Clinical trial NCT01492361
Conditions: Cardiovascular Diseases
Keywords: Coronary Artery Disease Myocardial Ischemia Coronary Disease Heart Diseases Acute Coronary Syndrome Cardiovascular Diseases Arteriosclerosis Arterial Occlusive Diseases Vascular Diseases Angina Pectoris Chest Pain Anticholesteremic Agents Hypolipidemic Agents Lipid Regulating Agents Hypertriglyceridemia Omega-3 Fatty Acids Statin Triglycerides EPA Docosahexaenoic Acid Fish Fatty acids Fibrates Niacin Lipids Lipoprotein Atorvastatin Lovaza Simvastatin Lovastatin Pravastatin Fluvastatin Rosuvastatin Trilipix Vytorin Simcor Ezetimibe Zetia Ethyl-EPA Ethyl Icosapentate Crestor Zocor Lipitor LDL HDL Cholesterol Dyslipidemia AMR101 Cardiovascular Disease, Unspecified VASCEPA Icosapent Ethyl
Sponsor: Amarin Pharma Inc.
Start date: 2011-11-01; Completion date: 2018-05-01
Enrollment: 8179 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
AMR101 (icosapent ethyl \[ethyl-EPA\]) is a highly purified ethyl ester of eicosapentaenoic acid (EPA) developed by Amarin Pharma Inc. for the treatment of cardiovascular disease in statin-treated patients with hypertriglyceridemia. The purpose of this study was to evaluate whether this drug, combined with a statin therapy, will be superior to the statin therapy alone, when used as a prevention in reducing long-term cardiovascular events in high-risk patients with mixed dyslipidemia.

Detailed description:

Arms: arm 1: AMR101 (icosapent ethyl) + statin therapy, daily arm 2: Placebo + statin therapy, daily
Interventions: intervention 1: AMR101 intervention 2: Placebo intervention 3: Statin therapy
Intervention descriptions: intervention 1: Parallel Assignment intervention 2: Parallel Assignment intervention 3: Stable statin therapy (± ezetimibe) for at least 28 days before lipid qualification measurement (LDL-C \>40 mg/dL and ≤100 mg/dL)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
Official Title: 
Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in 
Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular 
Disease: REDUCE-IT (Reduction of Cardiovascular Events With EPA - Intervention Trial) 
 
 
 
 
Protocol Number:  
AMR-01-01-0019 
 
 
 
 
NCT Number:  
NCT01492361 
 
 
 
 
Date of document: 
8 July 2016 
 


This document contains the following items: 
1.
REDUCE-IT Protocols/Protocol Amendments/Summary of Changes
-
Original Protocol dated 2 August 2011
3 
-
Protocol Amendment 1 dated 16 May 2013
101 
-
Final Protocol, Amendment 2 dated 8 July 2016
211 
-
Summary of Changes for Protocol Amendments 1 and 2
343 
2.
REDUCE-IT Original Statistical Analysis Plan (SAP) dated 8 July 2016
356 
-
SAP Addendum dated 15 August 2018
424 
-
Pre-Specified List of Additional Analyses dated 15 August 2018
437 


TM
 
 
 
CLINICAL STUDY PROTOCOL 
A Multi-Center, Prospective, Randomized, Double-Blind, 
Placebo-Controlled, Parallel-Group Study to Evaluate the Effect of AMR101 
on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients 
with Cardiovascular Disease or at High Risk for Cardiovascular Disease: 
REDUCE-IT (Reduction of Cardiovascular Events with EPA – Intervention Trial) 
 
Investigational Product: AMR101 (icosapent ethyl [ethyl-EPA]) 
Protocol Number: AMR-01-01-0019 
 
 
Sponsor: 
Amarin Pharma Inc. 
Mystic Packer Building 
12 Roosevelt Avenue 
Mystic, CT 06355 
Telephone: +1-860-572-4979 
Facsimile: +1-860-572-4940 
 
 
Version Number: Final v 1.0 
Original Protocol: 2 August 2011 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the 
written consent of Amarin Pharma Inc., except to the extent that disclosure would be required 
by law and for the purpose of evaluating and/or conducting a clinical trial for Amarin Pharma 
Inc. You are allowed to disclose the contents of this document only to your Institutional 
Review Board or Independent Ethics Committee and study personnel directly involved with 
conducting this study. Persons to whom the information is disclosed must be informed that 
the information is confidential and proprietary to Amarin Pharma Inc. and that it may not be 
further disclosed to third parties. 


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SIGNATURE PAGE 
TRIAL TITLE: A Multi-Center, Prospective, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group Study to Evaluate the Effect of AMR101 on Cardiovascular 
Health and Mortality in Hypertriglyceridemic Patients with Cardiovascular Disease or at 
High Risk for Cardiovascular Disease: REDUCE-IT (Reduction of Cardiovascular Events 
with EPA – Intervention Trial) 
 
We, the undersigned, have reviewed and approved this protocol. 
 
Signature 
Date 
 
 
 [Name / signature redacted]               
[Signed (09 August 2011)] 
Vice President & Head of Development Operations 
Amarin Pharma Inc. 
 
 
[Name / signature redacted]                 
[Signed (10 August 2011)] 
Senior Vice President & Head of Development 
Amarin Pharma Inc. 
 
 
[Name / signature redacted]                 
[Signed (10 August 2011)] 
Vice President & Head of Regulatory Affairs 
Amarin Pharma Inc. 
 
 
[Name / signature redacted]                 
[Signed (08 August 2011)] 
Principal Investigator 
 
 
 


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SYNOPSIS 
TITLE: 
A Multi-Center, Prospective, Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group Study to Evaluate the Effect of AMR101 on Cardiovascular Health and Mortality in 
Hypertriglyceridemic Patients with Cardiovascular Disease or at High Risk for 
cardiovascular Disease: REDUCE-IT (Reduction of Cardiovascular Events with EPA – 
Intervention Trial) 
PROTOCOL NUMBER: AMR-01-01-0019 
INVESTIGATIONAL PRODUCT: AMR101 (icosapent ethyl [ethyl-EPA]) 
PHASE: 3b 
INDICATION: 
Treatment with AMR101 to reduce the risk of cardiovascular events in patients with clinical 
cardiovascular disease or with multiple risk factors for cardiovascular disease. 
OBJECTIVES: 
The primary objective is, in patients at LDL-C goal while on statin therapy, with established 
cardiovascular disease (CVD) or at high risk for CVD, and hypertriglyceridemia (fasting 
triglycerides, TG, ≥150 mg/dL and <500 mg/dL), to evaluate the effect of 4 g/day AMR101 
for preventing the occurrence of a first major cardiovascular event of the composite endpoint 
that includes: 
• Cardiovascular (CV)  death, 
• Nonfatal myocardial infarction (MI), 
• Nonfatal stroke, 
• Coronary revascularization,  
• Unstable angina determined to be caused  by myocardial is chemia by invasive/non-
invasive testing and requiring emergent hospitalization. 
 
[Because of the variability in TG levels, the lower TG qualifying limit is 10% lower than the 
target of 150 mg/dL, i.e., 135 mg/dL.] 
 
The secondary objectives of this study are the following: 
The key secondary objective is to evaluate the effect of therapy on the composite of death 
from CV causes, nonfatal MI, coronary revascularization, unstable angina, nonfatal stroke, or 
peripheral CVD requiring intervention, angioplasty, bypass surgery, or aneurysm repair. 
 
Other secondary objectives : 
• To evaluate the effect of therapy on co
mbinations of each of the key secondary 
objective clinical events in addition to the following clinical events: 
o Cardiac arrhythmia requiring hospitalization  
o Cardiac arrest 


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o Peripheral CVD requiring intervention, angioplasty, bypass surgery, or 
aneurysm repair 
o Total mortality 
 
The tertiary objectives of this study are the following: 
• Evaluate the effect of therapy on the occu rrence of a second, third, fourth, and fifth 
major cardiovascular event (sam e as the pr imary composite endpoint but for events 
occurring after the first event); 
• To evaluate the effect of therapy on th
e primary endpoint in subgroups of patients 
including: 
o Diabetes mellitus 
o Metabolic syndrome as defined by the NCEP ATP III or future criteria as they 
may evolve; 
• To evaluate the effect of therapy on the individual endpoints of new congestive heart 
failure (CHF), on new  CHF as a prim
ary cause of hospitaliza tion, on transient 
ischemic attack, on amputation for vascular disease and on carotid revascularization; 
• Elective coronary revascularization and emergent coronary revascularization;  
• To assess the ef fects regarding lipids, lip oproteins and inf lammatory markers 
including triglycerides (TG), to tal cholesterol (TC), low-density  lipoprotein 
cholesterol (LDL-C), high- density lipoprotein choles terol (HDL-C), non-HDL-C, 
very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein B (apo B), high 
sensitivity C-reactive protein (hs-CRP) a nd high sensitivity troponin (hsTnT), as 
follows: 
o Assessment of the effect of AMR101 on each marker (on-treatment 
change of markers) 
o Assessment of the effect of the baseline value of each marker on 
treatment effects (baseline effect on outcomes) 
o To evaluate the effect of therapy for preventing clinical events, as 
defined above, among all patients in the study, and in subgroups such as 
patients with diabetes mellitus and patients with substantial on-treatment 
changes of any of the markers (on-treatment effect on outcomes). 
• To evaluate the effect of therapy on new onset diabetes (See appendix C); 
• To explore the effect of AMR101 on weight and waist circumference. 
 
ENDPOINTS: 
Primary endpoint: 
Time from randomization to the first occurrence of the composite of the following clinical 
events: 
• CV death, 


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• Nonfatal MI (including silent MI; ECGs will be performed annually for the detection 
of silent MIs), 
• Nonfatal stroke, 
• Coronary revascularization,  
• Hospitalization for unstable angina determined to be caused by myocardial ischemia 
by invasive/non-invasive testing.  
The first occurrence of any of these major adverse vascular events during the follow-up 
period of the study will be included in the incidence. 
 
Secondary endpoints: 
The key secondary efficacy endpoint is: 
• The composite of death from CV causes, nonfatal MI, coronary revascularization, 
unstable angina, nonfatal stroke, or peripheral CVD requiring intervention, 
angioplasty, bypass surgery, or aneurysm repair. 
Other secondary efficacy endpoints are as follows (to be tested in said order): 
• The composite of total mortality, nonfatal MI, or nonfatal stroke; 
• The composite of death from CV causes, nonfatal MI, coronary revascularization, 
unstable angina, peripheral CVD, or cardiac arrhythmia requiring hospitalization; 
• The composite of death from CV causes, nonfatal MI, coronary revascularization, or 
unstable angina; 
• The composite of death from CV causes or nonfatal MI; 
• Total mortality; 
• Fatal and nonfatal MI (including silent MI); 
• Coronary Revascularization;  
• Hospitalization for unstable angina determined to be caused by myocardial ischemia 
by invasive/non-invasive testing ; 
• Fatal and nonfatal stroke. 
For the secondary endpoints that count a single event, the first occurrence of this type of 
event will be counted in each patient. For secondary endpoints that are composites of two or 
more types of events, the first occurrence of any of the event types included in the composite 
will be counted in each patient. 
 
Tertiary endpoints: 
• The second, third, fourth, and fifth major CV event of the primary composite 
endpoint. The type of (nonfatal) events may occur in any order. 
• Primary endpoint in subset of patients with diabetes mellitus; 
• Primary endpoint in subset of patients with metabolic syndrome; 
• Individual endpoints of new CHF, new CHF leading to hospitalization, transient 
ischemic attack, amputation for CVD and carotid revascularization; 


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• Elective coronary revascularization and emergent coronary revascularization; 
• New onset  diabetes; 
• Fasting TG, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apo B, hs-CRP, and hsTnT: 
on treatment change and baseline effect; 
• CV mortality; 
• Cardiac Arrhythmias requiring hospitalization; 
• Cardiac Arrest; 
• To explore the effect of AMR101 on weight and waist circumference. 
For the tertiary endpoints that count a single event, the first occurrence of this type of event 
will be counted in each patient. For tertiary endpoints that are composites of two or more 
types of events, the first occurrence of any of the event types included in the composite will 
be counted in each patient (except when stated otherwise, for the second, third, fourth, and 
fifth major CV event). 
 
POPULATION: 
Inclusion Criteria: 
1. Fasting TG levels of ≥135 mg/dL and <500 mg/dL. The target for the lower end of the 
fasting TG level is ≥150 mg/dL but because of the variability in TG levels, patients will 
qualify for enrolment within 10% of this limit (i.e., ≥135 mg/dL). 
2. On stable therapy with a statin (with or without ezetimibe), for at least 4 weeks prior to 
the LDL-C/TG baseline qualifying measurements for randomization, to maintain          
LDL-C >40 mg/dL and ≤100 mg/dL  
• 
Stable therapy is defined as the same daily dose of the same statin for at least 28 
days before the lipid qualification measurements (TG and LDL-C) and, if applicable, 
the same daily dose of ezetimibe for at least 28 days before the lipid qualification 
measurements (TG and LDL-C). Patients who have their statin therapy or use of 
ezetimibe initiated at Visit 1, or have their statin, statin dose and/or ezetimibe dose 
changed at Visit 1, will need to go through a stabilization period of at least 28 days 
since initiation/change and have their qualifying lipid measurements measured (TG 
and LDL-C) after the washout period (at Visit 1.1).  
• 
Statins may be administered with or without ezetimibe.   
NOTE: If patients qualify at the first qualification visit (Visit 1) for TG and LDL-C, and 
meet all other inclusion/exclusion criteria, they may be randomized at Visit 2. If patients 
do not qualify at the first qualifying visit (Visit 1), a second re-qualifying visit (Visit 1.1) 
is allowed. For some patients, because they need to stabilize medications and/or need to 
washout medications, the second re-qualifying visit (Visit 1.1) will be needed after the 
stabilization/washout period. 
3. Either having established CVD (in CV Risk Category 1) or at high risk for CVD (in CV 
Risk Category 2). The CV risk categories are defined as follows: 


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CV Risk Category 1: defined as men and women ≥45 years of age with one or more of 
the following: 
o Documented coronary artery d isease (CAD; one or m ore of the following prim ary 
criteria must be satisfied): 
• Documented multi vessel CAD (one or 
more >50% ste nosis in tw o major 
epicardial coronary arteries – with or without antecedent revascularization); 
• Documented prior MI; 
• Hospitalization for high-risk NSTE ACS (w ith objective evidence of is chemia: 
ST-segment deviation or biomarker positivity). 
o Documented cerebrovascular or carotid disease (one of the following primary criteria 
must be satisfied): 
• Documented prior ischemic stroke; 
• Symptomatic carotid artery disease with ≥50% carotid arterial stenosis; 
• Asymptomatic carotid artery disease with ≥70% carotid arterial stenosis per 
angiography or duplex ultrasound; 
• History of carotid revascularization (catheter-based or surgical). 
o Documented peripheral arterial disease (PAD; one or m ore of the following prim ary 
criteria must be satisfied): 
• Ankle-brachial index (ABI) <0.9 with symptoms of intermittent claudication; 
• History of aorto-iliac or peripheral ar
terial intervention (catheter-based or 
surgical). 
OR 
CV Risk Category 2: defined as patients with: 
1. Diabetes mellitus (Type 1 or Type 2) requiring treatment with medication AND 
2. Men and women ≥50 years of age AND  
3. One of the following at Visit 1 (additional risk factor for CVD): 
• Men ≥55 years of age and Women ≥65 years of age; 
• Cigarette smoker or stopped smoking within 3 months before Visit 1; 
• Hypertension (blood pressure ≥140 mmHg systolic OR ≥90 mmHg diastolic) 
or on antihypertensive medication; 
• HDL-C ≤40 mg/dL for men or ≤50 mg/dL for women; 
• hs-CRP >3.0  mg/L; 
• Renal dysfunction: Creatinine clearance (CrCL) >30 and <60 mL/min; 


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• Retinopathy, defined as any of the fo llowing: non-proliferative retinopathy, 
preproliferative retinopathy, proliferative retinopathy, maculopathy, advanced 
diabetic eye disease or a history of photocoagulation; 
• Micro- or macroalbuminuria. Microalbuminuria is defined as either a positive 
micral or other strip test, an albumin
/creatinine ratio ≥2.5 mg/mmol or an 
albumin excretion r ate on tim ed collection ≥20 mg/min all on at least two 
successive occasions; macroalbuminuria, defined as albustix or other dipstick 
evidence of gross proteinuria, an album in/creatinine ratio ≥25 mg/mmol or an 
albumin excretion rate o n timed collection ≥200 mg/min all on at least two 
successive occasions; 
• ABI <0.9 without sym ptoms of intermittent claudication (patients with ABI 
<0.9 with symptoms of intermittent claudication are counted under CV Risk 
Category 1). 
Note: Patients with diabetes and vascular disease as defined above are eligible based 
on the vascular disease requirements and will be counted under CV Risk Category 1. 
Only patients with diabetes and no documented CV disease as defined above need at 
least one additional risk factor as listed, and will be counted under CV Risk 
Category 2. 
4. Women may be enrolled if all 3 of the following criteria are met: 
• They are not pregnant; 
• They are not breastfeeding; 
• They do not plan on becoming pregnant during the study. 
5. Women of child-bearing potential must have a negative urine pregnancy test before 
randomization. 
Note: Women are not considered to be of childbearing potential if they meet one of the 
following criteria as documented by the investigator: 
• They have had a hysterectomy, tubal ligation or bilateral oophorectomy prior to 
signing the informed consent form; 
• They are post-menopausal, defined as ≥1 year since their last menstrual period or 
have a follicle-stimulating hormone (FSH) level in a menopausal range. 
6. Women of childbearing potential must agree to use an effective method of avoiding 
pregnancy from screening to the end of the study, unless their sexual partner(s) is/are 
surgically sterile or the women is abstinent. Effective methods of avoiding pregnancy are 
contraceptive methods used consistently and correctly (including implantable 
contraceptives, injectable contraceptives, oral contraceptives, transdermal contraceptives, 
intrauterine devices, diaphragm with spermicide, male or female condoms with 
spermicide, or cervical cap). 
7. Understanding of the study procedures, willing to adhere to the study schedules, and 
agreement to participate in the study by giving written informed consent prior to 
screening. 


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8. Agree to maintain their current dietary regimen, and to not alter their normal activity 
routines maintain through the duration of the study. 
Exclusion Criteria: 
1. Severe (class IV) heart failure. 
2. Any life-threatening disease expected to result in death within the next 2 years (other 
than CVD). 
3. Active severe liver disease (evaluated at Visit 1): cirrhosis, active hepatitis, ALT or AST 
>3 x ULN, or biliary obstruction with hyperbilirubinemia (total bilirubin >2 x ULN). 
4. Hemoglobin A1c >10.0% at screening (Visit 1). If patients fail this criterion 
(HbA1c >10.0%) at Visit 1, they may have their antidiabetic therapy optimized and be 
retested at Visit 1.1. 
5. Poorly controlled hypertension: blood pressure ≥200 systolic mmHg OR ≥100 mmHg 
diastolic (despite antihypertensive therapy). 
6. Planned coronary intervention (such as stent placement or heart bypass) or any non-
cardiac major surgical procedure. Patients can be (re)evaluated for participation in the 
trial (starting with Visit 1.1) after their recovery from the intervention/surgery. 
7. Known familial lipoprotein lipase deficiency (Fredrickson Type I), apolipoprotein C-II 
deficiency, or familial dysbetalipoproteinemia (Fredrickson Type III)]. 
8. Participation in another clinical trial involving an investigational agent within 90 days 
prior to screening (Visit 1). Patients cannot participate in any other investigational 
medication or medical device trial while participating in this study. 
9. Intolerance or hypersensitivity to statin therapy. 
10. Known hypersensitivity to fish oil products. 
11. History of acute or chronic pancreatitis. 
12. Non-study drug related, non-statin, lipid-altering medications, supplements or foods: 
• Patients are excluded if they used niacin >200 mg/day or fibrates during the last 
28 days before Visit 1, during the screening period and/or plan to use during the 
treatment/follow-up period of the study; 
• Patients are excluded if they take any omega-3 fatty acid medications (prescription 
medicines containing EPA and/or DHA) during the screening period (after Visit 1) 
and/or plan to use during the treatment/follow-up period of the study. To be eligible 
for participation in the study, patients who are taking omega-3 fatty acid medications 
during the last 28 days before Visit 1, need to go through a washout period of at least 
28 days after their last use and have their qualifying lipid measurements measured 
(TG and LDL-C) after the washout period (at Visit 1.1); 
• Patients are excluded if they use dietary supplements containing omega-3 fatty acids 
(e.g., flaxseed, fish, krill, or algal oils) during the screening period (after Visit 1) 
and/or plan to use during the treatment/follow-up period of the study. To be eligible 
for participation in the study, patients who are taking >300 mg/day omega-3 fatty 


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acids (combined amount of EPA and DHA) within 28 days before Visit 1, need to go 
through a washout period of at least 28 days since their last use and have their 
qualifying lipid measurements measured (TG and LDL-C) after the washout period 
(at Visit 1.1); 
• Patients are excluded if they use bile acid sequestrants during the screening period 
(after Visit 1) and/or plan to use during the treatment/follow-up period of the study. 
To be eligible for participation in the study, patients who are taking bile acid 
sequestrants within 7 days before Visit 1, need to go through a washout period of at 
least 7 days since their last use and have their qualifying lipid measurements 
measured (TG and LDL-C) after the washout period (at Visit 1.1); 
13. Other medications (not indicated for lipid alteration): 
• Treatment with tamoxifen, estrogens, progestins, thyroid hormone therapy, systemic 
corticosteroids (local, topical, inhalation, or nasal corticosteroids are allowed), HIV-
protease inhibitors that have not been stable for ≥28 days prior to the qualifying lipid 
measurements (TG and LDL-C) during screening. To be eligible for participation in 
the study, patients who are not taking a stable dose of these medications within 
28 days before Visit 1, need to go through a stabilization period of at least 28 days 
since their last dose change and have their qualifying lipid measurements measured 
(TG and LDL-C) after the washout period (at Visit 1.1); 
• Patients are excluded if they use cyclophosphamide or systemic retinoids during the 
screening period (after Visit 1) and/or plan to use during the treatment/follow-up 
period of the study. To be eligible for participation in the study, patients who are 
taking bile acid sequestrants within 28 days before Visit 1, need to go through a 
washout period of at least 28 days since their last use and have their qualifying lipid 
measurements measured (TG and LDL-C) after the washout period (at Visit 1.1). 
14. Known to have AIDS (patients who are HIV positive without AIDS are allowed). 
15. Requirement for peritoneal dialysis or hemodialysis for renal insufficiency or creatinine 
clearance (CrCL) <30 mL/min. 
16. Unexplained creatine kinase concentration >10 × ULN or creatine kinase elevation due to 
known muscle disease (e.g., polymyositis, mitochondrial dysfunction) at Visit 1. 
17. Any condition or therapy which, in the opinion of the investigator, might pose a risk to 
the patient or make participation in the study not in the patient’s best interest. 
18. Drug or alcohol abuse within the past 6 months, and unable/unwilling to abstain from 
drug abuse and excessive alcohol consumption during the study. Excessive alcohol 
consumption is on average >2 units of alcohol per day. A unit of alcohol is defined as a 
12-ounce (350 mL) beer, 5-ounce (150 mL) wine, or 1.5-ounce (45 mL) of 80‐proof 
alcohol for drinks. 
19. Mental/psychological impairment or any other reason to expect patient difficulty in 
complying with the requirements of the study or understanding the goal and potential 
risks of participating in the study (evaluated at Visit 1). 
 


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STUDY DESIGN AND DURATION: 
This is a multi-center, multi-national, prospective, randomized, double-blind, placebo-
controlled, parallel-group study. 
 
