular failure 
Circulatory collapse 
Coma 
Complications of transplanted heart 
Computerised tomogram coronary artery abnormal 
Computerised tomogram head abnormal 
Conduction disorder 
Congestive cardiomyopathy 
Consciousness fluctuating 
Coordination abnormal 
Cor pulmonale 
Cor pulmonale acute 
Cor pulmonale chronic 
Coronary angioplasty 
Coronary arterial stent insertion 
Coronary artery aneurysm 
Coronary artery bypass 
Coronary artery compression 
Coronary artery dilatation 
Coronary artery disease 
Coronary artery dissection 
Coronary artery embolism 
Coronary artery insufficiency 
Coronary artery occlusion 
Coronary artery perforation 
Coronary artery reocclusion 
Coronary artery restenosis 
Coronary artery stenosis 
Coronary artery stent removal 
Coronary artery surgery 
Coronary artery thrombosis 
Coronary bypass thrombosis 
Coronary endarterectomy 
Coronary no-reflow phenomenon 
Coronary ostial stenosis 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
88 
Coronary revascularisation 
Cranial nerve disorder 
Cranial nerve palsies multiple 
Cranial nerve paralysis 
Craniocerebral injury 
Death 
Delayed ischaemic neurological deficit 
Depressed level of consciousness 
Diabetic cardiomyopathy 
Diastolic dysfunction 
Diplegia 
Dissecting coronary artery aneurysm 
Disturbance in attention 
Drain of cerebral subdural space 
Drop attacks 
Dysarthria 
Dysphonia 
Dyspnoea at rest 
Dyspnoea exertional 
Dyspnoea paroxysmal nocturnal 
ECG electrically inactive area 
ECG signs of myocardial ischaemia 
Ejection fraction decreased 
Electrocardiogram Q wave abnormal 
Electrocardiogram QRS complex prolonged 
Electrocardiogram QT interval abnormal 
Electrocardiogram QT prolonged 
Electrocardiogram repolarisation abnormality 
Electrocardiogram ST segment abnormal 
Electrocardiogram ST segment depression 
Electrocardiogram ST segment elevation 
Electrocardiogram ST-T segment abnormal 
Electrocardiogram ST-T segment depression 
Electrocardiogram ST-T segment elevation 
Electrocardiogram T wave abnormal 
Electrocardiogram U wave inversion 
Electrocardiogram U wave present 
Embolic cerebral infarction 
Embolic stroke 
Embolism 
Embolism arterial 
Endarterectomy 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
89 
Exercise electrocardiogram abnormal 
Exercise test abnormal 
Facial nerve disorder 
Facial paresis 
Gait apraxia 
Gait deviation 
Gait disturbance 
Gait spastic 
Generalised oedema 
Gerstmann's syndrome 
Glabellar reflex abnormal 
Graft thrombosis 
Grand mal convulsion 
Haemodynamic instability 
Haemorrhage coronary artery 
Haemorrhage intracranial 
Haemorrhagic cerebral infarction 
Haemorrhagic infarction 
Haemorrhagic stroke 
Haemorrhagic transformation stroke 
Heart and lung transplant 
Heart transplant 
Hemianopia 
Hemianopia heteronymous 
Hemianopia homonymous 
Hemiapraxia 
Hemihyperaesthesia 
Hemidysaesthesia 
Hemiparesis 
Hemiplegia 
Hemisensory neglect 
Hemitaxia 
Hepatojugular reflux 
Hoffmann's sign 
Horner's syndrome 
Hydrocephalus 
Hyperaesthesia 
Hyperdynamic left ventricle 
Hypertrophic cardiomyopathy 
Hypoaesthesia 
Hypogeusia 
Hypoglossal nerve disorder 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
90 
Hypoglossal nerve paralysis 
Hypoglossal nerve paresis 
Hypokinesia 
Hypoperfusion 
Hyporeflexia 
Hyposmia 
Hypovolaemic shock 
IIIrd nerve disorder 
IIIrd nerve paralysis 
IIIrd nerve paresis 
Implantable defibrillator insertion 
Incoherent 
Infarction 
Intra-aortic balloon placement 
Intracardiac pressure increased 
Intracardiac thrombus 
Intra-cerebral aneurysm operation 
Intracerebral haematoma evacuation 
Intracranial aneurysm 
Intracranial artery dissection 
Intracranial haematoma 
Intracranial hypotension 
Intracranial pressure increased 
Intracranial venous sinus thrombosis 
Intraoperative cerebral artery occlusion 
Intrapericardial thrombosis 
Intraventricular haemorrhage 
Ischaemic cardiomyopathy 
Ischaemic cerebral infarction 
Ischaemic mitral regurgitation 
Ischaemic stroke 
IVth nerve disorder 
IVth nerve paralysis 
IVth nerve paresis 
Jugular vein distension 
Kounis syndrome 
Lacunar infarction 
Lacunar stroke 
Lateral medullary syndrome 
Lateropulsion 
Left atrial appendage occlusion 
Left atrial dilatation 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
91 
Left ventricular dysfunction 
Left ventricular failure 
Life support 
Locked-in syndrome 
Long QT syndrome 
Loss of consciousness 
Loss of proprioception 
Low cardiac output syndrome 
Man-in-the-barrel syndrome 
Masked facies 
Mechanical ventilation 
Mechanical ventilation complication 
Meningorrhagia 
Metabolic cardiomyopathy 
Microvascular coronary artery disease 
Monoparesis 
Monoplegia 
Musculoskeletal Chest Pain 