This is an event-driven trial: It is expected that a minimum of 1612 primary efficacy endpoint 
events will be required during the study. Approximately 7990 patients will be randomized at 
multiple Research Sites worldwide over a planned period of 18 months. After randomization, 
patients will be treated and followed over 3.25-4.75 years with a planned median follow-up 
of 4 years. The study end date is determined to be when approximately 1612 primary efficacy 
events have occurred. 
 
Screening Period: 
During the screening period, patients will be evaluated for inclusion/exclusion criteria. 
Patients will be eligible for randomization if they meet all the inclusion/exclusion criteria. 
Prospectively, eligible patients with documented CVD or diabetes (with at least one 
additional risk factor for CVD) will undergo screening to establish suitability for inclusion in 
the trial. The qualifying lipid determination at Visit 1 requires that eligible patients must have 
a fasting TG level ≥135 mg/dL and <500 mg/dL in order to enter the treatment/follow-up 
period of the trial (and they need to meet all other inclusion/exclusion criteria). These 
patients will be randomized at Visit 2, which will occur soon after Visit 2 (there will be no 
Visit 1.1 for these patients). 
Patients who do not qualify at Visit 1, may return to the Research Site for a second qualifying 
visit (Visit 1.1) at which time procedures that caused failure of eligibility at Visit 1 will be 
repeated. In this case, patients will be eligible for randomization after Visit 1.1 if they meet 
all inclusion criteria and if they no longer fail the exclusion criteria. 
For some patients, Visit 1.1 will be mandatory at least 28 days after Visit 1 in order to check 
eligibility. These are patients who at Visit 1 started treatment with a statin, changed their 
statin, changed the daily dose of their statin, started to washout prohibited medications or 
started a stabilization period with certain medications. Any of these changes at Visit 1 may 
affect the qualifying lipid levels and therefore, patients will need to have Visit 1.1 to 
determine whether they qualify based on lipid level requirements (TG and LDL-C) 
determined at Visit 1. Other procedures that caused failure of eligibility at Visit 1 will also be 
repeated at Visit 1.1. Details are listed in the main section of the protocol. 
 
Treatment/Follow-Up Period: 
At Visit 2 (Day 0), eligible patients will be randomly assigned 1:1 to one of the following 
treatment groups: 
• AMR101 4 g daily, or 
• Placebo. 
Stratification will be by CV risk category (established CVD or the presence of diabetes with 
≥1 risk factor for CVD), use of ezetimibe and by geographical region (Westernized, Eastern 
European, and Asia Pacific countries). 
 


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During the treatment/follow-up period, patients will return to the Research Site at regular 
intervals for efficacy and safety evaluations, and drug supply and compliance checks. The 
visits after the randomization visit (Visit 2; Day 0) are at approximately after 6 months for 
Visit 3, and then every year thereafter. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Eligible patients will be randomly assigned at Visit 2 to receive orally AMR101 4 g daily or 
matching placebo. AMR101 is provided in 1000 mg liquid-filled, oblong, gelatin capsules. 
The matching placebo capsule is filled with light liquid paraffin and contains 0 mg of 
AMR101. AMR101 capsules are to be taken with food (i.e. with or at the end of a meal). 
 
During the treatment period, the daily dose of study drug is 4 capsules per day taken as two 
capsule taken on two occasions per day (2 capsule given twice daily). 
STATISTICAL ANALYSES: 
• Intent-to-treat analysis. 
• Parameters will be su mmarized using m ean, standard d eviation, median, minimum, 
maximum, and interquartile range for contin uous data an d percentage for catego rical 
data. 
• Survival analysis using the log-rank test for the primary efficacy outcome comparing the 
2 treatment groups (AMR101 and Placebo ) and including the stratification factors CV 
risk category, use of e
zetimibe and by ge ographical region ( Westernized, Eastern 
European, and Asia Pacific countries). 
• All statistical analyses for the efficacy and safety outcomes will be performed at the 5% 
significance level using 2-sided tests unless otherwise noted. 
• One interim analysis is planned when approximately 60% of the planned total number of 
events has occurred. 
 
The analysis is planned to: 
• Describe at base line: Patient characteristics, including lipids and lipo proteins, stroke 
history, cardiovascular risk factors, diabetes mellitus, or metabolic syndrome, among 
others. 
• Compare the primary, secondary, and tertiary endpoints between treatment groups at the 
corresponding follow-up time points. 


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SAMPLE SIZE DETERMINATION: 
Sample size estimation is based on the assumption that the primary composite endpoint (time 
from randomization to the first occurrence of CV death, non-fatal MI, non-fatal stroke, 
coronary revascularization, or unstable angina requiring hospitalization) would be relatively 
reduced by 15%, from an event rate by 4 years of 23.6% in the placebo group to 20.5% in the 
AMR101 group. It is expected that a minimum of 1612 primary efficacy endpoint events will 
be required during the study. A total of approximately 6990 patients are needed to be able to 
detect this difference at 4.76% significance level (decreased from 5.00% because of one 
interim analysis) and with 90% power, assuming an 18-month enrollment period and a 
median follow-up of 4 years. The current sample size calculation is based on an estimated 
placebo yearly event rate of 5.9% (23.6% over 4 years). To protect against the possibility that 
the actual placebo event rate is lower than estimated, an extra 1000 patients will be enrolled 
(approximately 7990 patients in total). By adding the extra 1000 patients, the event rate in the 
placebo group could be 5.2% per year (20.8% over 4 years) without having to modify the 
other sample size assumptions. Before completing the enrollment phase of the trial, the actual 
event rate based on pooled, blinded accumulation of primary efficacy endpoint events will be 
calculated and may be used to increase the sample size. If the sample size is increased, the 
enrollment phase will be extended to allow enrollment of the additional patients. 
SPONSOR: 
Amarin Pharma Inc. 
Mystic Packer Building 
12 Roosevelt Avenue 
Mystic, CT 06355 
Telephone: +1-860-572-4979 
Facsimile: +1-860-572-4940 
 
 


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TABLE OF CONTENTS 
1. 
INTRODUCTION AND BACKGROUND INFORMATION ...................................... 21 
1.1. 
Background ............................................................................................................. 21 
1.2. 
Summary of Amarin-Sponsored Clinical Studies with AMR101........................... 22 
1.3. 
Study AMR-01-01-0017 (ANCHOR Study) .......................................................... 22 
1.4. 
Clinical Safety ......................................................................................................... 24 
1.5. 
Rationale ................................................................................................................. 24 
1.6. 
Risk/Benefit ............................................................................................................ 32 
2. 
STUDY OBJECTIVES ................................................................................................... 32 
3. 
STUDY DESIGN............................................................................................................ 34 
3.1. 
Type of Study .......................................................................................................... 34 
3.2. 
Study Population ..................................................................................................... 34 
3.3. 
Study Periods .......................................................................................................... 34 
3.4. 
Study Duration ........................................................................................................ 35 
3.5. 
Study Groups .......................................................................................................... 35 
3.6. 
Number of Patients ................................................................................................. 36 
3.7. 
Number of Study Sites ............................................................................................ 36 
3.8. 
Randomization ........................................................................................................ 36 
3.9. 
Blinding................................................................................................................... 36 
3.10.  Stratification ............................................................................................................ 36 
4. 
STUDY POPULATION ................................................................................................. 37 
4.1. 
Inclusion Criteria .................................................................................................... 37 
4.2. 
Exclusion Criteria ................................................................................................... 39 
5. 
STUDY COMMITTEES ................................................................................................ 41 
5.1. 
Steering Committee ................................................................................................ 41 
5.2. 
Study Operations Committee (SOC) ...................................................................... 42 
5.3. 
Clinical Event Committee (CEC) ........................................................................... 42 
5.4. 
Data and Safety Monitoring Board (DSMB) .......................................................... 42 
6. 
STUDY PROCEDURES ................................................................................................ 42 
6.1. 
Assessment Schedule .............................................................................................. 42 


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6.1.1. 
Screening Period ............................................................................................. 42 
6.1.2. 
Treatment/Follow-Up Period .......................................................................... 44 
6.2. 
Telephone Follow-up Contact................................................................................. 47 
6.3. 
Laboratory Procedures ............................................................................................ 48 
6.3.1. 
Clinical Laboratory Procedures ...................................................................... 48 
6.3.2. 
Medical Procedures ......................................................................................... 50 
7. 
TREATMENT AND RESTRICTIONS ......................................................................... 51 
7.1. 
Treatment ................................................................................................................ 51 
7.1.1. 
Treatment Regimen, Dosage, and Duration .................................................... 51 
7.1.2. 
Treatment Assignment .................................................................................... 52 
7.1.3. 
Compliance Control ........................................................................................ 52 
7.2. 
Study Restrictions ................................................................................................... 53 
7.2.1. 
Concomitant Medications during Treatment/Follow-Up Period .................... 53 
7.2.2. 
Patient Restrictions ......................................................................................... 54 
8. 
INVESTIGATIONAL PRODUCT ................................................................................. 54 
8.1. 
Clinical Trial Material ............................................................................................. 54 
8.2. 
Pharmaceutical Formulations .................................................................................. 55 
8.3. 
Labeling and Packaging .......................................................................................... 55 
8.4. 
Dispensing Procedures and Storage Conditions ..................................................... 55 
8.4.1. 
Dispensing Procedures .................................................................................... 55 
8.4.2. 
Storage Conditions .......................................................................................... 56 
9. 
EFFICACY ASSESSMENTS ........................................................................................ 56 
9.1. 
Specification of Variables and Procedures ............................................................. 56 
9.2. 
Efficacy Endpoints .................................................................................................. 56 
9.2.1. 
Primary Efficacy Endpoint ............................................................................. 56 
9.2.2. 
Secondary Efficacy Endpoints ........................................................................ 56 
9.2.3. 
Tertiary Efficacy Endpoints: ........................................................................... 57 
10. 
SAFETY ASSESSMENTS ......................................................................................... 58 
10.1.  Specification of Variables and Procedures ............................................................. 58 
10.2.  Adverse Events ....................................................................................................... 58 
10.2.1. 
Serious Adverse Events .................................................................................. 60 
10.3.  Serious Adverse Event Reporting – Procedure for Investigators ........................... 60 
10.3.1. 
Initial Reports .................................................................................................. 60 
10.3.2. 
Follow-Up Reports.......................................................................................... 61 
10.3.3. 
Reporting by the Sponsor................................................................................ 61 
10.4.  Exposure In Utero During Clinical Trials .............................................................. 61 


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11. 
TREATMENT DISCONTINUATION/PATIENT WITHDRAWAL ........................ 61 
11.1.  Reasons for Early Study Drug Discontinuation ...................................................... 61 
11.2.  Follow-Up after Early Study Drug Discontinuation/Lost to Follow-Up ................ 62 
12. 
STATISTICS .............................................................................................................. 62 
12.1.  Analysis Populations ............................................................................................... 62 
12.1.1. 
Randomized Population .................................................................................. 62 
12.1.2. 
Intent-to-Treat Population ............................................................................... 63 
12.1.3. 
Per-Protocol Population .................................................................................. 63 
12.1.4. 
Safety Population ............................................................................................ 63 
12.2.  Statistical Methods .................................................................................................. 63 
12.2.1. 
Patient Disposition and Demographic/Baseline Characteristics ..................... 63 
12.2.2. 
Study Medication Exposure and Compliance ................................................. 63 
12.2.3. 
Concomitant Therapies ................................................................................... 64 
12.2.4. 
Analysis of Efficacy ........................................................................................ 64 
12.2.5. 
Analysis of Safety ........................................................................................... 66 
12.3.  Sample Size Determination ..................................................................................... 66 
13. 
MONITORING, DATA MANAGEMENT, AND RECORD KEEPING .................. 67 
13.1.  Data Management ................................................................................................... 67 
13.1.1. 
Data Handling ................................................................................................. 67 
13.2.  Record Keeping ...................................................................................................... 67 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ......................................... 67 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 67 
16. 
ETHICS AND GOOD CLINICAL PRACTICE COMPLIANCE ............................. 68 
17. 
INFORMED CONSENT ............................................................................................ 68 
18. 
PUBLICATION POLICY .......................................................................................... 69 
19. 
Financing and Insurance ............................................................................................. 69 
19.1.  Finances .................................................................................................................. 69 
19.2.  Insurance Compensation ......................................................................................... 69 
20. 
Completion of Study ................................................................................................... 69 
21. 
STUDY ADMINISTRATIVE INFORMATION ....................................................... 69 
21.1.  Protocol Amendments ............................................................................................. 69 
22. 
REFERENCES ........................................................................................................... 71 


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23. 
INVESTIGATOR’S AGREEMENT .......................................................................... 76 
APPENDIX A: 
SCHEDULE OF PROCEDURES........................................................... 77 
APPENDIX B: STANDARDIZED DEFINITIONS FOR END POINT EVENTS IN 
CARDIOVASCULAR TRIALS ............................................................................................. 79 
Definition of Cardiovascular Death ........................................................................................ 79 
Definition of Non-Cardiovascular Death ................................................................................ 81 
Definition of Undetermined Cause of Death .......................................................................... 82 
Definition of Myocardial Infarction ........................................................................................ 83 
Common Classification Schemes for Myocardial Infarction Categories ............................... 87 
Definition of Hospitalization for Unstable Angina ................................................................. 89 
Definition of Transient Ischemic Attack and Stroke .............................................................. 91 
Definition of Heart Failure Requiring Hospitalization ........................................................... 92 
Interventional Cardiology Definitions .................................................................................... 94 
Definition of Peripheral Arterial Revascularization Procedure .............................................. 96 
APPENDIX C: Criteria for the Diagnosis of Diabetes ........................................................... 98 
 
LIST OF TABLES 
Table 1. Incidence of Common TEAEs (>3% in Any Treatment Group) by Preferred Term
 ............................................................................................................................ 24 
Table 2.  Dosing Schedule during the Treatment Period .................................................. 51 
Table 3.  Components of AMR101 Capsules .................................................................... 55 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AA 
Arachidonic acid 
ABI 
Ankle-brachial index 
ACC 
American College of Medicine 
ACS 
Acute coronary syndrome 
AHA 
American Heart Association 
AIDS 
Acquired immune deficiency syndrome 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AP 
Angina pectoris 
apo B 
Apolipoprotein B 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CABG 
Coronary artery bypass graft 
CAD 
Coronary artery disease 
CBC 
Complete blood count 
CEC 
Clinical Event Committee 
CI 
Confidence interval 
CHD 
Coronary heart disease 
CHF 
Congestive heart failure 
CK-MB 
Creatine kinase-MB fraction 
CrCL 
Creatinine clearance 
CNS 
Central nervous system 
CRF 
Case Report Form 
CT 
Computed tomography 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
%CV 
Percent coefficient of variation 
DART 
Diet and Reinfarction Trial 
DCCT 
Diabetes Control and Complications Trial 
DHA 
Docosahexaenoic acid 
DSMB 
Data and Safety Monitoring Board 
EDC 
Electronic data capture 
ECG 
Electrocardiogram 
EPA 
Eicosapentaenoic acid 
Ethyl-EPA 
Ethyl icosapentaenoate; icosapent ethyl 
FSH 
Follicle-stimulating hormone 
GC/FID 
Gas chromatograph with flame ionization detector 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GISSI 
Gruppo Italiano per lo Studio della Sopravvivenza 
nell’Infarto Miocardico 
Hct 
Hematocrit 


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HDL-C 
High-density lipoprotein cholesterol 
HF 
Heart failure 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
hs-CRP 
High-sensitivity C-reactive protein 
hsTnT 
High-sensitivity troponin T 
HR 
Hazard ratio 
ICAM-1 
Intercellular adhesion molecule-1 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
EC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IVRS 
Interactive voice response system 
JELIS 
Japan Eicosapentaenoic Acid Lipid Intervention Study 
LBBB 
Left bundle branch block 
LC-MS/MS 
Liquid chromatography with tandem mass spectrometry 
LDL-C 
Low-density lipoprotein cholesterol 
MACE 
Major adverse coronary event 
MI 
Myocardial infarction 
NCEP 
National Cholesterol Education Program 
NGSP 
National Glycohemoglobin Standardization Program 
NMR 
Nuclear magnetic resonance 
NO 
Nitric oxide 
NSTE-ACS 
Non-ST-Segment Elevation Acute Coronary Syndrome 
O3FA 
Omega-3 fatty acid 
OGTT 
Oral Glucose Tolerance Test 
PAD 
Peripheral arterial disease 
PCI 
Percutaneous coronary intervention 
PH 
Proportional hazard 
PI 
Principal investigator 
PP 
Per protocol 
PROVE-IT 
Pravastatin or Atorvastatin Evaluation and Infection Therapy 
PTCA 
Percutaneous transluminal coronary angioplasty 
RBC 
Red blood cells 
RR 
Relative risk 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SCD 
Sudden cardiac death 
SD 
Standard deviation 
SOC 
Study Operations Committee 
SPC 
Summary of Product Characteristics 
ST 
Steering committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1/2 
Half-life 


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TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TG 
Triglycerides 
TIMI 
Thrombolysis In Myocardial Infarction 
Tmax 
Time of maximum concentration 
ULN 
Upper limit of normal 
USPI 
United States Prescribing Information 
VCAM-1 
Vascular cell adhesion molecule-1 
VF 
Ventricular fibrillation 
WBC 
White cell blood count 


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1. 
INTRODUCTION AND BACKGROUND INFORMATION 
AMR101 (icosapent ethyl [ethyl-EPA]) is a highly purified ethyl ester of eicosapentaenoic 
acid (EPA) derived from fish oil, and is being developed by Amarin Pharma Inc. (hereafter 
referred to as Amarin or the Sponsor) for the treatment of hypertriglyceridemia. The purpose 
of this study is to evaluate whether the triglyceride-lowering drug AMR101, combined with a 
statin therapy, will be superior to the statin therapy alone, when used as a prevention in 
reducing long-term clinical events in patients with mixed dyslipidemia at high risk for 
cardiovascular (CV) events. 
1.1. 
Background 
Since the initial observation of a link between fish oil consumption and the reduced incidence 
of coronary heart disease in the Eskimos of Greenland (Bang 1972), a large body of evidence 
has accumulated showing that regular intake of omega-3 fatty acids (O3FAs) exerts 
cardioprotective effects in both primary and secondary coronary heart disease prevention 
(Harris 2008, Lee 2008). Several mechanisms have been proposed to account for these 
beneficial effects, including the reduction of triglycerides (TG), suppression of cardiac 
arrhythmias, decreased platelet aggregation, improved plaque composition and stabilization, 
and hemodynamic changes. This mounting body of evidence has led the American Heart 
Association (AHA) to recommend the consumption of O3FAs in dietary fish or in capsule 
form at a dose of 1 g/day for secondary prevention of cardiovascular disease (CVD) (Kris-
Etherton 2002). This recommendation has now been included in American College of 
Cardiology/American Heart Association (ACC/AHA) guidelines for the long-term 
management of patients with stable angina and acute coronary syndromes (Antman 2004, 
Fraker 2007, Anderson 2007). 
A large number of studies have also demonstrated the triglyceride-lowering effects of O3FAs 
(Harris 1997, Ginsberg 2001). The US FDA has approved a product containing 
approximately 90% esters of the O3FAs EPA and DHA for use at a dose of 4 g/day as an 
adjunct to diet for the treatment of patients with very high triglyceride levels (≥500 mg/dL) 
(Lovaza® USPI 2009). The same medicinal product under the name Omacor® (Omacor SPC 
2008) is approved in Europe for the treatment of endogenous hypertriglyceridemia at a dose 
of up to 4 grams daily as a supplement to diet when dietary measures alone are insufficient to 
produce an adequate response. Omacor® at a dose of 1 gram daily is also approved in key 
European and certain Asian markets for the secondary prevention of myocardial infarction 
(Post-MI). 
Epadel® capsules, which contain highly purified (>95%) ethyl-EPA, have been marketed by 
Mochida in Japan since 1991 for the treatment of arteriosclerosis obliterans and since 1994 
for the treatment of hyperlipidemia (Epadel SPC 2007). The recommended dose is 1.8 g/day 
for arteriosclerosis obliterans and 1.8 to 2.7 g/day for hyperlipidemia. Hypertriglyceridemia 
is a feature of many dyslipidemias and often occurs in persons who are obese and/or have 
Type 2 diabetes mellitus in isolation or as a component of the metabolic syndrome (Jacobson 
2007, Bays 2008). 
Elevation in TG confers dual risks of acute pancreatitis (most marked in patients with severe 
hypertriglyceridemia [TG >1500 mg/dL]) (Yadav 2003) and accelerated atherosclerosis 


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leading to CV events, the latter even after correction for other lipid and non-lipid risk factors 
(Jacobson 2007). With this in mind, Amarin is assessing the potential of AMR101 capsules, 
which contain highly purified icosapent ethyl (ethyl-EPA), for the treatment of patients, as an 
adjunct to diet, with very high TG levels (≥500 mg/dL) and those with high TG levels (≥200 
and <500 mg/dL) despite optimal statin therapy. Amarin-sponsored studies with AMR101 in 
patients with very high TGs (Study AMR-01-01-0016, the MARINE study) and in patients 
with high TGs on statins (Study AMR-01-01-0017, the ANCHOR study) are in progress. 
1.2. 
Summary of Amarin-Sponsored Clinical Studies with AMR101 
To date, Amarin has completed 8 double-blind, placebo-controlled clinical trials with 
AMR101 in patients with CNS disorders including Huntington’s disease, depression, 
schizophrenia and age-associated memory impairment. Males and females were almost 
equally represented. The majority of patients were Caucasian, but the studies also included, 
among the patients receiving AMR101, 14 Blacks, 6 Asians and 11 patients of another race.  
The patients received 0.5-4 g/day AMR101 or placebo. The duration of the double-blind 
treatment period ranged from 6 weeks to 1 year. In addition, 24 healthy volunteers have 
received AMR101 2 g/day for up to 28 days in a pharmacokinetic study (LA01.01.0009). In 
these studies, AMR101 was administered in the form of 500-mg soft gelatin capsules, orally 
with meals as a twice-daily regimen with half of the daily dose in the morning and half in the 
evening. 
Across all 9 completed Amarin-sponsored studies (1 in healthy volunteers and 8 in patients), 
a total of 1243 patients were randomized (24 healthy volunteers and 1219 patients with CNS 
disorders). From the 1243 patients, 724 (24 healthy patients and 700 patients) were 
randomized to receive AMR101 and 519 to receive placebo. See the Investigator’s Brochure 
for more information. 
In 4 of the Amarin-sponsored studies in patients with CNS disorders, patients who completed 
the double-blind period were rolled-over into an open-label extension phase and received 1-
2 g/day AMR101 (most received 2 g/day). The treatment period in the open-label extensions 
ranged from 6 months to 1 year. Across all studies, including patients from the double-blind 
periods receiving AMR101 and also those switched from placebo to AMR101 in the open-
label extensions, a total of 1071 patients have been exposed to ethyl-EPA from AMR101 
capsules. 
In addition, two Phase 3 studies in patients with hypertriglyceridemia have been completed . 
These trials have investigated the efficacy of AMR101 in lowering triglycerides: 
• Study AMR-01-01-0016 (the MARINE study) in 229 patients with very high 
triglycerides (>500 mg/dL). 
• Study AMR-01-01-0017 (the ANCHOR study) in approximately 702 patients 
with mixed dyslipidemia (high triglycerides: ≥200 to <500 mg/dL) who are taking 
statins 
 
1.3. 
Study AMR-01-01-0017 (ANCHOR Study) 
The results from the ANCHOR study are particularly relevant for the dose selection of the 
present study since the ANCHOR study was conducted in the same patient population. The 


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primary objective in the ANCHOR study was to determine the efficacy of AMR101 2 g daily 
and 4 g daily, compared to placebo, in lowering fasting TG levels in patients with high risk 
for cardiovascular disease (CVD) and fasting TG levels ≥200 mg/dL and <500 mg/dL, 
despite treatment to low density lipoprotein cholesterol (LDL-C) goal (>40 mg/dL and <100 
mg/dL) on statin therapy. 
After a 6- to 8-week screening period which included diet and lifestyle stabilization, a 
washout period for excluded non-statin lipid-altering medications (if needed), and a TG 
qualifying period, patients were randomized to one of 3 treatment groups and received study 
medication during a 12-week, double-blind treatment period. Patients had to be treated with 
one of 3 statins (simvastatin, atorvastatin or rosuvastatin) to reach their LDL-C goal of 100 
mg/dL (+15% allowed for variability) and had to be on a stable dose for a minimum period 
of 4 weeks before the TG qualifying measurements. The TG target for enrollment was for 
patients to have qualifying fasting TG levels of ≥200 mg/dL and <500 mg/dL based on the 
mean of 2 measurements. During the 12-week double-blind treatment period, patients 
received orally AMR101 2 g/day, AMR101 4 g/day, or placebo. 
In the ITT population (687 patients), the baseline median TG level was 259.0 mg/dL (IQR: 
81.00 mg/dL), 264.8 mg/dL (IQR: 93.00 mg/dL) and 254.0 mg/dL (IQR: 92.50 mg/dL) for 
the patients receiving placebo, AMR101 4 g/day and AMR101 2 g/day, respectively. At the 
Week 12 endpoint, the median percent change from baseline TG level was +5.9%, -17.5% 
and-5.6% for the patients receiving placebo, AMR101 4 g/day and AMR101 2 g/day, 
respectively. The median difference between AMR101 4 g/day and placebo was -21.5% 
(p<0.0001). The median difference between AMR101 2 g/day was -10.1% (p=0.0005). 
The TG lowering effect of AMR101 was similar in males and females at the 4 g/day dose. 
Efficacy of AMR101 was similar in diabetics and non-diabetics, and was similar irrespective 
of the type of statin administered. The higher the potency of the statin regimen, the greater 
the TG reduction in the AMR101 4 g/day group. The higher the baseline TG tertile, the 
greater the TG reduction for both AMR101 dose groups. 
Key lipoprotein variables were decreased by AMR101 even after patients were on stable 
doses of statin therapy, with LDL-C levels at goal. Compared to placebo, statistically 
significant reductions with AMR101 were observed for non-HDL-C, Apo B, Lp-PLA2, 
VLDL-C, TC and VLDL-TG for both dose groups. The Apo B placebo-adjusted percent 
change from baseline was reduced by 9.3% in the AMR101 4 g/day group versus the placebo 
group (p<0.0001). 
The non-inferiority criterion for LDL-C was met at both AMR101 doses, because the pre-
specified upper boundary of the 97.5% confidence interval (-1.7 and 0.05 for AMR101 4 
g/day and AMR101 2 g/day, respectively) did not cross the 6% non-inferiority threshold. For 
the AMR101 4 g/day group, LDL-C decreased significantly by 6.2% versus placebo, 
demonstrating superiority over placebo (p=0.0067). 
TC and VLDL-TG decreased significantly relative to placebo in both AMR101 dose groups, 
and high sensitivity C-reactive protein (hsCRP) decreased significantly (p=0.0003) by 
0.5 mg/L relative to placebo in the AMR101 4 g/day group. HDL-C was unchanged in the 
groups, but relative to placebo, there were small decreases of -4.5% and -2.2% for the 
AMR101 4 g/day and 2 g/day treatment groups, respectively. The difference was statistically 
significant for the AMR101 4 g/day group compared to placebo (p=0.0013). 


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1.4. 
Clinical Safety 
Across all completed Amarin-sponsored studies, during the double-blind periods of the trials, 
a total of 1071 patients have been exposed to ethyl-EPA from AMR101 capsules. AMR101 
has been well tolerated (with incidence of adverse events similar to placebo) and there have 
been no major safety concerns. The most commonly reported side effects for AMR101 were 
diarrhea, nausea, headache, arthralgia, and skin rash. See the Investigator’s Brochure for 
more information. 
In the pivotal Phase 3 trials in patients with hypertriglyceridemia, treatment with AMR101 at 
doses of 2 and 4 g/day was safe and well tolerated with no safety concerns. The types (by 
preferred term) of common treatment-emergent adverse events (TEAEs) and their incidence 
in the MARINE and ANCHOR trials, are listed in Table 1. 
 
Table 1. Incidence of Common TEAEs (>3% in Any Treatment Group) by Preferred 
Term 
 
Number (%) of Patients with TEAE 
Preferred Term 
Placebo 
n (%)  
AMR101 
2 g/day 
n (%) 
AMR101 
4 g/day 
n (%) 
 
 
MARINE Study 
 
 
N=76 
N=76 
N=77 
Subjects with any TEAE 
28 (36.8) 
26 (34.2) 
27 (35.1) 
Diarrhea 
5 (6.6) 
4 (5.3) 
1 (1.3) 
Nausea 
4 (5.3) 
5 (6.6) 
1 (1.3) 
Eructation 
3 (3.9) 
1 (1.3) 
0 (0.0) 
 
 
ANCHOR Study 
 
 
N= 233 
N= 236 
N= 233 
Subjects with any TEAE 
112 (48.1) 
106 (44.9) 
106 (45.5) 
Diarrhea 
10 (4.3) 
9 (3.8) 
8 (3.4) 
Arthralgia 
1 (0.4) 
8 (3.4) 
4 (1.7) 
TEAE = treatment-emergent adverse event 
TEAE are adverse events that start after the first dose of randomized study medication or occur 
prior to the first dose and worsen in severity during the double-blind period. 
 
In a large study with Japanese patients (Japan EPA Lipid Intervention Study [JELIS]), long-
term administration of 1.8 g/day ethyl-EPA (Epadel®) was associated with an excellent safety 
and tolerability profile (Yokoyama 2007). Most AEs attributable to ethyl-EPA were regarded 
as mild. The most common adverse events were gastro-intestinal (nausea, diarrhea, epigastric 
discomfort) or dermatologic (eruption, itching, exanthema, eczema) in nature. 
1.5. 
Rationale 
Hypothesis 
The hypothesis is that combination anti-dyslipidemic therapy of a LDL-C lowering drug 
(statin therapy) with the triglyceride-lowering drug AMR101 will be superior to the LDL-C 


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lowering therapy alone when used as prevention in reducing long-term clinical events in 
patients with mixed dyslipidemia at high risk for cardiovascular events. 
TG-Lowering as a Therapeutic CV Target 
Studies have shown that elevated levels of total cholesterol (TC) and low-density lipoprotein 
cholesterol (LDL-C) are associated with increased risk of coronary heart disease (CHD) 
(LaRosa 2003), and therapeutic strategies that lead to a statistically significant reduction in 
LDL-C lower CHD event rates (Baigent 2005). One potential impediment, limiting further 
reduction in CHD events despite low on-treatment LDL-C, is residual elevation in serum TG 
levels (Miller 2000). Indeed, even after adjustment for HDL-C, detailed evaluation of 
population-based prospective studies has disclosed an independent effect of TG on CHD 
events (Sarwar 2007). Coupled with the knowledge that combined hyperlipidemia (i.e., 
elevated LDL-C and TG) promotes CHD to a significantly greater extent than either high 
LDL-C or TG alone (Manninem 1992), the hypothesis is strong that low on-treatment levels 
of TG when added to low LDL-C would be superior to low LDL-C alone in reducing 
subsequent CHD events. Supporting evidence for this hypothesis was obtained in a post hoc 
analysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In 
Myocardial Infarction 22 Trial (PROVE IT-TIMI 22) (Miller 2008) wherein among patients 
receiving statin therapy after acute coronary syndrome (ACS), on treatment TG <150 mg/dL 
was associated with a lower risk of recurrent CHD events independently of the level of LDL-
C. For each 10% lowering of TG attained during the first 30 days of treatment after an ACS 
event, the risk for death, myocardial infarction, or recurrent acute coronary syndrome was 
reduced by 2.3% (p =0.035) after adjustment for high LDL-C (>70 mg/dL) and HDL-C (<40 
and 50 mg/dL in men and women, respectively). 
Omega-3 Fatty Acids in Fish Oils 
There is a growing body of evidence, encompassing molecular, cellular, animal and human 
studies defining the roles for O3FAs as bioactive agents for reducing the risks of and treating 
CVD (Torrejon 2007). Many epidemiological studies have demonstrated inverse associations 
between fish intake and CV mortality, and more specifically between the intake and blood 
levels of O3FAs and CV mortality. For example, when comparing blood levels of O3FAs 
among men who had died of sudden cardiac death with controls matched for age and 
smoking status, it was found that participants with the highest blood levels of EPA and DHA 
had a 90% risk reduction for sudden cardiac death compared with those with the lowest 
levels (Albert 2002). 
Clinical trials and experimental studies, suggest important antiatherogenic and antithrombotic 
effects of O3FAs. These result from wide-ranging biological effects, including benefits on 
lipoprotein metabolism, blood pressure, endothelial function and vascular reactivity, 
inflammation, platelet and fibrinolytic function, cytokine production, coagulation and 
oxidative stress (Mori and Woodman 2006). Evidence suggests that increased consumption 
of O3FAs from fish or fish-oil supplements reduces the rates of all-cause mortality, cardiac 
and sudden death, and possibly stroke (Wang 2006). The effect was evident in both primary-
prevention (general population without a history of CVD) and secondary-prevention (patients 
with a history of CVD) studies with a stronger effect in secondary prevention. 
The Diet and Reinfarction Trial (DART) was one of the first randomized, controlled studies 
to demonstrate the beneficial effects of O3FAs in secondary prevention of CHD and reported 


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a 29% reduction in all-cause mortality over a 2-year period in 2033 male MI survivors 
advised to increase their intake of oily fish (200 to 400 g of fatty fish per week, which 
provided 500 to 800 mg/day of O3FAs) (Burr 1989). While not statistically significant, there 
was also a trend toward a reduction in recurrent ischemic heart disease events with increased 
fatty fish consumption. A post hoc analysis of patients receiving fish oil capsules 
(900 mg/day of EPA+DHA) in DART suggested that the protective effect was attributable to 
O3FAs (Burr 1994). The greatest benefit was seen in fatal MIs, and this observation led to 
the hypothesis that O3FAs might protect the myocardium against the adverse sequela of 
acute ischemic stress. 
A cardioprotective effect for O3FAs derived from fish oil is supported by prospective studies 
demonstrating inverse associations between fish intake and coronary heart disease mortality, 
especially amongst high-risk individuals (Mori and Woodman 2006). Early separation of 
survival curves in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto 
Miocardico (GISSI)-Prevenzione study (GISSI-Prevenzione Investigators 1999) and the 
DART trial support a reduction in ventricular fibrillation and a decreased incidence of 
myocardial infarction (Leaf 1996) as the primary mechanisms through which O3FAs prevent 
CVD (Mori and Woodman 2006). 
Many international bodies including the AHA, American College of Cardiology, and the 
European Society of Cardiology have found the overall evidence for benefit sufficiently 
strong to make public recommendations for increased O3FA intake for both primary and 
secondary prevention (Harris 2007). 
Omega-3 Fatty Acid Ethyl Esters 
The largest prospective, randomized, controlled trial to test the efficacy of O3FAs for 
secondary prevention of CHD is the GISSI study (GISSI-Prevenzione Investigators 1999). In 
this study, 11,324 patients with preexisting CHD (experienced an MI and were receiving 
conventional cardiac pharmacotherapy) were randomized to either 300 mg of vitamin E, 
850 mg of O3FA ethyl esters (as EPA and DHA), both, or neither. After 3.5 years of follow-
up, the group given the O3FAs alone experienced a 15% reduction in the primary end point 
of death, nonfatal MI, and nonfatal stroke (p <0.02). There was a 20% reduction in all-cause 
mortality (p =0.01) and a 45% reduction in sudden death (p <0.001) compared with the 
control group; vitamin E provided no additional benefit. Triglycerides decreased by 4% and 
LDL cholesterol levels increased by 2.5% after six months in the O3FA treatment groups 
compared with controls. This trial, although very large and carried out in a relatively "usual-
care" setting, was not placebo controlled, and dropout rates were high (>25%). A follow-up 
study (Marchioli 2002) assessed the time-course of the benefit of O3FAs on mortality in 
subjects in the GISSI-P Study and found that survival curves diverged early after 
randomization. Total mortality was significantly lowered by 28% after 3 months of treatment 
(RR =0.59), and by 4 months, the risk of sudden cardiac death was reduced by 45% 
(RR =0.47). 
Ethyl-EPA 
In another larger trial, the Japan EPA Lipid Intervention Study (JELIS), 18,645 patients with 
hypercholesterolemia (70% women; mean age, 61 years) were randomly assigned to either 
statin alone or statin and pure ethyl-EPA (1.8 g/day). Of all patients, 15,000 patients (80%) 
were without existing CAD and 3,645 (20%) with existing CAD (Matsuzaki 2009). The 


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primary endpoint was any major adverse coronary event (MACE including SCD, fatal and 
nonfatal MI, and other nonfatal events including unstable angina pectoris (determined to be 
caused by myocardial ischemia by invasive/non-invasive testing), angioplasty, stenting, and 
coronary artery bypass grafting).  
In the overall analysis (Yokoyama 2007), during the 4.6-year follow-up, ethyl-EPA reduced 
major adverse coronary events by 19% (p =0.011). EPA treatment was also associated with a 
significant 24% reduction in the incidence of unstable angina and a 19% decrease in nonfatal 
coronary events. This treatment also produced nonsignificant reductions of 21%, 25%, and 
14% in fatal MI, nonfatal MI, and revascularizations, respectively. 
In a subgroup analysis of primary prevention cases, compared to patients with normal serum 
TG and HDL-C levels, those with abnormal levels (TG ≥150 mg/dL; HDL-C <40 mg/dL) 
had a significantly higher major adverse coronary event (MACE) rate by 71% (p=0.014). In 
this higher risk group, ethyl-EPA treatment suppressed the MACE risk by 53% (p=0.043) 
(Saito 2008). 
While there was no significant difference in the incidence of first stroke between ethyl-EPA 
and control groups, the incidence of stroke recurrence was significantly lower in the EPA 
group at 6.8% versus the control group at 10.5%, a reduction of 20% (p<0.05; Tanaka 2008). 
Further, while there was no difference in the incidence of recurrent hemorrhagic cerebral 
events between the two groups, ethyl-EPA was effective in reducing the recurrence of 
ischemic cerebral vascular events such as cerebral infarction (Harris 2009).  
O3FA supplementation lowered CV risk in both the GISSI-Prevenzione study and JELIS, 
despite aggressive therapy with standard pharmacotherapy (e.g., statins, aspirin, β-blockers 
and angiotensin-converting enzyme inhibitors). Additionally, the JELIS trial established the 
safety and efficacy of combination therapy with ethyl-EPA and a statin vs statin therapy 
alone for improving CV prognosis. The JELIS trial was conducted with Epadel that contains 
the same active ingredient, ethyl-EPA, as AMR101. Ethyl-EPA was shown in the JELIS 
study to reduce CAD events even in a Japanese population with very high intakes of O3FAs 
due to the high fish consumption. The evidence supporting a benefit in primary prevention 
comes from an observed 18% decrease in CV events in the 80% of patients in the JELIS trial 
without documented CAD (p =0.13); this effect size was essentially the same as that 
observed in the secondary prevention cohort (19%, p <0.05) (Lee 2008). 
Medical Need 
CVD resulting from progressive atherosclerosis remains the most common cause of 
morbidity and mortality all over the world. Based on 2006 US statistics (American Heart 
Association 2010), an estimated 81 million American adults (more than one in three) have 
one or more types of CVD. Of these, 38 million are estimated to be age 60 or older. Total 
CVD includes coronary heart disease (CHD): 17.6 million, heart failure (HF): 5.8 million and 
stroke: 6.4 million. CHD further divided includes myocardial infarction (MI): 8.5 million, 
and angina pectoris (AP): 10.2 million. Final mortality data show that CVD as the underlying 
cause of death accounted for 34.4% of all deaths (about 830,000 of all 2.4 million deaths in 
2006). CHD is the leading cause of death in all Western industrialized countries, despite 
considerable improvement since the mid-1960s. In developing countries, the incidence of 
CVD is increasing alarmingly. In addition to death, CVD also causes many serious non-fatal 


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events and is the major cause of disability. Therefore, additional therapies for prevention of 
CVD would have a considerable public health benefit. 
A large number of studies have demonstrated the TG-lowering effects of O3FAs (Ginsberg 
2001; Harris 1997). Hypertriglyceridemia is a common lipid abnormality and often occurs in 
persons who are obese and have insulin resistance, Type 2 diabetes mellitus, or the metabolic 
syndrome (Jacobson 2007; Bays 2008). Elevation in TG is positively associated with 
accelerated atherosclerosis leading to CV events, the latter even after correction for other 
lipid and non-lipid risk factors (Jacobson 2007). In the US (American Heart Association 
2010), the mean TG level for American adults age 18 and older is 144.2 mg/dL (men, 
156.5 mg/dL; women, 132.1 mg/dL).  
Lifestyle modification is important for the management of patients with 
hypertriglyceridemia; however, for patients who do not adequately respond to dietary and 
lifestyle restrictions, relatively few classes of drugs are available to treat 
hypertriglyceridemia, and each is associated with risks that may limit their use alone or in 
combination. Currently available pharmacological treatments for hypertriglyceridemia 
include fibric acid derivatives (such as gemfibrozil and fenofibrate), niacin in various 
formulations, prescription omega-3-acid ethyl esters (Lovaza/Omacor) and statins (3 hydroxy 
3 methylglutaryl coenzyme A reductase inhibitors).  
Although the above agents have robust TG-lowering effects in patients with 
hypertriglyceridemia, the degree of TG-lowering is highly variable; generally greater TG-
lowering effects are observed for fibrates and niacin compared with statins. Many patients 
will be satisfactorily treated with one or more of the above range of drugs (combined with 
appropriate diet and attention to other CV risk factors and lifestyle). 
Lovaza, comprised predominantly of ethyl-EPA and the ethyl ester of docosahexaenoic acid 
(ethyl-DHA), is indicated only in patients with very high TG levels (>500 mg/dL), raises 
LDL-C even when combined with statins in patients with high TGs (200-499 mg/dL), and is 
approved at 4 g/day (equivalent to 4 capsules/day) resulting in poor patient compliance. A 
non-compliance rate of 35% was reported in one clinical trial (Leaf 2005). 
Fibrates are clearly effective at raising HDL-C and lowering TG concentrations. However, 
their effects on vascular events remain uncertain. Several large-scale trials of fibrate therapy 
have been completed in the past few years. Although some of these trials have suggested 
benefit, others have shown no effect, leading to uncertainty about the presence and 
magnitude of any cardiovascular protective effects and difficulties for clinicians in 
interpretation of the results (Jun 2010). The ACCORD study (Ginsberg 2010) reported no 
overall benefit for fenofibrate, raising further questions about the usefulness of these agents. 
There are also safety issues with the above agents that limit their clinical use. Statins, 
particularly at high doses, may cause increases in hepatic transaminases and are also known 
to cause myopathy and occasionally rhabdomyolysis, which may lead to death from acute 
renal failure. This risk may be increased when fibrates and statins are co-administered and 
many clinicians will avoid co-prescribing these 2 medications. Fibrates are also associated 
with interactions with warfarin and hepatic transaminase elevations. The utility of niacin is 
limited by the occurrence of severe flushing and associated symptoms which can be difficult 
to manage even with careful dose titration and pre administration of aspirin or other non-


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steroidal anti-inflammatory drugs. Niacin is also associated with impairment of glucose 
tolerance and precipitation of attacks of gout in susceptible patients. 
The DYSlipidemia International Study (DYSIS) assessed the prevalence of dyslipidemia 
among patients taking statins. This epidemiological observational study included more than 
22,000 patients in Europe and Canada aged 45 and older who received statin therapy for at 
least three months, and had a clinical diagnosis of coronary or other atherosclerotic disease, 
or were at high risk of developing CVD. The study found 48% of patients had LDL-C not at 
goal; 26% had low HDL-C levels; and 38% had elevated triglycerides. This study 
demonstrates that persistent dyslipidemia is highly prevalent in statin-treated patients. 
Patients with dyslipidemia, particularly those with established CVD or diabetes, have 
therapeutic needs that cannot be met by statin monotherapy. It is hypothesized that achieving 
target values for LDL-C/non-HDL-C in these patients using a therapeutic approach of the 
combination of AMR101 and a statin will benefit these patients. Such a combination therapy 
might increase the likelihood of therapeutic success in these patients with regards to future 
risk of CVD, based on meeting of both LDL-C/non-HDL-C goals and TG goals according to 
the ACC/AHA guidelines (Anderson 2007). Approximately 40 million Americans have high 
TG levels (>200 mg/dL), however only a minority (3.6%) are currently treated with 
prescription medication (Ford 2009). Patients with elevated TGs are currently under-served 
and would benefit from a new, safe and effective product that can provide the following 
attributes: 
• Robust efficacy to lower TGs 
• Safe to use with other lipid-lowering agents, including statins 
• Does not increase LDL-C when used in patients on statin therapy (TG = 200-499 
mg/dL) 
• Has convenient dosing regimen 
• Has class-specific positive outcomes data 
 
Pleiotropic Effects 
There is ample evidence that O3FAs decrease TGs in patients with hypertriglyceridemia 
which is a beneficial effect related to the fact that elevated TGs have been identified as an 
independent risk factor for CVD. Lowering TGs in patients with hypertriglyceridemia would 
lead to a slowing of the development of atherosclerosis. However O3FAs including EPA 
have a wide range of additional pharmacological effects that most likely contribute to a 
beneficial effect in patients with CVD. 
Beneficial effects in clinical trials have been attributed in part to reducing arrhythmias (Lee 
2003; Goel 2002; Calo 2005). The case for an antiarrhythmic effect of O3FAs comes from 
clinical trials and from animal studies. Clinical trials have shown that the risk of sudden 
death in patients who have survived myocardial infarction is greatly reduced by inclusion of 
O3FAs in the diet (Siscovick 2000). Thus it seems that fatal ventricular fibrillation is less 
likely to occur during sufficient intake of O3FAs. Animal studies support this. Coronary 
ligation studies in a variety of species (rats, dogs and marmosets) have shown that the 
incidence of ventricular fibrillation is lower in animals fed a diet rich in O3FAs before 