Myocardial haemorrhage 
Myocardial hypoperfusion 
Myocardial infarction 
Myocardial ischaemia 
Myocardial oedema 
Myocardial reperfusion injury 
Myocardial rupture 
Nervous system injury 
Neurological symptom 
Nocturnal dyspnoea 
Non-cardiac chest pain 
Non-cardiogenic pulmonary oedema 
N-terminal prohormone brain natriuretic peptide abnormal 
N-terminal prohormone brain natriuretic peptide increased 
Nystagmus 
Ocular ischaemic syndrome 
Oculocephalogyric reflex absent 
Oculofacial paralysis 
Oedema blister 
Oedema due to cardiac disease 
Oedema peripheral 
Optic nerve infarction 
Orthopnoea 
Ortner's syndrome 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
92 
Papillary muscle infarction 
Papillary muscle rupture 
Paraesthesia 
Paralysis 
Paralysis flaccid 
Paraparesis 
Paraplegia 
Paresis 
Paresis cranial nerve 
Percutaneous coronary intervention 
Pericardial disease 
Pericardial effusion 
Pericardial haemorrhage 
Pericardial rub 
Peripheral nerve paresis 
Peripheral paralysis 
Peripheral Swelling 
Phlebectomy 
Phrenic nerve paralysis 
Pituitary infarction 
Pleural effusion 
Post procedural myocardial infarction 
Post procedural stroke 
Post stroke epilepsy 
Post stroke seizure 
Posthaemorrhagic hydrocephalus 
Postinfarction angina 
Precerebral artery occlusion 
Prinzmetal angina 
Pseudostroke 
Pulmonary hilar enlargement 
Pulmonary microemboli 
Pulmonary oedema 
Pulse absent 
Pulseless electrical activity 
Putamen haemorrhage 
Pyramidal tract syndrome 
Quadriparesis 
Quadriplegia 
Rales 
Red blood cells CSF positive 
Reperfusion arrhythmia 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
93 
Respiratory arrest 
Respiratory failure 
Restenosis 
Restrictive cardiomyopathy 
Resuscitation 
Reversible ischaemic neurological deficit 
Right ventricular diastolic collapse 
Right ventricular dysfunction 
Right ventricular failure 
Ruptured cerebral aneurysm 
Shock 
SI QIII TIII pattern 
Silent myocardial infarction 
Sinoatrial block 
Slow response to stimuli 
Slow speech 
Spasmodic dysphonia 
Spastic diplegia 
Spastic paralysis 
Spastic paraplegia 
Speech disorder 
Spinal artery embolism 
Spinal artery thrombosis 
Spinal cord haematoma 
Spinal cord haemorrhage 
Spinal cord herniation 
Spinal cord infarction 
Spinal cord ischaemia 
Spinal cord paralysis 
Spinal epidural haemorrhage 
Spinal Stroke 
Spinocerebellar disorder 
Stent embolisation 
Stent placement 
Stress cardiomyopathy 
Stress echocardiogram abnormal 
Stroke in evolution 
Subdural effusion 
Subdural haematoma 
Subdural haematoma evacuation 
Subdural haemorrhage 
Subendocardial ischaemia 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
94 
Sudden cardiac death 
Sudden death 
Supranuclear palsy 
Thalamic infarction 
Thalamus haemorrhage 
Thrombectomy 
Thromboembolectomy 
Thrombolysis 
Thrombosis 
Thrombosis in device 
Thrombotic cerebral infarction 
Thrombotic stroke 
Torsade de pointes 
Transient ischaemic attack 
Transmyocardial revascularisation 
Trifascicular block 
Trigeminal nerve disorder 
Trigeminal nerve paresis 
Trigeminal palsy 
Troponin I increased 
Troponin increased 
Troponin T increased 
Ultrasonic angiogram abnormal 
Ultrasound Doppler abnormal 
Unresponsive to stimuli 
Vascular device occlusion 
Vascular graft 
Vascular graft occlusion 
Vascular graft thrombosis 
Vascular insufficiency 
Vascular occlusion 
Vascular stenosis 
Vascular stent insertion 
Vasogenic cerebral oedema 
Venous pressure increased 
Venous pressure jugular abnormal 
Venous pressure jugular increased 
Ventricular arrhythmia 
Ventricular assist device insertion 
Ventricular asystole 
Ventricular dysfunction 
Ventricular dyskinesia 


Statistical Analysis Plan  
Study Code D5881C00004 
Edition Number Version 5.0 
Date 22 April 2020 
 
95 
Ventricular failure 
Ventricular fibrillation 
Ventricular hypertrophy 
Ventricular remodeling 
Ventricular septal defect acquired 
Vertebral artery aneurysm 
Vertebral artery dissection 
Vertebral artery occlusion 
Vertebral artery perforation 
Vertebral artery stenosis 
Vertebral artery thrombosis 
Vertebrobasilar insufficiency 
Vertebrobasilar Stroke 
Vestibular nystagmus 
Vibratory sense increased 
VIIth nerve paralysis 
Visual field defect 
Visual midline shift syndrome 
Visual pathway disorder 
VIth nerve disorder 
VIth nerve paralysis 
VIth nerve paresis 
Wallenberg syndrome 
Wellens' syndrome 
White matter lesion 
XIth nerve paralysis 
 
 
 


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Document Name: d5881c00004-sap-edition-5
Document Title:
Statistical Analysis Plan Edition 5
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3.0 CURRENT LATEST APPROVED
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