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ligation (McLennan 1992; Leaf 1996). In isolated cells, the story is similar (Li 1997, Engler 
2000; Omura 2001). In neonatal rat cardiac myocytes, EPA prevents the arrhythmogenic 
action of many interventions, including high external Ca2+ and ouabain (Kang 1994). The 
antiarrhythmic effect is caused by a reduction in electrical excitability caused by partitioning 
O3FAs into the phospholipid cell membranes of the cardiac myocytes, which modulates 
membrane ion channels. This is the postulated direct mechanism that refers to the 
antiarrhythmic effect of O3FAs which inhibits the fast, voltage-dependent sodium current 
along with the L-type calcium currents. This reduces the action potential of cardiac 
myocytes, reducing the susceptibility to arrhythmia. These cellular alterations are likely to 
reduce the severity of ventricular arrhythmias by inhibiting the rapid accumulation of 
intracellular Ca2+ following ischemia. It was also shown in patients with coronary artery 
disease that long-term treatment with EPA augments both NO-mediated and non-NO-
mediated endothelium-dependent forearm vasodilatation (Tagawa 1999). 
Another, indirect mechanism refers to the effect of O3FAs on cardiac arrhythmias by 
modifying the balance of different eicosanoids which are produced as end-products from 
chain elongation of their parent polyunsaturated fatty acids (Nair 1997). Most investigations 
of the link between O3FAs and heart disease have demonstrated the competition between AA 
and O3FAs to become substrates in the production of eicosanoids. O3FAs compete with AA 
in several ways, but EPA in particular competes with AA as the substrate for the 
cyclooxygenase enzyme inhibiting the production of thromboxane A2 (TXA2) and in 
endothelial cells, prostaglandin I3 (PGI3) is synthesized from EPA (Nair 1997). The net result 
of these actions is vasodilatation. A reduced ratio of AA/EPA shifts the spectrum of 
eicosanoid production toward an increase in thromboxane A3 (TXA3) and PGI3 at the 
expense of TXA2 and PGI2, respectively. This shift was found to reduce the risk of 
ventricular fibrillation (VF) and sudden cardiac death (SCD) (Coker 1982). Excessive 
production of eicosanoids derived from omega-6 fatty acids have been associated with heart 
attacks, thrombotic stroke, and arrhythmia, while those from O3FAs are antiarrhythmic. 
Probably one of the most important pharmacologic properties of EPA is its anti-inflammatory 
and immune-modulating activity (Calder 2006; Calder 2010). Because of the inflammatory 
events underlying plaque rupture, the variety of anti-inflammatory effects of O3FAs may be 
of relevance to atherosclerosis and its clinical manifestations of myocardial infarction, 
sudden death, and stroke (Mori 2004; Thies 2003). A randomized controlled study, in 
patients awaiting surgery to remove atherosclerotic plaques in the carotid artery, has shown 
that an anti-inflammatory response might be involved, by demonstrating an association 
between the intake of O3FAs as a supplement (1.4 g/day) and the stability of atherosclerotic 
plaques (Thies 2003). This improved stability was achieved by incorporation of the O3FAs 
into the plaque. 
The omega-6 fatty acid AA gives rise to eicosanoid mediators that have established roles in 
inflammation and AA metabolism is a long recognized target for commonly used anti-
inflammatory therapies. O3FAs, are incorporated into inflammatory cell phospholipids in a 
time- and dose-dependent manner. They are incorporated partly at the expense of AA, but 
also other omega-6 fatty acids. EPA and DHA inhibit AA metabolism. Thus production of 
AA-derived eicosanoids is decreased by these O3FAs. EPA gives rise to an alternative family 
of eicosanoids (e.g. PGE3), which frequently have lower anti-inflammatory potency than 
those produced from AA, and to resolvins (E- and D-series) which have potent anti-


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inflammatory and inflammation resolving properties (Serhan 2006; Dona 2008). The plasma 
AA/EPA ratio has been used as a marker of the inflammatory status in patients with CVD 
(Rupp 2004; Holub 2009). In favor of the concept that less pro-inflammatory processes can 
be observed already at lower AA/EPA ratios is the finding that 1.4 g/day ethyl-EPA reduced 
the incidence of plaque rupture (Thies 2003). The AA/EPA ratio had a strong relationship 
with the incidence of CV events such as MACE in patients undergoing elective PCI (Domei 
2009). 
In addition to modifying the profile of lipid-derived mediators, O3FAs can also influence 
peptide mediator (i.e. cytokine) production. Pro-inflammatory cytokines, or cytokines 
reflecting inflammatory processes, e.g. IL-1beta, IL-2, IL-6, TNFalpha, platelet-derived 
growth factor (PDGF)-A and -B and monocyte chemoattractant protein-1 (MCP-1), are 
reduced by EPA and DHA in human subjects (von Schacky 2007), and soluble cytokines 
reflecting interactions between blood cells and the vessel wall, such as intercellular adhesion 
molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) (Yamada 2008). 
EPA and DHA intake also resulted in a decreased expression of genes involved in 
inflammatory- and atherogenic-related pathways, such as nuclear transcription factor κB 
signaling, eicosanoid synthesis, scavenger receptor activity, adipogenesis, and hypoxia 
signaling (Bouwens 2009). 
In conclusion, the pleiotropic effects of EPA may contribute to the overall beneficial effects 
on the risk of CVD, in addition to the TG-lowering effect. Therefore, it is possible that the 
efficacious dose of EPA that decreases the CV event rate is lower than the dose needed to 
exert the maximum TG-lowering effect, and/or that a modest decrease of TGs after EPA 
treatment could still lead to a significant decrease in the risk for CVD. 
Dose Selection 
This trial will be conducted with a dose of AMR101 of 4 g/day (4 capsules/day). 
To date, only one study was published investigating the effects of combination treatment 
with an O3FA plus statins on clinical cardiovascular events. This is the Japan EPA Lipid 
Intervention Study (JELIS) (Yokoyama 2007), as previously discussed, wherein ethyl-EPA 
combined with low-dose pravastatin or simvastatin compared with statin therapy alone 
reduced major coronary events without altering rates of sudden cardiac death. These effects 
were achieved without any significant changes in total, LDL- or HDL-C and a statistically 
significant (p <0.0001) decrease in triglycerides, suggesting that EPA can lower CVD risk by 
mechanisms other than LDL-C lowering (Yokoyama 2007). In a subanalysis of this study, 
the addition of ethyl-EPA to pravastatin or simvastatin reduced also the incidence of 
coronary heart disease events in high-risk patients with metabolic syndrome and atherogenic 
dyslipidemia characterized by high triglycerides and low HDL-C (Saito 2008). The JELIS 
study was performed in a large patient population wherein an ethyl-EPA dose of 1.8 g/day 
translated to significant benefits on CV events. 
In the ANCHOR study (Amarin-sponsored), both the 2 and 4 g/day dosing regimens of 
AMR101 resulted in statistically significant reductions of TGs (see Section 1.3). However, 
since the 4 g/day dose caused a larger reduction in TG and other lipid, lipoprotein and 
inflammatory markers, the AMR101 4 g/day dose was selected for the present study. 


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1.6. 
Risk/Benefit 
Across all completed Amarin-sponsored studies, the proportion of patients (based on the 
safety population from the randomized, double-blind periods of the studies) experiencing any 
adverse events was similar for patients on placebo (light paraffin oil) and patients on 
AMR101 (57.1% and 57.4% for placebo and AMR101, respectively). The proportion of 
patients experiencing a serious adverse event (SAE) was also similar for both treatment 
groups (5.2% and 6.0% for placebo and AMR101, respectively). The safety profile in the 
open-label extensions was similar to that observed in the double-blind treatment periods. 
There were no SAEs attributed to AMR101 during the open-label extension periods of the 
studies. 
In summary, AMR101 is very well tolerated at daily doses up to 4 g. The side effects 
reported by the patients taking AMR101 were generally similar to those reported by the 
patients taking placebo. Ethyl-EPA is a pro-drug, and is rapidly and completely hydrolyzed 
to EPA. EPA is a natural substance found universally as a component of all cell membranes. 
It is classified as an essential fatty acid. Because of the nature of EPA, as an essential 
component of normal tissue and its part in normal metabolism, human studies have 
demonstrated that it is safe. See the Investigator’s Brochure for more information. 
2. 
STUDY OBJECTIVES 
The primary objective is, in patients at LDL-C goal while on statin therapy, with established 
cardiovascular disease (CVD) or at high risk for CVD, and hypertriglyceridemia (fasting 
triglycerides, TG, ≥150 mg/dL and <500 mg/dL), to evaluate the effect of 4 g/day AMR101 
for preventing the occurrence of a first major cardiovascular event of the composite endpoint 
that includes: 
• Cardiovascular (CV)  death, 
• Nonfatal myocardial infarction (MI), 
• Nonfatal stroke, 
• Coronary revascularization,  
• Unstable angina determined to be caused  by myocardial is chemia by invasive/non-
invasive testing and requiring emergent hospitalization.  
 
[Because of the variability in TG levels, the lower TG qualifying limit is 10% lower than the 
target of 150 mg/dL, i.e., 135 mg/dL.] 
 
Refer to Appendix B for cardiovascular event definitions 
 
The secondary objectives of this study are the following: 
The key secondary objective is to evaluate the effect of therapy on the composite of death 
from CV causes, nonfatal MI, coronary revascularization, unstable angina, nonfatal stroke, or 
peripheral CVD requiring intervention, angioplasty, bypass surgery, or aneurysm repair. 
 
Other secondary objectives : 


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• To evaluate the effect of therapy on co
mbinations of each of the key secondary 
objective clinical events in addition to the following clinical events: 
o Cardiac arrhythmia requiring hospitalization  
o Cardiac arrest 
o Peripheral CVD requiring intervention, angioplasty, bypass surgery, or 
aneurysm repair 
o Total mortality 
 
The tertiary objectives of this study are the following: 
• Evaluate the effect of therapy on the occu rrence of a second, third, fourth, and fifth 
major cardiovascular event (sam e as the pr imary composite endpoint but for events 
occurring after the first event); 
• To evaluate the effect of therapy on th
e primary endpoint in subgroups of patients 
including: 
o Diabetes mellitus 
o Metabolic syndrome as defined by the NCEP ATP III or future criteria as they 
may evolve; 
• To evaluate the effect of therapy on the individual endpoints of new congestive heart 
failure (CHF), on new  CHF as a prim
ary cause of hospitaliza tion, on transient 
ischemic attack, on amputation for vascular disease and on carotid revascularization; 
• Elective coronary revascularization and emergent coronary revascularization;  
• To assess the ef fects regarding lipids, lip oproteins and inf lammatory markers 
including triglycerides (TG), to tal cholesterol (TC), low-density  lipoprotein 
cholesterol (LDL-C), high- density lipoprotein choles terol (HDL-C), non-HDL-C, 
very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein B (apo B), high 
sensitivity C-reactive protein (hs-CRP) a nd high sensitivity troponin (hsTnT), as 
follows: 
o Assessment of the effect of AMR101 on each marker (on-treatment 
change of markers) 
o Assessment of the effect of the baseline value of each marker on 
treatment effects (baseline effect on outcomes) 
o To evaluate the effect of therapy for preventing clinical events, as 
defined above, among all patients in the study, and in subgroups such as 
patients with diabetes mellitus and patients with substantial on-treatment 
changes of any of the markers (on-treatment effect on outcomes). 
• To evaluate the effect of therapy on new onset diabetes (See appendix C); 
• To explore the effect of AMR101 on weight and waist circumference. 


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3. 
STUDY DESIGN 
3.1. 
Type of Study 
Phase 3b, multi-Center, multinational, prospective, randomized, double-blind, placebo-
controlled, parallel-group study 
3.2. 
Study Population 
The population for this study is men and women ≥45 years of age with established CVD, or 
men and women ≥50 years of age with diabetes in combination with one additional risk 
factor for CVD. In addition, all patients will have atherogenic dyslipidemia defined as on 
treatment for hypercholesterolemia (but at treatment goal for LDL-C, by treatment with a 
statin) and hypertriglyceridemia. More details are listed in the inclusion criteria. 
The patients will need to provide written consent to participate in the study and be willing 
and able to comply with the protocol and the study procedures. 
3.3. 
Study Periods 
This study consists of the following study periods: 
• Screening Period: During the screening period, patients will be evaluated for 
inclusion/exclusion criteria. 
At the first visit to the Research Unit (Visit 1), study procedures will be performed for 
evaluation of patient’s eligibility in the study. At this screening visit, patients will sign an 
informed consent form before any study procedure is performed; the informed consent 
form will cover the treatment/follow-up period. Based on the evaluation from Visit 1, the 
following situations may occur: 
o 
Patients who are eligible for participation based on the study procedures on Visit 1 
will return to the Research Unit for Visit 2 (randomization visit) to start the 
treatment/follow-up period. This case includes, for example, patients at Visit 1who 
are on a stable dose of a statin, are planning to stay on the same statin and the same 
dose of the statin, and who not need to wash out any non-statin lipid-altering 
medications. 
o 
Patients who are not eligible for participation based on the study procedures on 
Visit 1 and are unlikely to become eligible in the next 28 days (for example: 
unlikely to stabilize statin dose, unable to wash out non-statin lipid-altering 
medications, etc.): these patients will be screen failed after Visit 1. 
o 
Patients not eligible for participation in the study based on the study procedures on 
Visit 1 may possibly become eligible in the next 28 days: these patients may return 
at the discretion of the investigator for a second optional screening visit (Visit 1.1) 
at which time the procedures needed for re-evaluation of the previously failed 
inclusion/exclusion criteria will be repeated. This case includes, for example, 
patients who are started on a statin at Visit 1, whose statin dose is changed at Visit 1, 
and/or needed to wash out non-statin lipid-altering medications. The following 
applies for these patients: 
• 
Patients with a change in the statin or statin dose on Visit 1 will need to be on a 
stable statin dose for at least 28 days before the lipid qualifying measurements 


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at Visit 1.1. Other concomitant medications (antidiabetic therapy, for example) 
can be optimized or stabilized during this period. 
• 
Patients starting a washout at Visit 1 will have a washout period of at least 
28 days (only 7 days for bile acid sequestrants) before the lipid qualifying 
measurements at Visit 1.1. 
• 
Patients at Visit 1 who are on a stable dose of a statin, are planning to stay on 
the same statin at the same dose, and who do not need any medication washout, 
but were asked to return for Visit 1.1 to repeat one or more of the other study 
procedures not related to concomitant medications  
o 
Patients who become eligible for participation based on the additional study 
procedures at Visit 1.1 will return to the Research Unit for Visit 2 (randomization 
visit) to start the treatment/follow-up period. 
At the end of the screening period, patients will need to meet all inclusion/exclusion criteria 
before they can be randomized. Patients who are not eligible for participation after the 
screening period (based on study procedures at Visit 1 and/or Visit 1.1) may return at a later 
date for rescreening. These patients will need to re-start with all procedures starting with 
Visit 1. This includes patients who need more time to stabilize one or more conditions or 
therapies (for example: statin, antidiabetic, antihypertensive, thyroid hormone, HIV-protease 
inhibitor therapy). 
• Treatment/Follow-Up Period: Within 42 days after the first screening visit and within 
14 days after the second screening visit, if one is conducted, eligible patients will enter 
the treatment/follow-up period. During this period, the patients will receive study drug 
during the planned visits at the Research Site and take the study drug while away from 
the Research Site. 
During the visits, study procedures will be performed for evaluation of efficacy and safety. A 
detailed schedule of procedures is provided in Appendix A. 
3.4. 
Study Duration 
The estimated study duration includes a planned 18-month enrollment period followed by a 
follow-up period of approximately 3.5 years in expected duration (approximately 5 years in 
total). Patients will be randomized at different times during the enrollment period but will all 
end the study at the same date (study end date). It is planned that all randomized patients will 
receive study medication and be followed-up until the study end date. This is an event-driven 
trial and patients will continue in the trial if the trial runs longer than expected, or will 
terminate earlier if the trial runs shorter than expected. 
The total duration of the trial is based on a median 4-year follow-up period across patients. 
The first patient randomized would be followed for 4.75 years (the longest individual follow-
up duration), and the last patient randomized would be followed for 3.25 year (the shortest 
individual follow-up duration). 
3.5. 
Study Groups 
At Visit 2 (Day 0), eligible study patients will be randomly assigned to the following 
treatment groups: 
• Group 1: AMR101 4 g daily (four 1000 mg capsules daily) 


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• Group 2: placebo (four capsules daily) 
The four AMR101 or placebo capsules daily will be taken as two capsules in the morning 
and two capsules in the evening (twice-per-day dosing regimen). 
3.6. 
Number of Patients 
This is an event-driven trial: It is expected that a minimum of 1612 primary efficacy endpoint 
events will be required during the study. A total of approximately 7990 patients will be 
entered into the study to either receive AMR101 or placebo (approximately 3995 patients per 
treatment group) in order to observe an estimated 1612 events that make up the primary 
composite endpoint for efficacy. 
3.7. 
Number of Study Sites 
Participants will be enrolled at multiple Research Sites in multiple countries. 
3.8. 
Randomization 
On Day 0, eligible patients will be randomized to one of 2 study groups using a computer-
generated randomization schema. Randomized treatment assignment to either AMR101 or 
placebo in a 1:1 ratio will be provided using the internet or a touch-tone telephone via an 
interactive voice response system (IVRS). 
3.9. 
Blinding 
This is a double-blind study. Patients, investigators, pharmacists and other supporting staff at 
the Research Sites, personnel and designees of the Sponsor, study administrators and 
personnel at the organization(s) and vendors supporting the study will be unaware of the 
randomization code (i.e., they will not know which study participants are receiving the 
experimental drug and which are receiving the placebo drug). The study medication, 
AMR101 and placebo capsules, will be similar in size and appearance to maintain blinding. 
During the double-blind treatment/follow-up period, everyone (patients, investigators, 
pharmacists and other supporting staff at the Research Sites, personnel and designees of the 
Sponsor, study administrators and personnel at the organization(s) and vendors 
managing/supporting the study), with the exception of the laboratory personnel performing 
the analysis, will be blinded to individual results of the efficacy laboratory measurements 
(including lipid values). Individual results from the lipid profile may be unblinded in the 
event of an emergency for a patient. 
3.10. 
Stratification 
Participants will be assigned to treatment groups stratified by CV risk category, use of 
ezetimibe and by geographical region (Westernized, Eastern European, and Asia Pacific 
countries). There are two CV risk categories: 
• 
CV Risk Category 1: patients with established CVD defined in the inclusion criteria. 
Patients with diabetes and established CVD are included in this category. 
• 
CV Risk Category 2: patients with diabetes and at least one additional risk factor for 
CVD, but no established CVD. This is primary prevention group. 
Stratification will be recorded in the IVRS at the time of enrollment. Approximately 70% of 
randomized patients will be in the CV Risk Category 1 and approximately 30% of 


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randomized patients will be in the CV Risk Category 2. Enrollment with patients of a CV 
risk category will be stopped when the planned number of patients in that risk category is 
reached. 
4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Patients meeting the following criteria will be eligible to participate in the study: 
1. Fasting TG levels of ≥135 mg/dL and <500 mg/dL. The target for the lower end of the 
fasting TG level is ≥150 mg/dL but because of the variability in TG levels, patients will 
qualify for enrolment within 10% of this limit (i.e., ≥135 mg/dL). 
2. On stable therapy with a statin (with or without ezetimibe), for at least 4 weeks prior to 
the LDL-C/TG baseline qualifying measurements for randomization, to maintain          
LDL-C >40 mg/dL and ≤100 mg/dL 
• 
Stable therapy is defined as the same daily dose of the same statin for at least 28 
days before the lipid qualification measurements (TG and LDL-C) and, if applicable, 
the same daily dose of ezetimibe for at least 28 days before the lipid qualification 
measurements (TG and LDL-C). Patients who have their statin therapy or use of 
ezetimibe initiated at Visit 1, or have their statin, statin dose and/or ezetimibe dose 
changed at Visit 1, will need to go through a stabilization period of at least 28 days 
since initiation/change and have their qualifying lipid measurements measured (TG 
and LDL-C) after the washout period (at Visit 1.1).  
• 
Statins may be administered with or without ezetimibe.  
NOTE: If patients qualify at the first qualification visit (Visit 1) for TG and LDL-C, and 
meet all other inclusion/exclusion criteria, they may be randomized at Visit 2. If patients 
don’t qualify at the first qualifying visit (Visit 1), a second re-qualifying visit (Visit 1.1) 
is allowed. For some patients, because they need to stabilize medications and/or need to 
washout medications, the second re-qualifying visit (Visit 1.1) will be needed after the 
stabilization/washout period. 
3. Either having established CVD (in CV Risk Category 1) or at high risk for CVD (in CV 
Risk Category 2). The CV risk categories are defined as follows: 
CV Risk Category 1: defined as men and women ≥45 years of age with one or more of 
the following: 
o Documented coronary artery disease (CAD; one or more of the following primary 
criteria must be satisfied): 
• Documented multivessel CAD (one or more >50% stenoses in two major 
epicardial coronary arteries – with or without antecedent revascularization) 
• Documented prior MI 
• Hospitalization for high-risk NSTE-ACS (with objective evidence of 
ischemia: ST-segment deviation or biomarker positivity) 


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o Documented cerebrovascular or carotid disease (one of the following primary 
criteria must be satisfied): 
• Documented prior ischemic stroke 
• Symptomatic carotid artery disease with ≥50% carotid arterial stenosis 
• Asymptomatic carotid artery disease with ≥70% carotid arterial stenosis per 
angiography or duplex ultrasound 
• History of carotid revascularization (catheter-based or surgical) 
o Documented peripheral arterial disease (PAD; one or more of the following 
primary criteria must be satisfied):  
• ABI <0.9 with symptoms of intermittent claudication 
• History of aorto-iliac or peripheral arterial intervention (catheter-based or 
surgical) 
OR 
CV Risk Category 2: defined as patients with: 
1. Diabetes mellitus (Type 1 or Type 2) requiring treatment with medication AND 
2. Men and women ≥50 years of age AND  
3. One of the following at Visit 1 (additional risk factor for CVD): 
• Men ≥55 years of age or women ≥65 years of age; 
• Cigarette smoker or stopped smoking within 3 months before Visit 1; 
• Hypertension (blood pressure ≥140 mmHg systolic OR ≥90 mmHg diastolic) 
or on antihypertensive medication; 
• HDL-C ≤40 mg/dL for men or ≤50 mg/dL for women; 
• Hs-CRP >3.0 mg/L; 
• Renal dysfunction: CrCL >30 and <60 mL/min; 
• Retinopathy, defined as any of the following: non-proliferative retinopathy, 
preproliferative retinopathy, proliferative retinopathy, maculopathy, advanced 
diabetic eye disease or a history of photocoagulation; 
• Micro- or macroalbuminuria. Microalbuminuria is defined as either a positive 
micral or other strip test, an albumin creatinine ratio ≥2.5 mg/mmol or an 
albumin excretion rate on timed collection ≥20 mg/min all on at least two 
successive occasions; macroalbuminuria, defined as albustix or other dipstick 
evidence of gross proteinuria, an albumin:creatinine ratio ≥25 mg/mmol or an 
albumin excretion rate on timed collection ≥200 mg/min all on at least two 
successive occasions; 
• ABI <0.9 without symptoms of intermittent claudication (patients with ABI 
<0.9 with symptoms of intermittent claudication are counted under CV Risk 
Category 1). 
Note: Patients with diabetes with CVD as defined above are eligible based on the 
CVD requirements and will be counted under CV Risk Category 1. Only patients 


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with diabetes and no documented CVD as defined above need at least one 
additional risk factor as listed, and will be counted under CV Risk Category 2. 
4. Women may be enrolled if all 3 of the following criteria are met: 
• 
They are not pregnant; 
• 
They are not breastfeeding; 
• 
They do not plan on becoming pregnant during the study. 
5. Women of child-bearing potential must have a negative urine pregnancy test before 
randomization. 
Note: Women are not considered to be of childbearing potential if they meet one of the 
following criteria as documented by the investigator: 
• 
They have had a hysterectomy, tubal ligation or bilateral oophorectomy prior to 
signing the informed consent form; 
• 
They are post-menopausal, defined as ≥1 year since their last menstrual period or 
have a follicle-stimulating hormone (FSH) level in a menopausal range. 
6. Women of childbearing potential must agree to use an effective method of avoiding 
pregnancy from screening to the end of the study, unless their sexual partner(s) is/are 
surgically sterile or the women is abstinent. Effective methods of avoiding pregnancy are 
contraceptive methods used consistently and correctly (including implantable 
contraceptives, injectable contraceptives, oral contraceptives, transdermal contraceptives, 
intrauterine devices, diaphragm with spermicide, male or female condoms with 
spermicide, or cervical cap). 
7. Understanding of the study procedures, willing to adhere to the study schedules, and 
agreement to participate in the study by giving written informed consent prior to 
screening. 
8. Agree to maintain their current dietary regimen, and to not alter their normal activity 
routines maintain through the duration of the study. 
4.2. 
Exclusion Criteria 
Patients are excluded from participation in the study if any of the following criteria apply: 
1. Severe (class IV) heart failure. 
2. Any life-threatening disease expected to result in death within the next 2 years (other than 
CVD). 
3. Active severe liver disease (evaluated at Visit 1): cirrhosis, active hepatitis, ALT or AST 
>3 x ULN, or biliary obstruction with hyperbilirubinemia (total bilirubin >2 x ULN). 
4. Hemoglobin A1c >10.0% at screening (Visit 1). If patients fail this criterion (HbA1c 
>10.0%) at Visit 1, they may have their antidiabetic therapy optimized and be retested at 
Visit 1.1. 
5. Poorly controlled hypertension: blood pressure ≥200 systolic mmHg OR ≥100 mmHg 
diastolic (despite antihypertensive therapy). 


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6. Planned coronary intervention (such as stent placement or heart bypass) or any non-
cardiac major surgical procedure. Patients can be (re)evaluated for participation in the 
trial (starting with Visit 1.1) after their recovery from the intervention/surgery. 
7. Known familial lipoprotein lipase deficiency (Fredrickson Type I), apolipoprotein C-II 
deficiency, or familial dysbetalipoproteinemia (Fredrickson Type III)]. 
8. Participation in another clinical trial involving an investigational agent within 90 days 
prior to screening (Visit 1). Patients cannot participate in any other investigational 
medication or medical device trial while participating in this study. 
9. Intolerance or hypersensitivity to statin therapy. 
10. History of acute or chronic pancreatitis. 
11. Known hypersensitivity to fish oil products. 
 
12. Non-study drug related, non-statin, lipid-altering medications, supplements or foods: 
• 
Patients are excluded if they used niacin >200 mg/day or fibrates during the last 
28 days before Visit 1, during the screening period and/or plan to use during the 
treatment/follow-up period of the study; 
• 
Patients are excluded if they take any omega-3 fatty acid medications (prescription 
medicines containing EPA and/or DHA) during the screening period (after Visit 1) 
and/or plan to use during the treatment/follow-up period of the study. To be eligible 
for participation in the study, patients who are taking omega-3 fatty acid medications 
during the last 28 days before Visit 1 need to go through a washout period of at least 
28 days after their last use and have their qualifying lipids measured (TG and LDL-
C) after the washout period (at Visit 1.1); 
• 
Patients are excluded if they use dietary supplements containing omega-3 fatty acids 
(e.g., flaxseed, fish, krill, or algal oils) during the screening period (after Visit 1) 
and/or plan to use during the treatment/follow-up period of the study. To be eligible 
for participation in the study, patients who are taking >300 mg/day omega-3 fatty 
acids (combined amount of EPA and DHA) within 28 days before Visit 1, need to go 
through a washout period of at least 28 days since their last use and have their 
qualifying lipid measurements measured (TG and LDL-C) after the washout period 
(at Visit 1.1); 
• 
Patients are excluded if they use bile acid sequestrants during the screening period 
(after Visit 1) and/or plan to use during the treatment/follow-up period of the study. 
To be eligible for participation in the study, patients who are taking bile acid 
sequestrants within 7 days before Visit 1, need to go through a washout period of at 
least 7 days since their last use and have their qualifying lipid measurements 
measured (TG and LDL-C) after the washout period (at Visit 1.1); 
13. Other medications (not indicated for lipid alteration): 
• 
Treatment with tamoxifen, estrogens, progestins, thyroid hormone therapy, systemic 
corticosteroids (local, topical, inhalation, or nasal corticosteroids are allowed), HIV-
protease inhibitors, and antihypertensive that have not been stable for ≥28 days prior 


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to the qualifying lipid measurements (TG and LDL-C) during screening. To be 
eligible for participation in the study, patients who are not taking a stable dose of 
these medications within 28 days before Visit 1, need to go through a stabilization 
period of at least 28 days since their last dose change and have their qualifying lipid 
measurements measured (TG and LDL-C) after the washout period (at Visit 1.1). 
• 
Patients are excluded if they use cyclophosphamide or systemic retinoids during the 
screening period (after Visit 1) and/or plan to use during the treatment/follow-up 
period of the study. To be eligible for participation in the study, patients who are 
taking these medications within 28 days before Visit 1, need to go through a washout 
period of at least 28 days since their last use and have their qualifying lipid 
measurements measured (TG and LDL-C) after the washout period (at Visit 1.1). 
14. Known to have AIDS (patients who are HIV positive without AIDS are allowed). 
15. Requirement for peritoneal dialysis or hemodialysis for renal insufficiency or if 
creatinine clearance (CrCL) <30 mL/min. 
16. Unexplained creatine kinase concentration >10 × ULN or creatine kinase elevation due to 
known muscle disease (e.g., polymyositis, mitochondrial dysfunction) at Visit 1. 
17. Any condition or therapy which, in the opinion of the investigator, might pose a risk to 
the patient or make participation in the study not in the patient’s best interest. 
18. Drug or alcohol abuse within the past 6 months, and unable/unwilling to abstain from 
drug abuse and excessive alcohol consumption during the study. Excessive alcohol 
consumption is on average >2 units of alcohol per day. A unit of alcohol is defined as a 
12-ounce (350 mL) beer, 5-ounce (150 mL) wine, or 1.5-ounce (45 mL) of 80-proof 
alcohol for drinks. 
19. Mental/psychological impairment or any other reason to expect patient difficulty in 
complying with the requirements of the study or understanding the goal and potential 
risks of participating in the study (evaluated at Visit 1). 
5. 
STUDY COMMITTEES 
5.1. 
Steering Committee 
The Steering Committee (SC) will include the chairperson, the Principal Investigator (PI), 
key representatives from the Sponsor and its designees (for example, from the 
organization(s) conducting the study as delegated by the Sponsor), and key representatives 
from each region who are deemed to have clinical and methodological expertise (national 
coordinators). 
The SC has overall responsibility for: 
• 
Scientific and strategic direction for the trial. The SC must address and resolve all 
scientific issues regarding the conduct of the trial. All sub-studies must be approved 
by the SC. 
• 
The execution of the study protocol, and the reporting and publication of the study 
results. 


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• 
Logistical coordination of the different study committees. 
The SC will meet at least twice per year. 
5.2. 
Study Operations Committee (SOC) 
The Study Operations Committee (SOC) is responsible for ensuring that study execution and 
management is of the highest quality, and will monitor recruitment, compliance, and the 
adjudication process and address the day to day issues arising from the trial. The SOC will be 
composed of representatives from the Sponsor and the organization(s) conducting the study 
(as delegated by the sponsor), and at least two investigators participating in the trial. This 
committee will meet by telephone and/or in person on a monthly or bimonthly basis, and 
each meeting will be documented with minutes. 
5.3. 
Clinical Event Committee (CEC) 
The CEC is composed of multidisciplinary medical experts. This committee will be 
responsible for blindly validating all the primary and secondary efficacy outcome events 
reported by the investigators (event adjudication). The committee will create a charter with 
details of the adjudication process and methods based on the definitions of the events. 
5.4. 
Data and Safety Monitoring Board (DSMB) 
A DSMB will be instituted for this study in order to ensure its ongoing safety and to oversee 
and review the interim analysis. Recommendation for trial continuation will be guided by 
monitoring boundaries at an interim analysis at which a formal efficacy analysis is performed 
as well as safety evaluations at all safety data reviews. Members of the DSMB will not be 
otherwise participating in the trial. The committee will include at least one cardiologist and 
one independent statistician. A DSMB Charter will be drafted and approved by the DSMB 
and the Steering Committee. The Charter will provide details regarding the interim analysis 
and monitoring plan. 
6. 
STUDY PROCEDURES 
6.1. 
Assessment Schedule  
A detailed schedule of procedures is provided in Appendix A. 
6.1.1. 
Screening Period 
6.1.1.1. 
Screening Visit (Visit 1) 
Patients will come to the Research Site for Visit 1. They will be instructed to fast for at least 
10 hours before their visit. 
If patients qualify for randomization based on the procedures at Visit 1, they need to be 
randomized within 42 days after Visit 1. The following procedures will be performed at the 
screening visit: 
• 
Obtain signed informed consent 
• 
Assign the patient a patient number 
• 
Obtain medical, surgical and family history 


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• 
Record demographics 
• 
Obtain height, weight, and body mass index 
• 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and oral body temperature) 
• 
Obtain a 12-lead electrocardiogram 
• 
Evaluate inclusion/exclusion criteria 
• 
This includes procedures and (fasting) blood samples (for example, hs-CRP, 
calculated creatinine clearance) as needed to determine the CV risk category (see 
inclusion criteria) 
• 
Obtain fasting blood samples for chemistry and hematology testing 
• 
Obtain a fasting blood sample for the lipid profile (TG, TC, HDL-C, LDL-C, non-
HDL-C, VLDL-C) 
• 
Perform a urine pregnancy test on women of childbearing potential 
• 
Record concomitant medication(s) 
• 
Instruct patient to fast for ≥10 hours prior to the next visit 
6.1.1.2. 
Screening Visit (Visit 1.1) 
Some patients will skip Visit 1.1: Patients who qualify for study participation after Visit 1 
because they meet all inclusion criterion and none of the exclusion criteria, may return to the 
Research Site for Visit 2 to be randomized and to start the treatment/follow-up period of the 
study. For these patients, Visit 2 will occur soon after Visit 1. 
Patients, who do not qualify at Visit 1, may return to the Research Site for a second 
qualifying visit (Visit 1.1) at the discretion of the investigator. At Visit 1.1, procedures that 
caused failure of eligibility at Visit 1 will be repeated. Patients will be eligible for 
randomization after Visit 1.1 if they meet all inclusion criteria and if they no longer fail the 
exclusion criteria. If patients are evaluated at Visit 1.1 and qualify for randomization based 
on the repeated procedures at Visit 1.1, they need to be randomized within 14 days after 
Visit 1.1. 
For some patients, Visit 1.1 will be mandatory at least 28 days after Visit 1 in order to check 
eligibility. These are patients who at Visit 1 started treatment with a statin, changed their 
statin, changed the daily dose of their statin, started to washout prohibited medications or 
started a stabilization period with certain medications (see inclusion/exclusion criteria for 
details). Any of these changes at Visit 1 may affect the qualifying lipid levels and therefore, 
patients will need to have Visit 1.1 to determine whether they qualify based on lipid level 
requirements (TG and LDL-C) determined at Visit 1. Other procedures that caused failure of 
eligibility at Visit 1 will also be repeated at Visit 1.1. 
The following procedures will be performed at the screening visit: 
• 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and oral body temperature) 


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• 
Evaluate inclusion/exclusion criteria; only those evaluations will be repeated that 
deemed the patient not eligible on Visit 1. 
• 
Obtain fasting blood samples for chemistry and hematology testing. Only those 
samples will be obtained that deemed the patient not eligible on Visit 1. 
• 
Obtain a fasting blood sample for the lipid profile (TG, TC, HDL-C, LDL-C, non-
HDL-C, VLDL-C) if the patient was deemed not eligible on Visit 1. This includes 
patients who at Visit 1 started treatment with a statin, changed their statin, changed 
the daily dose of their statin, started to washout prohibited medications or started a 
stabilization period with certain medications (see inclusion/exclusion criteria for 
details). These patients will have a fasting blood sample collected at Visit 1.1 for the 
qualifying lipid values (TG and LDL-C), and the TG and LDL-C inclusion criteria 
will be evaluated. 
• 
Record concomitant medication(s) 
6.1.2. 
Treatment/Follow-Up Period 
Every attempt should be made to complete the follow-up visits during the defined window 
periods. 
6.1.2.1. 
Randomization visit (Visit 2; Day 0) 
Qualified patients will return to the Research Site for Visit 2. 
The following procedures will be performed at Visit 2: 
• 
Perform physical examination 
• 
Obtain weight 
• 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and oral body temperature) 
• 
Measure waist circumference (one of the factors to diagnose metabolic syndrome) 
• 
Obtain a 12-lead electrocardiogram 
• 
Evaluate inclusion/exclusion criteria 
• 
Obtain fasting blood samples for: 
o 
Chemistry and hematology testing 
o 
Lipid profile (baseline) 
o 
Biomarker assays (baseline) 
o 
Genetic testing (optional blood sample) 
o 
Archiving (in countries and at sites approved by IRB/IEC and dependent on 
country regulations) 
• 
Perform a urine pregnancy test on women of childbearing potential (must be 
negative for randomization) 
• 
Dispense study drug and record randomization number 
• 
Instruct patient on how to take study drug 


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• 
Administer study drug - Note: Study drug should be taken orally with food following 
the collection of all fasting blood samples 
• 
Assess for and record adverse events 
• 
Record concomitant medication(s) 
• 
Instruct patient: 
o 
To bring all study supplies with them to the next visit 
o 
Not to take study drug on the morning of their next visit 
o 
To fast for ≥10 hours prior to the next visit 
6.1.2.2. 
Visit 3 (Day 120; ~4 Months) 
Patients will return to the Research Site for Visit 3 on Day 120 ±10 days. 
The following procedures will be performed: 
• 
Perform physical examination 
• 
Obtain weight 
• 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and oral body temperature) 
• 
Obtain fasting blood samples for: 
o 
Chemistry and hematology testing 
o 
Lipid profile 
• 
Review study drug compliance by unused capsule count; discuss with and counsel 
patients about compliance if needed 
• 
Administer study drug - Note: Study drug should be taken orally with food following 
the collection of all fasting blood samples 
• 
Assess and record efficacy events 
• 
Assess for and record adverse events 
• 
Record concomitant medication(s) 
• 
Instruct patient: 
o 
To bring all study supplies with them to the next visit 
o 
Not to take study drug on the morning of their next visit 
o 
To fast for ≥10 hours prior to the next visit 
6.1.2.3. 
Visits 4, 5, 6 and 7 
At Visit 4: Day 360 ± 10; Visit 5: Day 720 ± 10; Visit 6: Day 1080 ± 10; and Visit 7: 
Day 1440 ± 10, the following procedures will be performed: 
• 
Perform physical examination 
• 
Obtain weight 


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• 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and oral body temperature) 
• 
Measure waist circumference (collected at Visit 5 only) 
• 
Obtain a 12-lead electrocardiogram 
• 
Obtain fasting blood samples for: 
o 
Chemistry and hematology testing 
o 
Lipid profile 
o 
Biomarker assays (collected at Visit 5 only) 
o 
Archiving (in countries and at sites approved by IRB/IEC and dependent on 
country regulations) 
• 
Review study drug compliance by unused capsule count; discuss with and counsel 
patients about compliance if needed 
• 
Administer study drug - Note: Study drug should be taken orally with food following 
the collection of all fasting blood samples 
• 
Assess and record efficacy events 
• 
Assess for and record adverse events 
• 
Record concomitant medication(s) 
• 
Instruct patient: 
o 
To bring all study supplies with them to the next visit 
o 
Not to take study drug on the morning of their next visit 
o 
To fast for ≥10 hours prior to the next visit 
6.1.2.4. 
Additional Visits 
The end date of the study is expected for Day 1800 but the actual end date will be dependent 
on the determination of the study end date by the DSMB. The study end date is determined to 
be when approximately 1612 primary efficacy events have occurred. If the actual study end 
date is later than the expected end date, additional visits will be planned between Visit 7 and 
the Last Visit with a maximum of 360 ±10 days between visits. If the actual study end date is 
sooner than the expected end date, fewer visits will occur, and the last visit (See Section 
6.1.2.5) will occur sooner. 
On additional visits the same procedures will be performed as listed in Section 6.1.2.3. 
Irrespective of the number of additional visits, after the DSMB has established the end of the 
study date, there will be a last visit with procedures as listed in Section 6.1.2.5. 
6.1.2.5. 
Last Visit – End of Study 
All patients will complete the study at the same time (within a 30-day window after the study 
end date), irrespective of the date that they were randomized. The end date of the study is 
planned for Day 1800 but the actual end date will be dependent on the determination of the 
study end date by the DSMB when approximately 1612 primary efficacy events have 
occurred (event-driven trial). For each patient, the last visit may occur within 30 day after the 


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actual study end date as determined by the DSMB. However, for the efficacy endpoints based 
on CV events, only events occurring up to and including the scheduled actual study end date 
will be included in the efficacy analyses. 
A final follow-up visit is required for all patients. In the rare cases that a final follow-up visit 
cannot occur within the 30-day timeframe following the study end date, any attempt to 
contact the patient must be recorded on a special contact form, until/unless appropriate 
information is obtained. 
At Visit 13, the following procedures will be performed: 
• 
Perform physical examination 
• 
Obtain weight 
• 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and oral body temperature) 
• 
Measure waist circumference  
• 
Obtain a 12-lead electrocardiogram 
• 
Obtain fasting blood samples for: 
o 
Chemistry and hematology testing 
o 
Lipid profile 
o 
Biomarker assays 
o 
Archiving (in countries and at sites approved by IRB/IEC and dependent on 
country regulations) 
• 
Determine study drug compliance by unused capsule count 
• 
Assess and record efficacy events 
• 
Assess for and record adverse events 
• 
Record concomitant medication(s) 
6.2. 
Telephone Follow-up Contact 
Site personnel will contact each patient by telephone on the following study days: 
• 
Day 60 ±3 days 
• 
Day 180 ±5 days 
• 
Day 450 ±5 days 
• 
Day 540±5 days 
• 
Day 630 ±5 days 
• 
Day 810 ±5 days 
• 
Day 900 ±5 days 
• 
Day 990 ±5 days 


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• 
Day 1170 ±5 days 
• 
Day 1260 ±5 days 
• 
Day 1350 ±5 days 
• 
Day 1530 ±5 days 
• 
Day 1620 ±5 days 
• 
Day 1710 ±5 days 
If the treatment/follow-up period of the study is extended beyond the expected end date 
(Day 1800), additional follow-up phone calls will be made every 3 months in-between 
additional visits ±5 days. See Section 6.1.2.4 for the timing of the additional visits. If the 
treatment/follow period of the study is shorter than the expected end date, less follow-up 
phone calls will be needed. 
Every attempt will be made to talk to each patient within this time frame. 
The following information will be collected from the patient: 
• 
Possible efficacy endpoints related to CV events. Patients will be asked to return to 
the Research Site to assess for any endpoints or events identified. 
• 
Adverse events 
• 
Concomitant medications 
• 
Current address and contact information (update if changed or will be changing) 
Patients will be reminded about the following items: 
• 
To take the study medication according to the dosing schedule assigned, with food 
• 
When to return to the Research Center for the next visit 
• 
To bring the unused study medication to the next visit 
• 
To not take study drug on the morning of their next visit 
• 
To fast for at least 10 hours prior to the next visit 
6.3. 
Laboratory Procedures 
6.3.1. 
Clinical Laboratory Procedures 
All clinical laboratory determinations for screening and safety will be performed by a 
certified clinical laboratory under the supervision of the Sponsor or its designee. 
Whenever possible and appropriate, samples for the clinical laboratory procedures will be 
collected after fasting for at least 10 hours. For the purposes of this study, fasting is defined 
as nothing by mouth except water (and any essential medications). 
The investigator must review and sign all laboratory test reports. At screening, patients who 
have laboratory values that are outside the exclusionary limits specified in the exclusion 
criteria may not be enrolled in the study (patients can be considered for the study if values 
are classified as not clinically significant by the investigator). After randomization, the 


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investigator will be notified if laboratory values are outside of their normal range. In this 
case, the investigator will be required to conduct clinically appropriate follow-up procedures. 
6.3.1.1. 
Safety Laboratory Tests 
The safety laboratory tests include: 
• 
Hematology with complete blood count (CBC), including RBC, hemoglobin (Hgb), 
hematocrit (Hct), white cell blood count (WBC), white cell differential, and platelet 
count 
• 
Biochemistry panel including total protein, albumin, alkaline phosphatase, alanine 
aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), total 
bilirubin, glucose, calcium, electrolytes (sodium, potassium, chloride), blood urea 
nitrogen (BUN), serum creatinine, uric acid, creatinine phosphokinase, HbA1c. 
6.3.1.2. 
Fasting Lipid Profile 
The fasting lipid panel includes: TG, TC, LDL-C, HDL-C, non-HDL-C, and VLDL-C.  
At all visits, LDL-C will be calculated using the Friedewald equation, or measured by 
preparative ultracentrifugation (Beta Quant) if at the same visit TG >400 mg/dL . These 
LDL-C values will be used for the evaluation of the LDL-C inclusion criterion (LDL-C 
qualifying measurements for randomization) and for the assessment of changes in the statin 
therapy when LDL-C is not at goal. In addition, irrespective of the TG levels, at Visit 2 (0 
Months of Follow-up, baseline) and at Visit 4 (12 Months of Follow-up), LDL-C will be 
measured by ultracentrifugation (Beta Quant). These direct LDL-C measurements will be 
used in the statistical analysis including the calculation of the percent change from baseline 
(1 year versus baseline). 
6.3.1.3. 
Genetic testing 
A fasting blood sample will be stored for future genetic testing at the discretion of the 
sponsor. The specifics of this test will be determined at a later date. This sample is optional 
as local regulations may prohibit genetic samples to be collected or shipped outside the 
country, or patients may not consent. 
6.3.1.4. 
Biomarkers Assays 
The biomarker assays include: hs-CRP, Apo B and hsTnT. 
6.3.1.5. 
Additional laboratory tests 
Additional laboratory tests include: 
• 
A urine pregnancy test will be administered to women of childbearing potential at 
certain visits as listed in schedule of procedures (Appendix A). The urine pregnancy 
tests will be performed at the Research Site utilizing marketed test kits, or at a 
certified clinical laboratory. 
• 
A fasting blood sample (12 mL) for archiving. This sample will be collected only at 
sites in countries where allowed by local regulations and at sites for which approved 
by the IRB or IEC. The plasma from the archiving sample will be stored frozen in 2 
separate equal aliquots, and will be used at the Sponsor’s discretion to perform 


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repeat analyses described in the protocol or to perform other tests related to 
cardiovascular health. 
6.3.1.6. 
Blinding of Laboratory Results 
All efficacy laboratory results during the double-blind period of the trial will be blinded 
(values not provided) to patients, investigators, pharmacists and other supporting staff at the 
Research Sites, personnel and designees of the Sponsor, study administrators and personnel 
at the organization(s) and vendors managing and/or supporting the study, with the exception 
of the laboratory personnel conducting the assays. 
6.3.1.7. 
Flagging of Critical Lab Values 
Critical lab values are values that may warrant medical intervention to avoid possible harm to 
a patient. Critical lab values will be defined in the Laboratory Manual for the study, and the 
Research Site will be notified of the occurrence of a critical lab value (critical high or critical 
low) by a special annotation (flag) in the laboratory reports provided to the Research Sites. 
Although laboratory values that are part of the efficacy endpoints during the double-blind 
period of the study will not be provided to the Research Site (see Section 6.3.1.6), the sites 
will be notified when the TG value of a patient sample is >1000 mg/dL (critical high TG 
value) or if the LDL-C values of a patient sample is >130 mg/dL. These critical high values 
will need to be confirmed by a repeat measurement (new fasting blood sample) within 7 
days.  
If TG values are confirmed high, patients may be discontinued from study drug with the 
option to remain on study (see Section 11.1 ODIS).  
If LDL-C values are confirmed high the investigator may either increase the dose of the 
present statin therapy or may add ezetimibe to lower LDL-C. The investigator should use the 
best clinical judgment for each patient. 
6.3.2. 
Medical Procedures 
6.3.2.1. 
Medical, Surgical and Family History 
Medical history, including family history and details regarding all illnesses and allergies, 
date(s) of onset, status of current condition, and smoking and alcohol use will be collected on 
all patients. 
6.3.2.2. 
Demographics 
Demographic information including day, month, and year of birth, race, and gender will be 
collected for all patients. 
6.3.2.3. 
Vital Signs 
Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, and oral 
body temperature. Blood pressure will be measured using a standardized process: 
• 
Patient should sit for ≥5 minutes with feet flat on the floor and measurement arm 
supported so that the midpoint of the manometer cuff is at heart level. 
• 
Use a mercury sphygmomanometer or automatic blood pressure device with an 
appropriately sized cuff with the bladder centered over the brachial artery. 


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Blood pressure should be recorded to the nearest 2 mmHg mark on the manometer or to the 
nearest whole number on an automatic device. A blood pressure reading should be repeated 1 
to 2 minutes later, and the second reading should also be recorded to the nearest 2 mmHg 
mark. 
6.3.2.4. 
Physical Examination 
A physical examination must include source documentation of general appearance, skin, and 
specific head and neck, heart, lung, abdomen, extremities, and neuromuscular assessments.  
 
6.3.2.5. 
Height, Weight and Body Mass Index 
Height and weight will be measured. Measurement of weight should be performed with the 
patient dressed in indoor clothing, with shoes removed, and bladder empty.  
 
6.3.2.6. 
Waist Circumference 
Waist circumference will be measured with a tape measure, as follows: Start at the top of the 
hip bone then bring the tape measure all the way around – level with the navel. Make sure the 
tape measure is snug, but without compressing the skin, and that it is parallel with the floor.  
Patients should not hold their breath while measuring waist circumference. 
 
6.3.2.7. 
Electrocardiogram (ECG) 
ECGs (standard 12-lead) will be obtained annually. Site personnel should make every 
attempt to perform a patient’s ECG using the same equipment at each visit. ECGs will be 
reviewed by the site for the detection of silent MI. Silent MIs will be sent for event 
adjudication.  
7. 
TREATMENT AND RESTRICTIONS 
7.1. 
Treatment 
7.1.1. 
Treatment Regimen, Dosage, and Duration 
Eligible study patients will be randomly assigned on Day 0 to one of the 2 treatment groups. 
Patients in each group will receive either 4 g/day AMR101 or placebo for up to 4.75 years 
(4 years planned median treatment duration) according to Table 1. 
The daily dose of study drug is 4 capsules per day taken as two capsules taken on two 
occasions per day (2 capsules given twice daily). 
 
Table 2. 
Dosing Schedule during the Treatment Period 
Treatment 
Group 
Daily Dose 
Number of Capsules per Day 
1 
4 g 
4 capsules of 1000 mg AMR101 


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Patients will be instructed to take study drug with food (i.e., with or at the end of their 
morning and evening meals). On days that patients are scheduled for study visits, the daily 
dose of study drug will be administered by site personnel with food provided by the site 
following collection of all fasting blood samples. For the purposes of this study, fasting is 
defined as nothing by mouth except water (and any essential medications) for at least 10 
hours. 
7.1.2. 
Treatment Assignment 
7.1.2.1. 
Identification number 
A unique patient identification number (patient number) will be established for each patient 
at each site. The patient number will be used to identify the patient throughout the study and 
will be entered on all documentation. If a patient is not eligible to receive treatment, or if a 
patient discontinues from the study, the patient number cannot be reassigned to another 
patient. The patient number will be used to assign patients to one of the 2 treatment groups 
according to the randomization schedule. 
7.1.2.2. 
Drug Randomization 
Only qualified patients who meet all of the inclusion criteria and none of the exclusion 
criteria will be randomized and will receive study medication starting at Visit 2 (Day 0). 
Eligible patients will be randomly assigned to one of the 2 treatment groups. Randomization 
will be stratified by CV risk category, use of ezetimibe and by geographical region 
(Westernized, Eastern European, and Asia Pacific countries) (See Section 3.10). 
Approximately 70% of randomized patients will be in the CV Risk Category 1, including 
patients with established CVD, and approximately 30% of randomized patients will be in the 
CV Risk Category 2, including patients with diabetes and at least one additional risk factor 
but no established CVD. Enrollment with patients of a CV risk category will be stopped 
when the planned number of patients in that risk category is reached. 
7.1.2.3. 
Emergency Unblinding 
In an emergency, when knowledge of the patient’s treatment assignment is essential for the 
clinical management or welfare of the patient, the investigator may request the patient’s 
treatment assignment for unblinding. Prior to unblinding the patient’s individual treatment 
assignment, the investigator should assess the relationship of an adverse event to the 
administration of the study drug (Yes or No). If the blind is broken for any reason, the 
investigator must record the date and reason for breaking the blind on the appropriate Case 
Report Form (CRF) and source documents. 
7.1.3. 
Compliance Control 
It is recommended that, unless clear contraindications arise, patients be strongly encouraged 
to adhere to their treatment regimen with the study drug for the duration of the trial. Any 
2 
Placebo 
4 capsules of matching placebo 


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interruptions of therapy should, if possible, be brief (e.g., <4 weeks) and only for clinically 
indicated reasons, such as adverse events. Discontinuations will be discouraged as much as 
possible. Any discontinuations should be based on compelling clinical reasons. 
For every patient, an assessment of compliance to the study drug treatment regimen must be 
obtained at each scheduled visit. Study medication will be dispensed in amounts exceeding 
the amount required for the study. Patients will be instructed to return all unused study 
medication at the next visit. Compliance to the study drug regimen will be evaluated at each 
visit by counting unused capsules. Discrepancies will be evaluated and discussed with each 
patient to assess compliance. If compliance is unsatisfactory, the patient will be counseled 
about the importance of compliance to the dosing regimen. At the end of the study, the final 
study medication compliance will be determined by unused capsule count (see Section 
12.2.2). 
7.2. 
Study Restrictions 
7.2.1. 
Concomitant Medications during Treatment/Follow-Up Period 
Any medications administered during the study period must be documented on the 
Concomitant Medication CRF. Patients must not have taken any investigational agent within 
90 days prior to screening. Patients cannot participate in any other investigational medication 
trial while participating in this study.  
The following non-study drug related, non-statin, lipid-altering medications and supplements, 
and foods are prohibited during the screening period (after Visit 1 to Visit 2), and are 
strongly discouraged during the study after Visit 2: 
• 
niacin >200 mg/day; 
• 
fibrates; 
• 
prescription omega-3 fatty acid medications; 
• 
dietary supplements containing omega-3 fatty acids (e.g., flaxseed, fish, krill, or 
algal oils); 
• 
bile acid sequestrants; 
• 
cyclophosphamide; 
• 
systemic retinoids 
If any of these products would be used during the treatment/follow-up period of the study, it 
should be for compelling medical reasons, and it should be documented in the Concomitant 
Medication CRF. 
Foods enriched with omega-3 fatty acids are strongly discouraged after Visit 1 for the 
duration of the study.  
The following products are allowed: statins, ezetimibe, and herbal products & dietary 
supplements not containing omega-3 fatty acids. 
Statins: 


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• 
The same statin at the same dose should be continued until the end of the study, 
unless deemed medically necessary to change because of an adverse event or lack of 
efficacy (LOE).  It is preferred that if LOE is the determining factor that ezetimibe 
be added to the present dose. 
• 
Switching between a brand name statin and the generic version of the same statin is 
allowed at any time during the study. 
• 
 Statins may be administered with or without ezetimibe. 
• 
Based on the FDA recommendation, simvastatin 80 mg be used only in patients who 
have been taking this dose for 12 months or more and have not experienced any 
muscle toxicity. (See reference:  FDA Drug Safety Communication: Ongoing safety 
review of high-dose Zocor (simvastatin) and increased risk of muscle injury. 
(http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatient
sandProviders/ucm204882.htm)  
• 
Changing of the type of statin or the statin dose during the treatment/follow-up 
period of the study should only be done for compelling medical reasons and must be 
documented in the CRF. 
LDL-C Rescue: 
• If the level of LDL-C exceeds 130 mg/dL during the study (initial measurement and 
confirmed by a second determination at least 1 week later), the investigator may 
either increase the dose of the present statin therapy or may add ezetimibe to lower 
LDL-C. The investigator should use the best clinical judgment for each patient.  
No data are available with regard to potential interactions between ethyl-EPA and oral 
contraceptives. There are no reports suggesting that omega-3 fatty acids, including ethyl-
EPA, would decrease the efficacy of oral contraceptives. 
 
7.2.2. 
Patient Restrictions 
Beginning at the screening visit, all patients should be instructed to refrain from excessive 
alcohol consumption, to maintain their current dietary regimen, and to not alter their normal 
activity routines. Excessive alcohol consumption is on average >2 units of alcohol per day. A 
unit of alcohol is defined as a 12-ounce (350 mL) beer, 5-ounce (150 mL) wine, or 1.5-ounce 
(45 mL) of 80‐proof alcohol for drinks. 
8. 
INVESTIGATIONAL PRODUCT 
8.1. 
Clinical Trial Material 
The following will be supplied by the Sponsor: 
• AMR101 1000 mg capsules 
• Placebo capsules 


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The Sponsor will supply sufficient quantities of AMR101 1000 mg capsules and placebo 
capsules to allow for completion of the study. The lot numbers of the drugs supplied will be 
recorded in the final study report. 
Records will be maintained indicating the receipt and dispensation of all drug supplies. At 
the conclusion of the study, any unused study drug will be destroyed. 
8.2. 
Pharmaceutical Formulations 
AMR101 1000 mg and placebo capsules are provided in liquid-filled, oblong, gelatin 
capsules. Each capsule is filled with a clear liquid (colorless to pale yellow in color). The 
capsules are approximately 25.5 mm in length with a diameter of approximately 9.5 mm.  
Table 2 summarizes the components of each capsule. 
Table 3. 
Components of AMR101 Capsules 
Component 
AMR101 
1000 mg capsules
Quantity 
(mg/capsule) 
Placebo 
capsules 
Quantity 
(mg/capsule) Function 
Capsule fill 
 
 
 
 
Icosapent ethyl 
998 
- 
Active 
 
Paraffin, light liquid 
- 
932 
 
 
All-rac-α-tocopherol 
2 
1.86 
Antioxidant 
Capsule shell 
 
 
 
 
Gelatin 
279 
279 
Capsule shell material
 
Sorbitol, liquid 
 
(non-crystallizing) 
78 
78 
Plasticizer 
 
Glycerol 
44 
44 
Plasticizer 
 
Purified water 
37 
37 
Solvent 
 
Maltitol, liquid 
28 
28 
Plasticizer 
 
8.3. 
Labeling and Packaging 
Study medication will be packaged in high-density polyethylene bottles. Labeling and 
packaging will be performed according to GMP guidelines and all applicable country-
specific requirements. The bottles will be numbered for each patient based on the 
randomization schedule. The patient randomization number assigned by IVRS or a designee 
of the Sponsor for the study (if no IVRS system is used), will correspond to the number on 
the bottles. The bottle number for each patient will be recorded in the Electronic Data 
Capture (EDC) system for the study. 
8.4. 
Dispensing Procedures and Storage Conditions 
8.4.1. 
Dispensing Procedures 
At Visit 2 (Day 0), patients will be assigned study drug according to their treatment group 
determined by the randomization schedule. Once assigned to a treatment group, patients will 
receive study drug supplies. At each visit, patients will bring unused drug supplies dispensed 
to them earlier. From the drug supplies assigned to each patient, site personnel will 
administer drug while the patients are at the Research Site. 


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The investigator or designee must contact the IVRS system or a designee of the Sponsor for 
the study (if no IVRS system is used) when any unscheduled replacements of study 
medication are needed. 
During the last visit during the treatment period, patients will bring the unused drug supplies 
for site personnel to calculate the final study medication compliance by unused capsule count 
(see Section 12.2.2). 
8.4.2. 
Storage Conditions 
At the Research Sites, study drugs must be stored at room temperature, 68°F to 77°F (20°C 
to 25°C). Do not allow storage temperature to go below 59°F (15°C) or above 86°F (30°C). 
Store in the original package. 
Study drugs must be stored in a pharmacy or locked and secure storage facility, accessible 
only to those individuals authorized by the investigator to dispense the drug. The investigator 
or designee will keep accurate dispensing records. At the conclusion of the study, study site 
personnel will account for all used and unused study drug. Any unused study drug will be 
destroyed. The investigator agrees not to distribute study drug to any patient, except those 
patients participating in the study. 
9. 
EFFICACY ASSESSMENTS 
9.1. 
Specification of Variables and Procedures 
The primary endpoint and the majority of the secondary and tertiary endpoints are based on 
clinical events related to CVD and mortality. All events occurring between randomization 
and the study end date (inclusive) must be recorded. Only adjudicated events will be included 
in the final analyses. Further details on the assessment of clinical events and their definitions 
will be found in the CEC charter. Important definitions are listed in Appendix B of this 
protocol. 
9.2. 
Efficacy Endpoints 
9.2.1. 
Primary Efficacy Endpoint 
Time from randomization to the first occurrence of the composite of the following clinical 
events: 
• CV death, 
• Nonfatal MI (including silent MI; ECGs will be performed annually for the detection 
of silent MIs), 
• Nonfatal stroke, 
• Coronary revascularization  
• Hospitalization for unstable angina determined to be caused by myocardial ischemia 
by invasive/non-invasive testing . 
The first occurrence of any of these major adverse vascular events during the follow-up 
period of the study will be included in the incidence. 
9.2.2. 
Secondary Efficacy Endpoints 
The key secondary efficacy endpoint is: 


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• The composite of death from CV causes, nonfatal MI, coronary revascularization, 
unstable angina, nonfatal stroke, or peripheral CVD requiring intervention, 
angioplasty, bypass surgery, or aneurysm repair. 
Other secondary efficacy endpoints are as follows (to be tested in said order): 
• The composite of total mortality, nonfatal MI, or nonfatal stroke; 
• The composite of death from CV causes, nonfatal MI, coronary revascularization, 
unstable angina, peripheral CVD, or cardiac arrhythmia requiring hospitalization; 
• The composite of death from CV causes, nonfatal MI, coronary revascularization, or 
unstable angina; 
• The composite of death from CV causes or nonfatal MI; 
• Total mortality; 
• Fatal and nonfatal MI (including silent MI); 
• Coronary Revascularization;  
• Hospitalization for unstable angina determined to be caused by myocardial ischemia 
by invasive/non-invasive testing ; 
• Fatal and nonfatal stroke. 
For the secondary endpoints that count a single event, the first occurrence of this type of 
event will be counted in each patient. For secondary endpoints that are composites of two or 
more types of events, the first occurrence of any of the event types included in the composite 
will be counted in each patient. 
 
9.2.3. 
Tertiary Efficacy Endpoints: 
• The second, third, fourth, and fifth major CV event of the primary composite 
endpoint. The type of (nonfatal) events may occur in any order. 
• Primary endpoint in subset of patients with diabetes mellitus; 
• Primary endpoint in subset of patients with metabolic syndrome; 
• New CHF, new CHF leading to hospitalization, transient ischemic attack, amputation 
for CVD and carotid revascularization; 
• Elective coronary revascularization and emergent coronary revascularization; 
• New onset  diabetes; 
• Fasting TG, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apo B, hs-CRP, and hsTnT: 
on treatment change and baseline effect; 
• CV mortality; 
• Cardiac Arrhythmias requiring hospitalization; 
• Cardiac Arrest; 
• To explore the effect of AMR101 on weight and waist circumference. 


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For the tertiary endpoints that count a single event, the first occurrence of this type of event 
will be counted in each patient. For tertiary endpoints that are composites of two or more 
types of events, the first occurrence of any of the event types included in the composite will 
be counted in each patient (except when stated otherwise, for the second, third, fourth, and 
fifth major CV event). 
10. 
SAFETY ASSESSMENTS 
10.1. 
Specification of Variables and Procedures 
Safety assessments will include adverse events, clinical laboratory measurements (chemistry, 
hematology), 12-lead ECGs, vital signs (systolic and diastolic blood pressure, heart rate, 
respiratory rate, and oral body temperature), and physical examinations as per Study 
Procedures/Appendix A. 
A complete medical, surgical and family history will be completed at Visit 1. 
A list of the analytes to be measured for the safety evaluation is found in Section 6.3.1.1. All 
laboratory test results must be evaluated by the investigator as to their clinical significance. 
Any observations at physical examinations or laboratory values considered by the 
investigator to be clinically significant should be considered an adverse event. 
10.2. 
Adverse Events 
An adverse event is defined as any untoward medical occurrence, which does not necessarily 
have a causal relationship with the medication under investigation. An adverse event can 
therefore be any unfavorable and/or unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an investigational 
medication product, whether or not related to the investigational medication product. All 
adverse events, including observed or volunteered problems, complaints, or symptoms, are to 
be recorded on the appropriate CRF. Each adverse event is to be evaluated for duration, 
intensity, and causal relationship with the study medication or other factors. 
Adverse events, which include clinical laboratory test variables, will be monitored from the 
time of informed consent until study participation is complete. Patients should be instructed 
to report any adverse event that they experience to the investigator. Beginning with Visit 2, 
investigators should assess for adverse events at each visit and record the event on the 
appropriate adverse event CRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the investigator and recorded on the CRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the investigator, it should be recorded as a separate adverse event on the CRF. 
Any medical condition that is present when a patient is screened or present at baseline that 
does not deteriorate should not be reported as an adverse event. However, medical conditions 
or signs or symptoms present at baseline and that change in severity or seriousness at any 
time during the study should be reported as an adverse event. 
Clinically significant abnormal laboratory findings or other abnormal assessments that are 
detected during the study or are present at baseline and significantly worsen will be reported 
as adverse events or SAEs. The investigator will exercise his or her medical and scientific 


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judgment in deciding whether an abnormal laboratory finding or other abnormal assessment 
is clinically significant. 
The investigator will rate the severity (intensity) of each adverse event as mild, moderate, or 
severe, and will also categorize each adverse event as to its potential relationship to study 
drug using the categories of Yes or No. 
Severity: 
• Mild – An event that is usually transient in nature and generally not interfering with 
normal activities. 
• Moderate – An event that is suf
ficiently discomforting to interf ere with norm al 
activities. 
• Severe – An event that is incap acitating with inability to work or do usual activity or 
inability to work or perform normal daily activity. 
 
Causality Assessment: 
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 
• No (unrelated, not related, no relation) – Th e time course between the administration 
of study drug and the occurrence or worseni ng of the adverse event rules out a causal 
relationship and another cause (concom itant drugs, therapies, complications, etc.) is 
suspected. 
• Yes – The tim e course between the adm inistration of study drug and the occurrence 
or worsening of the adverse event is consistent with a causal relationship and no other 
cause (concomitant drugs, therapies, complications, etc.) can be identified. 
 
The following factors should also be considered: 
• The temporal sequence from study medication administration 
• The event should occur after the study m edication is given. The length of tim e from 
study medication exposure to event should be evaluated in th e clinical context of the 
event. 
• Underlying, concomitant, intercurrent diseases 
• Each report should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have. 
• Concomitant medication 
• The other m edications the patien t is taking or the tre
atment the patien t receives 
should be examined to determine whether any of them might be recognized to cause 
the event in question. 
• Known response pattern for this class of study medication 
• Clinical and/or preclinical data may indicate whether a particular response is likely to 
be a class effect. 
• Exposure to physical and/or mental stresses 
• The exposure to stress m ight induce advers e changes in the patient and provide a 
logical and better explanation for the event. 
• The pharmacology and pharmacokinetics of the study medication 


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• The known pharm acologic properties (absor ption, distribution, m etabolism, and 
excretion) of the study medication should be considered. 
Unexpected Adverse Events – An unexpected adverse event is an adverse event either not 
previously reported or where the nature, seriousness, severity, or outcome is not consistent 
with the current Investigator’s Brochure. 
10.2.1. 
Serious Adverse Events 
A serious adverse event (SAE) is defined as an adverse event that meets any of the following 
criteria: 
• Results in death 
• Is life-threatening- Note: The term  “life-threatening” in the definition of “serious” 
refers to an event in which the patient was at risk of death at the tim e of the event. It 
does not refer to an event, which hypotheti cally might have caused death, if it were 
more severe. 
• Requires hospitalization or prolongation of ex isting hospitalization- Note: In general, 
hospitalization for treatment of a pre-existing condition(s) that did no t worsen from 
baseline is not considered adverse events and should not be reported as SAEs. 
• Results in disability/incapacity 
• Is a congenital anomaly/birth defect; 
• Is an important medical event- Note: Important medical events that may not result in 
death, be life threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate m edical judgment, they may jeopardize the patient and m ay 
require medical or surgical intervention to  prevent one of the outcom es listed above. 
Examples of such m edical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalizations, or the development of drug dependency. 
For the purposes of this study SAEs that are primary endpoint events will only be recorded 
for the endpoint determination and not captured as SAEs. Following adjudication if the event 
is determined to not meet the criteria for a primary event, the event will be evaluated as an 
SAE beginning with that day as Day 0. 
10.3. 
Serious Adverse Event Reporting – Procedure for Investigators 
10.3.1. 
Initial Reports 
All SAEs occurring from the time of informed consent until 30 days following the last 
administration of study medication must be reported to the Sponsor or designee within 24 
hours of the knowledge of the occurrence (this refers to any adverse event that meets any of 
the aforementioned serious criteria). SAEs that the investigator considers related to study 
medication occurring after the 30-day follow-up period will also be reported to the Sponsor 
or designee. 
The investigator is required to submit SAE reports to the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) in accordance with local requirements. All 
investigators involved in studies using the same investigational medicinal product (IMP) will 
receive any Suspected Unexpected Serious Adverse Reaction (SUSAR) reports for onward 
submission to their local IRB as required. All reports sent to investigators will be blinded. 


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10.3.2. 
Follow-Up Reports 
The investigator must continue to follow the patient until the SAE has subsided, or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
patient dies. Within 24 hours of receipt of follow-up information, the investigator must 
update the SAE form electronically in the EDC system for the study and submit any 
supporting documentation (e.g., laboratory test reports, patient discharge summary, or 
autopsy reports) to the Sponsor or designee via fax or email. 
10.3.3. 
Reporting by the Sponsor 
IRBs and IECs will be informed of SUSARs according to local requirements. Cases will be 
unblinded for reporting purposes as required. 
10.4. 
Exposure In Utero During Clinical Trials 
If a patient becomes pregnant during the study, the investigator should report the pregnancy 
to the Sponsor or designee within 24 hours of being notified. The Sponsor or designee will 
then forward the Exposure In Utero form to the investigator for completion. 
The patient should be followed by the investigator until completion of the pregnancy. If the 
pregnancy ends for any reason before the anticipated date, the investigator should notify the 
Sponsor or designee. At the completion of the pregnancy, the investigator will document the 
outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, 
neonatal death, or congenital anomaly), the investigator should follow the procedures for 
reporting an SAE. 
11. 
TREATMENT DISCONTINUATION/PATIENT WITHDRAWAL 
Patients may withdraw from the study at any time and for any reason. Study drug 
administration may also be discontinued at any time, at the discretion of the investigator. In 
any case, follow-up for efficacy and safety should be continued. 
11.1. 
Reasons for Early Study Drug Discontinuation 
Study drug discontinuation should be avoided as much as possible, but may be done for any 
of the following reasons: 
• Patient withdraws consent or requests earl y discontinuation from the study for any 
reason. Patients should be en couraged to continue to participate in the study for the 
entire duration of the study even if they choose not to take study m
edication any 
longer. 
• Occurrence of a clinical or laborato ry adverse event, either serious or non-serious, at 
the discretion of the investigator. T he Sponsor or designee shoul d be notified if a 
patient is discontinued because of an advers e event or laboratory abnormality. It is 
recommended that, u nless clear contraindi cations arise, patients be strong ly 
encouraged to adhere to their treatment regimen with the study drug for the duration 
of the trial. Any interruptions of therapy should, if possible, be brief (e.g., <4 weeks) 
and only for clinically indi cated reasons, such  as adverse events. Th e following 
should be considered reason for discontinuation: 
o ALT > 3x ULN and bilirubin > 1.5x ULN 


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o ALT >5x ULN 
o ALT >3x ULN and appearance or worsening of hepatitis 
o ALT > 3x ULN persisting for >4weeks 
o ALT > 3x ULN and cannot be monitored weekly for 4 weeks 
• Any medical condition or personal circ
umstance that, in the opinion of the 
investigator, exposes the patient to risk
 by continuing in th e study or precludes 
adherence to the protocol. 
• Sponsor discontinues the study. 
• A TG value that is flagged as critically high, i.e., > 1000 mg/dL, and confirmed as 
critically high by a repeat measurement (new fasting blood sample) within 7 days. In 
this case, a patient m ay be discontinue d from study drug and other lipid-altering 
medications may be (re)initiated. 
Occurrence of an outcome event according to the judgment of the investigator is not 
considered a valid reason for study drug discontinuation. 
Patients whose treatment with study medication is discontinued early, and have not 
withdrawn consent, may stay in study and will be monitored until the end of the study. 
Patients that continue in the study after indefinite cessation of therapy will be characterized 
as Off Drug In Study (ODIS). If not contraindicated, patients will also have the option to 
restart study medication at any point once characterized as ODIS. 
The reason for study drug discontinuation or interruption will be recorded on the CRF. 
11.2. 
Follow-Up after Early Study Drug Discontinuation/Lost to Follow-Up 
• Patients who prematurely discontinue study drug are not to be replaced. 
• All randomized patients must be followed up according to the st udy flowchart until 
the study end date or death, regardless of
 whether they discontinue study drug 
prematurely or not. Any event occurring after early study drug discontinuation will be 
recorded up through the study end date. 
• In order to f ollow the medical status of the patients, especially when they withdraw 
after having experienced an advers e event, investigators are encouraged to obtain  
information from the patient’s prim ary care practitioner (phys ician or any other 
medical care provider). Investigators are also requested to try as much as possible to 
re-contact those patients at th e end of the trial to obta in at least their vital status as 
well as their status with respect to the primary endpoint, and thus avoid lost to follow-
up for the efficacy assessment. 
• If patients are lost to follo w-up, the CRF m ust be completed up to the last visit or 
contact. Patients who didn’t have a study visit for 1 year or longer are considered lost 
to follow-up. 
12. 
STATISTICS 
12.1. 
Analysis Populations 
12.1.1. 
Randomized Population 
The randomized population will include all patients who sign the informed consent form and 
are assigned a randomization number at Visit 2 (Day 0). 


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12.1.2. 
Intent-to-Treat Population  
The Intent-to-Treat (ITT) population will consist of all randomized patients who take at least 
one dose of study drug. The ITT population is the primary analysis population. All efficacy 
analyses will be performed on the ITT population. 
12.1.3. 
Per-Protocol Population 
The per-protocol (PP) population will include all ITT patients without any major protocol 
deviations, and who had ≥80% compliance with study drug while on treatment (up to 
discontinuation for patients whose treatment is terminated early). The per-protocol efficacy 
analysis for CV events will be restricted to each patient’s time on study drug plus 30 days 
thereafter. 
12.1.4. 
Safety Population 
All safety analyses will be conducted based on the safety population, which is defined as all 
randomized patients who receive at least one dose of study drug. This is the same as the ITT 
population. 
12.2. 
Statistical Methods 
Safety and efficacy variables will be analyzed using appropriate statistical methods to be 
described in detail in a separate Statistical Analysis Plan (SAP). The SAP will be finalized 
before study unblinding. 
12.2.1. 
Patient Disposition and Demographic/Baseline Characteristics 
The numbers of patients screened, the number of patients randomized per treatment group 
(randomized population), and the number of patients in the ITT and PP populations by 
treatment group will be listed. 
For randomized patients who discontinued treatment with study drug, the primary reason for 
discontinuation will be listed and summarized by treatment group. 
Summary statistics (mean, standard deviation, median, minimum and maximum) will be 
provided by treatment group for demographic characteristics (e.g., age, sex, race, and 
ethnicity) and baseline characteristics (e.g., body weight, height, and body mass index) in the 
ITT and PP populations. 
Demographic data and baseline characteristics will be compared among treatment groups for 
the ITT and PP population. Differences in demographic and baseline characteristics will be 
tested using a chi-square test (for categorical variables) or a 1-way analysis of variance 
model with treatment as a factor (for continuous variables). The p-values will be used as 
descriptive statistics, primarily as an assessment of the adequacy of randomization. 
12.2.2. 
Study Medication Exposure and Compliance 
The final compliance to study drug will be calculated as the percent of doses taken relative to 
doses scheduled to be taken. Overall percent compliance will be calculated per patient in the 
ITT and PP populations and summarized by treatment group using summary statistics (n, 
mean, standard deviation, median, minimum, and maximum). 


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12.2.3. 
Concomitant Therapies 
Concomitant medication/therapy verbatim terms will be coded using the latest version of the 
World Health Organization Drug Dictionary. The numbers and percentages of patients in 
each treatment group taking concomitant medications will be summarized by anatomic and 
therapeutic chemical classification and preferred term. 
12.2.4. 
Analysis of Efficacy 
For efficacy endpoints including CV events, only adjudicated events will be included in the 
final statistical analyses. 
12.2.4.1. 
Summary Statistics 
Summary statistics (n, mean, standard deviation, median, minimum, and maximum) for the 
baseline and post-baseline measurements, the percent changes, or changes from baseline will 
be presented by treatment group and by visit for all efficacy variables to be analyzed. The 
summary statistics will include changes in body weight and body mass index from baseline 
by treatment group and by visit. 
12.2.4.2. 
Primary Endpoint 
The primary efficacy endpoint is the time from randomization to the first occurrence of any 
component of the composite of the following clinical events: 
• CV death, 
• Nonfatal MI (including silent MI), 
• Nonfatal stroke, 
• Coronary revascularization,  
• Hospitalization for unstable angina determined to be caused by myocardial ischemia 
by invasive/non-invasive testing. 
The analysis of the primary efficacy endpoint will be performed using the log-rank test 
comparing the 2 treatment groups (AMR101 and placebo) and including the stratification 
factor “CV risk category”, use of ezetimibe and by geographical region (Westernized, 
Eastern European, and Asia Pacific countries) as recorded in the IVRS at the time of 
enrollment. Treatment difference will be tested at alpha level of 0.0476 accounting for one 
interim efficacy analysis. The hazard ratio for treatment group (AMR101 vs. placebo) from a 
Cox proportional hazard model that includes the stratification factor will also be reported, 
along with the associated 95% confidence interval. Kaplan-Meier estimates from the time to 
the primary efficacy endpoint will be plotted. 
12.2.4.3. 
Secondary Endpoints 
The statistical analyses of the secondary endpoints will be analyzed by the same log-rank test 
specified above for the primary efficacy endpoint. Treatment differences will be tested at 
alpha level of 0.05 using a sequential procedure for controlling type 1 error starting with the 
key secondary variable.  The remaining secondary variables will be tested in the order 
specified in Section 9.2.2. Estimates of the hazard ratios from the Cox proportional hazard 
and the associated 95% confidence intervals will also be provided. Kaplan-Meier estimates 
from the time to the secondary efficacy endpoints will be plotted. 


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12.2.4.4. 
Tertiary Endpoints 
For event rates, the statistical analyses of the tertiary endpoints will be similar to the analysis 
of the secondary efficacy endpoints. 
For measurements of lipids, lipoproteins and inflammatory markers the change from baseline 
will be analyzed in the units of each marker, and the percent change from baseline. 
New onset diabetes is defined as Type 2 diabetes newly diagnosed during the 
treatment/follow-up period (i.e. patients with no history of diabetes at randomization, with 
the test as listed in Appendix C). 
 
12.2.4.5. 
Subgroup Analyses  
The following subgroups will be explored. Log-rank tests, treatment effects and the 
associated 95% confidence intervals for the primary and secondary efficacy endpoints within 
each subgroup will be provided using the Cox proportional hazard model with treatment 
(AMR101 or placebo), and stratification as a factor (with the exception of the subgroup 
analyses of those subgroup variables related to the stratification factors, i.e., CV risk category 
that will not have stratification as a factor): 
• Gender, 
• age (<65 yr and ≥65 yr), 
• race (white and nonwhite, or any other subset with at least 10% of the total number of 
patients), 
• CV risk category (previous CV disease or not), 
• the presence/absence of diabetes at baseline, 
• baseline LDL-C (by tertile), 
• baseline HDL-C (by tertile), 
• baseline TG (by tertile), 
• hs-CRP (≤3 mg/L and >3 mg/L), 
• Apo B (by tertile) 
The consistency of the treatment effects in subgroups will be assessed for the primary and 
secondary efficacy endpoints. For each subgroup variable, a Cox proportional hazard model 
with terms for treatment, stratification factors (with the exception of those subgroup variables 
related to the stratification factors, i.e., CV risk category), subgroup, and treatment-by-
subgroup interaction will be performed. The main treatment effect will not be tested with this 
model. P-values for testing the interaction terms will be provided. 
12.2.4.6. 
Interim Efficacy Analysis 
One interim analysis will be performed for the primary efficacy endpoint using best available 
data (adjudicated events and site reported endpoints) based on data when approximately 60% 
of the total number of primary endpoint events is reached. The interim analysis will be based 
on a group sequential design that includes early stopping rules for benefit while preserving 
the overall Type I error rate (O’Brien-Fleming). This allows for interim analysis and 
preserves the overall Type I error probability of α=0.05 for the primary endpoint. 


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Approximately 1612 events are planned to be observed during the trial, based on sample size 
calculation assumptions. Therefore, the interim analysis will occur after at least 967 events 
have been observed. According to this boundary, the critical p-value at the interim analysis 
has to be p<=0.0076, resulting in the final evaluation p-value of 0.0476.  
The interim results of the study will be monitored by an independent DSMB. The analyses 
will be performed by the independent statistical group unblinded to the treatment assignment. 
The results will be reported only to the DSMB. The unblinded information will not be 
released to sponsor under any circumstance before the completion of the study. Specific 
statistical guidelines for data monitoring will be discussed and formalized in a separate 
Interim Statistical Analysis Plan and DSMB Charter. 
12.2.5. 
Analysis of Safety 
All analyses of safety will be conducted on the safety population, which is defined as all 
randomized patients who receive at least one dose of study drug. The safety assessment will 
be based on the frequency of adverse events, physical exams, vital signs and safety 
laboratory tests. 
Adverse events with new onset during the study between the initiation of study drug and 
30 days after the last dose of study drug for each patient will be considered treatment-
emergent (TEAEs). This will include any AE with onset prior to initiation of study drug and 
increased severity after the treatment initiation. 
Treatment-emergent adverse events will be summarized by system organ class and preferred 
term, and by treatment. This will include overall incidence rates (regardless of severity and 
relationship to study drug), and incidence rates for moderate or severe adverse events. A 
summary of SAEs, and adverse events leading to early discontinuation from the study will be 
presented through data listings. 
Safety laboratory tests and vital signs will be summarized by post-treatment change from 
baseline for each of the parameters using descriptive statistics by treatment group. Those 
patients with significant laboratory abnormalities will be identified in data listings. 
Additional safety parameters will be summarized in data listings. 
12.3. 
Sample Size Determination 
Sample size estimation is based on the assumption that the primary composite endpoint (time 
from randomization to the first occurrence of CV death, non-fatal MI, non-fatal stroke, 
coronary revascularization, or unstable angina requiring hospitalization) event rate by 4 years 
would be relatively reduced by 15%, from an event rate by 4 years of 23.6% in the placebo 
group to 20.5% in the AMR101 group. It is expected that a minimum of 1612 primary 
efficacy endpoint events will be required during the study. A total of approximately 
6990 patients are needed to be able to detect this difference at 4.76% significance level 
(because of the interim analysis described in Section 12.2.4.6) and with 90% power, 
assuming an 18-month enrollment period and a median follow-up of 4 years. The current 
sample size calculation is based on an estimated placebo yearly event rate of 5.9% (23.6% 
over 4 years). To protect against the possibility that the actual placebo event rate is lower 
than estimated, an extra 1000 patients will be enrolled (approximately 7990 patients in total). 
By adding the extra 1000 patients, the event rate in the placebo group could be 5.2% per year 
(20.8% over 4 years) without having to modify the other sample size assumptions. 


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Before completing the enrollment phase of the trial, the actual event rate based on pooled, 
blinded accumulation of primary efficacy endpoint events will be calculated and may be used 
to increase the sample size. If the sample size is increased, the enrollment phase will be 
extended to allow enrollment of the additional patients.  
13. 
MONITORING, DATA MANAGEMENT, AND RECORD KEEPING 
13.1. 
Data Management 
13.1.1. 
Data Handling 
Data will be recorded at the site on CRFs. All entries on a CRF are ultimately the 
responsibility of the Investigator, who is expected to review each form for completeness, 
accuracy and legibility before signing. All forms must be filled out by using ink. Errors 
should be lined out but not obliterated and the correction inserted, initialed and dated. A CRF 
must be completed for each randomized patient. The CRFs and source documents must be 
made available to the Sponsor and/or its designee. 
13.2. 
Record Keeping 
The Investigator must maintain all documents and records, originals or certified copies of 
original records, relating to the conduct of this trial, and necessary for the evaluation and 
reconstruction of the clinical trial. This documentation includes, but is not limited to 
protocol, CRFs, AE reports, patient source data (including records of patients, patient visit 
logs, clinical observations and findings), correspondence with health authorities and IRB, 
consent forms, inventory of study product, Investigator’s curriculum vitae, monitor visit logs, 
laboratory reference ranges and laboratory certification or quality control procedures, and 
laboratory director curriculum vitae. 
The Investigator and affiliated institution should maintain the trial documents as required by 
the applicable regulations. The Investigator and affiliated institution should take measures to 
prevent accidental or premature destruction of documents. Clinical trial documents must be 
kept in the clinical site’s archives indefinitely, unless written authorization is obtained from 
the Sponsor. 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator and research institution agree that the Sponsor, their representatives and 
designees, the IRB or IEC, and representatives from worldwide regulatory agencies will have 
the right, both during and after the clinical trial, to review and inspect pertinent medical 
records related to the clinical trial. 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor and/or its designee(s), will perform quality control and quality assurance checks 
of all clinical trials that it sponsors. Before the enrollment of any patient in this study, the 
Sponsor or its designee will review with the investigator and site personnel the following 
documents: protocol, Investigator’s Brochure, CRFs and procedures for their completion, the 
informed consent process, and the procedure for reporting SAEs. Site visits will be 


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performed by the Sponsor and/or its designees. During these visits, information recorded on 
the CRFs will be verified against source documents and requests for clarification or 
correction may be made. After the CRF data is entered by the site, the Sponsor or designee 
will review for safety information, completeness, accuracy, and logical consistency. 
Computer programs that identify data inconsistencies may be used to help monitor the 
clinical trial. If necessary, requests for clarification or correction will be sent to investigators. 
By signing the protocol, the Sponsor agrees directly or through its designee(s) to be 
responsible for implementing and maintaining quality control and quality assurance systems 
with written standard operating procedures to ensure that trials are conducted and data are 
generated, documented, and reported in compliance with the protocol, accepted standards of 
Good Clinical Practice (GCP), International Conference on Harmonization (ICH) and other 
applicable regulations. 
16. 
ETHICS AND GOOD CLINICAL PRACTICE COMPLIANCE 
Good Clinical Practice is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting trials that involve human patients. 
Compliance with this standard provides public assurance that the rights, safety, and well 
being of trial patients are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki, and that the clinical trial data are credible. In this study, the 2008 
version of the Declaration of Helsinki will be adhered to. It can be found on the website of 
The World Medical Association: 
http://www.wma.net/en/30publications/10policies/b3/17c.pdf 
17. 
INFORMED CONSENT 
Prior to participation in a study, the participant, or participant’s legal representative must sign 
an IRB/IEC-approved written informed consent form (ICF). The approved written informed 
consent must abide to all applicable laws in regards to the safety and confidentiality of the 
patients. To obtain and document informed consent, the Investigator should comply with 
applicable regulations; adhere to GCP standards and the ethical principles in the Declaration 
of Helsinki (see Section 16). 
The language in the oral and written information about the trial, including the written 
informed consent form should be as non-technical as practical and should be understandable 
to the participant or participant’s legal representative and the impartial witness, where 
applicable. Before informed consent is obtained, the Investigator should provide the 
participant, or participant’s legal representative ample time and opportunity to inquire about 
the trial and to decide whether or not to participate. 
All questions about the trial should be answered to the satisfaction of the participant, or the 
participant’s legal representative. The written ICF should be signed and personally dated by 
the participant or participant’s legal representative, and by the person who conducted the 
informed consent discussion. Participants will be informed that participation is voluntary and 
that he/she can withdraw from the study at any time. A signed copy of the consent form must 
be given to the participant, and this fact will be documented in the CRF. 


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Of special concern regarding informed consent is the collection of blood samples for genetic 
analysis. Local regulations may not allow the collection of blood samples for genetic testing 
or the shipment of blood samples for genetic testing outside the region. In these cases, blood 
samples for genetic testing will not be collected, and the portion of the ICF describing the 
genetic component of the study will not be included. If blood samples for genetic testing will 
be collected, the ICF will clearly indicate that a sample will be drawn for this purpose, but 
that the participant has the right to refuse this procedure. 
18. 
PUBLICATION POLICY  
The Steering Committee (SC) is responsible for the reporting and publication of the study 
results. All decisions regarding the use of study data for public presentation, and publication 
including issues of authorship must be approved by the Sponsor. The results of the study will 
be published irrespective of whether the endpoints are met, or whether the results are 
regarded positive or negative. 
Confidentiality, publication, and patent applications related to unpublished study-related 
information and unpublished information given to the investigator by the Sponsor and/or its 
designee(s) shall be handled as set forth in the Clinical Trial Agreement. 
19. 
FINANCING AND INSURANCE 
19.1. 
Finances 
Prior to starting the study, the Principal Investigator and/or institution will sign a Clinical 
Trial Agreement with the Sponsor and/or its designee(s). This agreement will include the 
financial information agreed upon by the parties. 
19.2. 
Insurance Compensation 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical 
trials under its sponsorship. This insurance policy is in accordance with local laws and 
requirements. The insurance of the Sponsor does not relieve the investigator and the other 
collaborators from maintaining their own liability insurance policy. An insurance certificate 
will be provided to the IRB/IEC and Competent Authority according to country specific 
regulatory requirements. 
20. 
COMPLETION OF STUDY 
The end of the study will be at the time of the last patient-last visit of the follow-up period of 
the study. The IRB and IEC will be notified about the end of the study according to country-
specific regulatory requirements. 
21. 
STUDY ADMINISTRATIVE INFORMATION 
21.1. 
Protocol Amendments 
Any amendments to the study protocol considered to be a substantial amendment will be 
communicated to the investigator by the Sponsor or its designee. All substantial protocol 
amendments will undergo the same review and approval process as the original protocol and 


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may be implemented after it has been approved by the IRB/IEC and Competent Authority  , 
unless immediate implementation of the change is necessary for patient safety. In this case, 
the situation must be documented and reported to the IRB/IEC and Competent Authority 
according to all relevant country-specific regulatory requirements. 
A protocol amendment is considered to be a substantial amendment if it is likely to affect the 
safety, physical, or mental integrity of patients in the study; the scientific value of the study; 
the conduct or management of the study; or the quality or safety of any IMP used in the 
study. 
Any other minor changes to the protocol not considered to be substantial amendments will 
not need prior approval of the IRB/IEC and Competent Authority and will be communicated 
to the investigator by the Sponsor or its designee. 
 


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22. 
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23. 
INVESTIGATOR’S AGREEMENT 
This document is a confidential communication of Amarin. The authorized investigators 
agree to personally conduct or supervise the conduct of this investigational study in 
compliance with the current protocol, good clinical practices, and all applicable laws, 
regulations, and guidelines. No changes will be made to the protocol without prior 
notification to Amarin, except to protect the safety, rights, and welfare of the study patients, 
and always in compliance with all applicable laws, regulations, and guidelines. Acceptance 
of this document constitutes the agreement by the Investigator that no unpublished 
information contained herein or related to the study will be published or disclosed without 
prior written approval from Amarin. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly. 
 
 
 
 
_____________________________  
____________________ 
Signature 
 
 
 
 
Date 
Principal Investigator 
 
 
_____________________________ 
Printed Name 
 


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APPENDIX A: SCHEDULE OF PROCEDURES 
 
Screening 
Follow-Up (FU) 13 
Study Day 
Up to 42 days 
before Day 0 
Up to 14 days 
before Day 02 
0 
 
120 
± 10 
360 
± 10 
720 
± 10 
1080 
± 10 
1440 
± 10 
1800 
+ 30 
Months of FU 
 
 
0 
4 
12 
24 
36 
48 
60 
Years of FU 
 
 
0 
0.33 
1 
2 
3 
4 
5 
Visit # 
1 
1.1 
2 
3 
4 
5 
6 
7 
LV 14 
Study Procedures: 
Informed Consent 
X 
 
 
 
  
 
 
 
Medical, Surgical & 
Family History 
X 
 
 
 
  
 
 
 
Demographics 
X 
 
 
 
  
 
 
 
Evaluate inclusion / 
exclusion criteria 
X 1 
X 3 
X 
 
  
 
 
 
Physical Examination 
 
 
X 
X 
X X 
X 
X 
X 
Weight, Height 4 
X 
 
X 
X 
X X 
X 
X 
X 
Vital Signs 5 
X 
X 
X 
X 
X X 
X 
X 
X 
Waist Circumference 
 
 
X 
 
 
X 
 
 
X 
12-Lead ECG 
X 
 
X 
 
X 
X 
X 
X 
X 
Urine pregnancy test 6 
X 
 
X 
 
  
 
 
 
Concomitant Meds 
X 
X 
X 
X 
X X 
X 
X 
X 
Randomization 
 
 
X 
 
  
 
 
 
Dosing 
at the Research Site 7 
 
 
X 
X 
X X 
X 
X 
 
Efficacy events 
 
 
 
X 
X X 
X 
X 
X 
AE Evaluations 
 
 
X 
X 
X X 
X 
X 
X 
Compliance Check 8 
 
 
 
X 
X X 
X 
X 
X 
Chemistry and 
hematology 9 
X 
X 3 
X 
X 
X X 
X 
X 
X 
Fasting lipid profile 10 
X 
X 3 
X 
X 
X X 
X 
X 
X 
Genetic testing 11 
 
 
X 
 
  
 
 
 
Biomarkers: hs-CRP,  apo 
B, hsTNT 
 
 
X 
 
 
X 
 
 
X 
Fasting blood sample 
for archiving 12 
 
 
X 
 
X 
X 
X 
X 
X 
 
1. Includes procedures and (fasting) blood samples (for example, hs-CRP, calculated creatinine clearance) as needed to determine the CV risk category (see 
inclusion criteria). 
2. Screening visit to re-evaluate inclusion/exclusion criteria for patients who are not eligible for participation based on data from Visit 1. 


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3. Inclusion/exclusion criteria will be re-evaluated for selected study procedures that are performed on Visit 1.1 because patients failed to meet them at Visit 1. 
4. Height at first screening visit only. 
5. Vital signs, including systolic and diastolic blood pressure (mmHg), heart rate, respiratory rate and oral body temperature. Participants must be seated for at 
least 5 minutes before assessments of vital signs. 
6. For women of childbearing potential. 
7. The patients will fast of at least 10 hours before arriving at the Research Site, when all fasting blood samples will be obtained. After blood samples are 
obtained, patients will be given drug with food. 
8. Review study drug compliance by unused capsule count, discuss with and counsel patients about compliance if needed; final study compliance at last visit. 
9. Safety Laboratories — Complete Blood Count: Includes RBC, Hgb, Hct, WBC and differential, and platelet count. Biochemistry includes total protein, 
albumin, alkaline phosphatase, ALT, AST, total bilirubin, glucose, calcium, electrolytes (sodium, potassium, chloride), blood urea nitrogen (BUN), serum 
creatinine, uric acid, creatinine phosphokinase, HbA1c. Safety labs may be repeated as deemed necessary by the Investigator. 
10. TG, TC, HDL-C, LDL-C, non-HDL-C, and VLDL-C. 
11. Fasting blood sample that will be stored for future genetic testing at the discretion of the sponsor. This sample is optional as local regulations may prohibit 
genetic samples to be collected or shipped outside the country, or patients may not consent. 
12. Used at the sponsor’s discretion to perform repeat analyses described in the protocol or to perform other tests related to cardiovascular health. 
13. Site personnel will contact each patient by telephone in-between Visit 2 and Visit 3 and between Visit 3 and Visit 4. After Visit 4 contact will be made every 
3 months. The purpose of the contact is to collect information about efficacy events, adverse events, concomitant medications, confirm patient’s current 
address and contact information and remind patients about taking their study medication and logistics for the next visit. 
14. The last visit (LV) may occur within 30 day after the study end date as determined by the DSMB; the study end date is tentatively schedule for Day 1800 but 
the actual date as determined by the DSMB may be different.


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APPENDIX B: STANDARDIZED DEFINITIONS FOR END POINT 
EVENTS IN CARDIOVASCULAR TRIALS 
 
Reference: 
http://www.cdisc.org/stuff/contentmgr/files/0/2356ae38ac190ab8ca4ae0b222392b37/misc/cdisc_
november_16__2010.pdf 
 
DEFINITION OF CARDIOVASCULAR DEATH  
  
Cardiovascular death includes death resulting from an acute myocardial infarction, sudden 
cardiac death, death due to heart failure, death due to stroke, and death due to other 
cardiovascular causes, as follows:  
  
1. Death due to Acute Myocardial Infarction refers to a death by any mechanism  
(arrhythmia, heart failure, low output) within 30 days after a myocardial infarction (MI) 
related to the immediate consequences of the myocardial infarction, such as progressive 
congestive heart failure (CHF), inadequate cardiac output, or recalcitrant arrhythmia.  If these 
events occur after a “break” (e.g., a CHF and arrhythmia free period of at least a week), they 
should be designated by the immediate cause, even though the MI may have increased the 
risk of that event (e.g., late arrhythmic death becomes more likely after an acute myocardial 
infarction (AMI)).  The acute myocardial infarction should be verified to the extent possible 
by the diagnostic criteria outlined for acute myocardial infarction or by autopsy findings 
showing recent myocardial infarction or recent coronary thrombus.  Sudden cardiac death, if 
accompanied by symptoms suggestive of myocardial ischemia, new ST elevation, new 
LBBB, or evidence of fresh thrombus by coronary angiography and/or at autopsy should be 
considered death resulting from an acute myocardial infarction, even if death occurs before 
blood samples or 12-lead electrocardiogram (ECG) could be obtained, or at a time before the 
appearance of cardiac biomarkers in the blood.  
 
Death resulting from a procedure to treat a myocardial infarction (percutaneous coronary 
intervention (PCI), coronary artery bypass graft surgery (CABG), or to treat a complication 
resulting from myocardial infarction, should also be considered death due to acute MI.    
  
Death resulting from a procedure to treat myocardial ischemia (angina) or death due to a 
myocardial infarction that occurs as a direct consequence of a cardiovascular 
investigation/procedure/operation should be considered as a death due to other cardiovascular 
causes.  
 
2. Sudden Cardiac Death refers to a death that occurs unexpectedly, not following an acute 
AMI, and includes the following deaths:  
a. Death witnessed and instantaneous without new or worsening symptoms  
b. Death witnessed within 60 minutes of the onset of new or worsening cardiac symptoms, 
unless the symptoms suggest AMI  
c. Death witnessed and attributed to an identified arrhythmia (e.g., captured on an 


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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 non-
cardiac etiology (Post-Cardiac Arrest Syndrome)  
f. Unwitnessed death without other cause of death (information regarding the patient’s 
clinical status preceding death should be provided, if available)  
General Considerations  
 
o A subject seen alive and clinically stable 12-24 hours prior to being found dead without 
any evidence or information of a specific cause of death should be classified as “sudden 
cardiac death.”  Typical scenarios include  
• 
Subject well the previous day but found dead in bed the next day  
• 
Subject found dead at home on the couch with the television on  
 
o Deaths for which there is no information beyond “Patient found dead at home” may be 
classified as “death due to other cardiovascular causes” or in some trials, “undetermined 
cause of death.”  Please see Definition of Undetermined Cause of Death, for full details.  
 
3. Death due to Heart Failure or Cardiogenic Shock refers to a death occurring in the  
context of clinically worsening symptoms and/or signs of heart failure (see Definition of 
Heart Failure Requiring Hospitalization) without evidence of another cause of death and not 
following an AMI.  Note that deaths due to heart failure can have various etiologies, 
including one or more AMIs (late effect), ischemic or non-ischemic cardiomyopathy, or 
valve disease.  
 
Death due to Heart Failure or Cardiogenic shock should include sudden death occurring 
during an admission for worsening heart failure as well as death from progressive heart 
failure or cardiogenic shock following implantation of a mechanical assist device.  
  
New or worsening signs and/or symptoms of congestive heart failure (CHF) include any of 
the following:  
a. New or increasing symptoms and/or signs of heart failure requiring the initiation of, or an 
increase in, treatment directed at heart failure or occurring in a patient already receiving 
maximal therapy for heart failure  
b. Heart failure symptoms or signs requiring continuous intravenous therapy or chronic 
oxygen administration for hypoxia due to pulmonary edema  
c. Confinement to bed predominantly due to heart failure symptoms  
d. Pulmonary edema sufficient to cause tachypnea and distress not occurring in the context of 
an acute myocardial infarction, worsening renal function, or as the consequence of an 
arrhythmia occurring in the absence of worsening heart failure  
e. Cardiogenic shock not occurring in the context of an acute myocardial infarction or as the 
consequence of an arrhythmia occurring in the absence of worsening heart failure  
 Cardiogenic shock is defined as systolic blood pressure (SBP) < 90 mm Hg for greater than 


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1 hour, not responsive to fluid resuscitation and/or heart rate correction, and felt to be 
secondary to cardiac dysfunction and associated with at least one of the following signs of 
hypoperfusion:  
• 
 Cool, clammy skin or  
• 
 Oliguria (urine output < 30 mL/hour) or  
• 
 Altered sensorium or  
• 
 Cardiac index < 2.2 L/min/m2  
Cardiogenic shock can also be defined if SBP < 90 mm Hg and increases to ≥ 90 mm Hg 
in less than 1 hour with positive inotropic or vasopressor agents alone and/or with 
mechanical support.  
  
General Considerations  
 
Heart failure may have a number of underlying causes, including acute or chronic 
ischemia, structural heart disease (e.g. hypertrophic cardiomyopathy), and valvular heart 
disease.  Where treatments are likely to have specific effects, and it is likely to be 
possible to distinguish between the various causes, then it may be reasonable to separate 
out the relevant treatment effects.  For example, obesity drugs such as fenfluramine 
(pondimin) and dexfenfluramine (redux) were found to be associated with the 
development of valvular heart disease and pulmonary hypertension.  In other cases, the 
aggregation implied by the definition above may be more appropriate.  
  
4. Death due to Stroke refers to death occurring up to 30 days after a stroke that is either due  
to the stroke or caused by a complication of the stroke.   
 
5. Death due to Other Cardiovascular Causes refers to a cardiovascular death not included in 
the above categories (e.g. dysrhythmia unrelated to sudden cardiac death, pulmonary 
embolism, cardiovascular intervention (other than one related to an AMI), aortic aneurysm 
rupture, or peripheral arterial disease).  Mortal complications of cardiac surgery or non-
surgical revascularization should be classified as cardiovascular deaths.  
 
DEFINITION OF NON-CARDIOVASCULAR DEATH  
  
Non-cardiovascular death is defined as any death that is not thought to be due to a 
cardiovascular cause.  Detailed recommendations on the classification of non-cardiovascular 
causes of death are beyond the scope of this document.  The level of detail required and the 
optimum classification will depend on the nature of the study population and the anticipated 
number and type of non-cardiovascular deaths.  Any specific anticipated safety concern should 
be included as a separate cause of death.  The following is a suggested list of non-cardiovascular* 
causes of death:  
  
Non-Malignant Causes  
• 
 Pulmonary  


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• 
 Renal  
• 
 Gastrointestinal  
• 
 Hepatobiliary  
• 
 Pancreatic  
• 
 Infection (includes sepsis)  
• 
 Non-infectious (e.g., systemic inflammatory response syndrome (SIRS))  
• 
 Hemorrhage, not intracranial  
• 
 Non-cardiovascular system organ failure (e.g., hepatic failure)  
• 
 Non-cardiovascular surgery  
• 
 Other non-cardiovascular  
• 
 Accidental/Trauma  
• 
 Suicide  
• 
 Drug Overdose  
 
*Death due to a gastrointestinal bleed should not be considered a cardiovascular death.  
 
Malignant Causes  
Malignancy should be coded as the cause of death if:  
• 
 Death results directly from the cancer; or  
• 
 Death results from a complication of the cancer (e.g. infection, complication of surgery / 
chemotherapy / radiotherapy); or  
• 
 Death results from withdrawal of other therapies because of concerns relating to the poor 
prognosis associated with the cancer  
 
Cancer deaths may arise from cancers that were present prior to randomization or which 
developed subsequently.  It may be helpful to distinguish these two scenarios (i.e. worsening of 
prior malignancy; new malignancy).  
  
Suggested categorization includes common organ systems, hematologic, or unknown.  
 
DEFINITION OF UNDETERMINED CAUSE OF DEATH 
  
Undetermined Cause of Death refers to a death not attributable to one of the above categories 
of cardiovascular death or to a non-cardiovascular 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 in well-run clinical trials.  
  
A common analytic approach for cause of death analyses is to assume that all undetermined cases 
are included in the cardiovascular category (e.g., presumed cardiovascular death, specifically 
“death due to other cardiovascular causes”).  Nevertheless, the appropriate classification and 
analysis of undetermined causes of death depends on the population, the intervention under 
investigation, and the disease process.  The approach should be prespecified and described in the 
protocol and other trial documentation such as the end point adjudication procedures and/or the 


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statistical analysis plan.  
 
DEFINITION OF MYOCARDIAL INFARCTION  
  
1. General Considerations  
  
The term myocardial infarction (MI) should be used when there is evidence of myocardial 
necrosis in a clinical setting consistent with myocardial ischemia.  
  
In general, the diagnosis of MI requires the combination of:  
• 
 Evidence of myocardial necrosis (either changes in cardiac biomarkers or post-
mortem pathological findings); and  
• 
 Supporting information derived from the clinical presentation, electrocardiographic 
changes, or the results of myocardial or coronary artery imaging  
 
The totality of the clinical, electrocardiographic, and cardiac biomarker information should be 
considered to determine whether or not a MI has occurred.  Specifically, timing and trends in 
cardiac biomarkers and electrocardiographic information require careful analysis.  The 
adjudication of MI should also take into account the clinical setting in which the event occurs.  
MI may be adjudicated for an event that has characteristics of a MI but which does not meet the 
strict definition because biomarker or electrocardiographic results are not available.  
  
2. Criteria for Myocardial Infarction 
  
a. Clinical Presentation  
The clinical presentation should be consistent with diagnosis of myocardial ischemia 
and infarction.  Other findings that might support the diagnosis of MI should be taken 
into account because a number of conditions are associated with elevations in cardiac 
biomarkers (e.g., trauma, surgery, pacing, ablation, congestive heart failure, 
hypertrophic cardiomyopathy, pulmonary embolism, severe pulmonary hypertension, 
stroke or subarachnoid hemorrhage, infiltrative and inflammatory disorders of cardiac 
muscle, drug toxicity, burns, critical illness, extreme exertion, and chronic kidney 
disease).  Supporting information can also be considered from myocardial imaging and 
coronary imaging.  The totality of the data may help differentiate acute MI from the 
background disease process.  
 
b. Biomarker Elevations  
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.  CK-MB and troponin are preferred, but CK may be used in 


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the absence of CK-MB and troponin.  
 
For MI subtypes, different biomarker elevations for CK, CK-MB, or troponin will be 
required.  The specific criteria will be referenced to the URL.  
  
In many studies, particularly those in which patients present acutely to hospitals which 
are not participating sites, it is not practical to stipulate the use of a single biomarker or 
assay, and the locally available results are to be used as the basis for adjudication.  
However, if possible, using the same cardiac biomarker assay and preferably, a core 
laboratory, for all measurements reduces inter-assay variability.  
  
Since the prognostic significance of different types of myocardial infarctions (e.g., 
periprocedural myocardial infarction versus spontaneous myocardial infarction) may be 
different, consider evaluating outcomes for these subsets of patients separately.  
  
c. Electrocardiogram (ECG) Changes  
Electrocardiographic changes can be used to support or confirm a MI.  Supporting 
evidence may be ischemic changes and confirmatory information may be new Q waves.  
  
• 
Criteria for acute myocardial ischemia (in absence of left ventricular 
hypertrophy (LVH) and left bundle branch block (LBBB)):  
 
o ST elevation  
New ST elevation at the J point in two anatomically contiguous leads with the 
cut-off points:  ≥ 0.2 mV in men (> 0.25 mV in men < 40 years) or ≥ 0.15 mV in 
women in leads V2-V3 and/or ≥ 0.1 mV in other leads.   
  
o 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.  
  
 
The above ECG criteria illustrate patterns consistent with myocardial ischemia.  In 
patients with abnormal biomarkers, it is recognized that lesser ECG abnormalities may 
represent an ischemic response and may be accepted under the category of abnormal 
ECG findings.  
  
• 
Criteria for pathological Q-wave  
  
o Any Q-wave in leads V2-V3 ≥ 0.02 seconds or QS complex in leads V2 and V3  
o Q-wave ≥ 0.03 seconds and ≥ 0.1 mV deep or QS complex in leads I, II, aVL, 
aVF, or V4-V6 in any two leads of a contiguous lead grouping (I, aVL, V6;  V4-
V6; II, III, and aVF)a   
 
aThe same criteria are used for supplemental leads V7-V9, and for the Cabrera 
frontal plane lead grouping.  
 
• 
 Criteria for Prior Myocardial Infarction  


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o Pathological Q-waves, as defined above  
o R-wave ≥ 0.04 seconds in V1-V2 and R/S ≥ 1 with a concordant positive T-
wave in the absence of a conduction defect  
 
3. Myocardial Infarction Subtypes 
Several MI subtypes are commonly reported in clinical investigations and each are defined 
below:  
 
a. Spontaneous MI  
  
1.  Detection of rise and/or fall of cardiac biomarkers with at least one value above the 
URL with at least one of the following:  
• 
 Clinical presentation consistent with ischemia  
• 
 ECG evidence of acute myocardial ischemia  
• 
 New pathological Q waves  
• 
 Imaging evidence of new loss of viable myocardium or new regional wall 
motion abnormality  
• 
 Autopsy evidence of acute MI  
 
2. If biomarkers are elevated from a prior infarction, then a spontaneous myocardial 
infarction is defined as:  
a. One of the following:  
o Clinical presentation consistent with ischemia  
o ECG evidence of acute myocardial ischemia  
o New pathological Q waves  
o Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality  
o Autopsy evidence of acute MI  
AND  
 b. Both of the following:  
o Evidence that cardiac biomarker values were decreasing (e.g., two samples  3-6 
hours apart) prior to the suspected MI*  
o ≥ 20% increase (and > URL) in troponin or CK-MB between a measurement made 
at the time of the initial presentation and a further sample taken 3-6 hours later  
*If biomarkers are increasing or peak is not reached, then a definite diagnosis of 
recurrent MI is generally not possible. 
 


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b. Percutaneous Coronary Intervention-Related Myocardial Infarction  
Peri-PCI MI is defined by any of the following criteria.  Symptoms of cardiac ischemia are not 
required.  
  
1. Biomarker elevations within 48 hours of PCI:  
• 
Troponin or CK-MB (preferred) > 3 x URL and  
• 
No evidence that cardiac biomarkers were elevated prior to the procedure;  
OR  
• 
Both of the following must be true:  
o ≥ 50%1 increase in the cardiac biomarker result  
o Evidence that cardiac biomarker values were decreasing (e.g., two samples  3-6 
hours apart) prior to the suspected MI  
2. New pathological Q waves   
3. Autopsy evidence of acute MI  
 
c. Coronary Artery Bypass Grafting-Related Myocardial Infarction  
 
Peri-coronary artery bypass graft surgery (CABG) MI is defined by the following criteria.  
Symptoms of cardiac ischemia are not required.  
  
1.  Biomarker elevations within 72 hours of CABG:  
• Troponin or CK-MB (preferred) > 5 x URL and  
• No evidence that cardiac biomarkers were elevated prior to the procedure;   
 
OR  
• Both of the following must be true:  
o ≥ 50%2 increase in the cardiac biomarker result  
o Evidence that cardiac biomarker values were decreasing (e.g., two samples  3-6 
hours apart) prior to the suspected MI.  
 
AND  
 
2. One of the following:  
•  New pathological Q-waves persistent through 30 days  
•  New persistent non-rate-related LBBB  
•  Angiographically documented new graft or native coronary artery occlusion  
•  Other complication in the operating room resulting in loss of myocardium  
•  Imaging evidence of new loss of viable myocardium  
                                                 
 
 
1, 2 Data should be collected in such a way that analyses using ≥ 20% or ≥ 50% could both be performed. 


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OR  
  
3.  Autopsy evidence of acute MI  
 
d. Silent Myocardial Infarction  
Silent MI is defined by the following:  
  
1. No evidence of acute myocardial infarction  
 
AND  
  
2. Any one of the following criteria:  
•  New pathological Q-waves.  A confirmatory ECG is recommended if there have been 
no clinical symptoms or history of myocardial infarction.  
•  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  
•  Autopsy evidence of a healed or healing MI  
 
COMMON CLASSIFICATION SCHEMES FOR MYOCARDIAL INFARCTION 
CATEGORIES   
  
For some trials, categorization of MI end points may be helpful or necessary using one or more 
of the classification schemes below:  
  
1.  By the Universal MI Definition: 
 
a. Clinical Classification of Different Types of Myocardial Infarction  
 
• 
 Type 1  
Spontaneous myocardial infarction related to ischemia due to a primary coronary 
event such as plaque erosion and/or rupture, fissuring, or dissection  
• 
 Type 2  
Myocardial infarction secondary to ischemia due to either increased oxygen 
demand or decreased supply, e.g., coronary artery spasm, coronary embolism, 
anemia, arrhythmias, hypertension, or hypotension  
• 
 Type 3  
Sudden unexpected cardiac death, including cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, accompanied by presumably new ST 
elevation, or new LBBB, or evidence of fresh thrombus in a coronary artery by 
angiography and/or at autopsy, but death occurring before blood samples could 
be obtained, or at a time before the appearance of cardiac biomarkers in the blood  
• 
Type 4a  


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Myocardial infarction associated with PCI  
• 
Type 4b  
Myocardial infarction associated with stent thrombosis as documented by 
angiography or at autopsy  
• 
Type 5  
Myocardial infarction associated with CABG  
 
b. Sample Clinical Trial Tabulation of Randomized Patients by Types of Myocardial 
Infarction  
 
Types of MI 
Treatment A 
Number of patients (N = ) 
Treatment B 
Number of patients (N = ) 
MI Type 1 
n, % 
n, % 
MI Type 2 
n, % 
n, % 
MI Type 3 
n, % 
n, % 
MI Type 4 
n, % 
n, % 
MI Type 5 
n, % 
n, % 
Total number 
n, % 
n, % 
N = total number of patients; n = number of patients with a particular MI. 
 
2. 
By Electrocardiographic Features: 
• 
ST-Elevation MI (STEMI)  
o  Additional subcategories may include:  
 
 Q-wave  
 
 Non-Q-wave  
 
 Unknown (no ECG or ECG not interpretable)  
• 
Non-ST-Elevation MI (NSTEMI)  
o Additional subcategories may include:  
 
Q-wave  
 
Non-Q-wave  
 
Unknown (no ECG or ECG not interpretable)  
• 
Unknown (no ECG or ECG not interpretable)  
 
3. 
By Biomarker Elevation (per Universal MI Definition):  
 
The magnitude of cardiac biomarker elevation can be calculated as a ratio of the peak 
biomarker value divided by the 99th percentile URL.  
  
The biomarker elevation can be provided for various MI subtypes, as shown in the example 
below.  


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Classification of the Different Types of Myocardial Infarction According to Multiples of the 
99th percentile URL of the Applied Cardiac Biomarker 
 
Multiples 
X 99% 
M1 
Type 
(spontaneous) 
MI Type 2 
(secondary) 
M1 Type 3 
(sudden 
death) 
M1 Type 
4** (PCI) 
M1 Type 
5** 
(CABG) 
Total 
Number 
1-2X 
 
 
>2-3X 
 
 
>3-5X 
 
 
>5-10X 
 
 
Total 
Number 
 
 
 
*Biomarkers are not available for this type of myocardial infarction since the patients expired 
before biomarker determination could be performed. 
 
** For the sake of completeness, the total distribution of biomarker values should be reported.  
The hatched areas represent biomarker elevations below the decision limit used for these types of 
myocardial infarction. 
 
DEFINITION OF HOSPITALIZATION FOR UNSTABLE ANGINA  
 Unstable angina requiring hospitalization is defined as   
  
1.  Symptoms of myocardial ischemia at rest (chest pain or equivalent) or an accelerating 
pattern of angina with frequent episodes associated with progressively decreased exercise 
capacity  
 
AND  
  
2.  Prompting an unscheduled visit to a healthcare facility and hospitalization (including chest 
pain observation units) within 24 hours of the most recent symptoms  
 
AND  
  
3.  At least one of the following: 
 
a. New or worsening ST or T wave changes on resting ECG  
• 
 ST elevation  
New ST elevation at the J point in two anatomically contiguous leads with the cut-off 
points:  ≥ 0.2 mV in men (> 0.25 mV in men < 40 years) or ≥ 0.15 mV in women in 
leads V2-V3 and/or ≥ 0.1 mV in other leads.  
  
• 
 ST depression and T-wave changes  
New horizontal or down-sloping ST depression ≥ 0.05 mV in two contiguous leads; 


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and/or new T inversion ≥ 0.1 mV in two contiguous leads.  
  
The above ECG criteria illustrate patterns consistent with myocardial ischemia.  It is 
recognized that lesser ECG abnormalities may represent an ischemic response and may 
be accepted under the category of abnormal ECG findings.  
 
b. Definite evidence of myocardial ischemia on myocardial scintigraphy (clear reversible 
perfusion defect), stress echocardiography (reversible wall motion abnormality), or MRI 
(myocardial perfusion deficit under pharmacologic stress) that is believed to be 
responsible for the myocardial ischemic symptoms/signs  
 
c. Angiographic evidence of ≥ 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) during the same hospital 
stay.  This criterion would be fulfilled if the admission for myocardial ischemia led to 
transfer to another institution for the revascularization procedure without interceding 
home discharge  
 
AND  
 
4. No evidence of acute myocardial infarction 
 
General Considerations  
  
1. Escalation of pharmacotherapy for ischemia, such as intravenous nitrates or increasing  
dosages of β-blockers, should be considered supportive 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, would be 
insufficient alone to support classification as hospitalization for unstable angina.  
 
2. If subjects 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 rehospitalization for performance of an elective revascularization in the absence of  
symptoms at rest prompting admission should not be considered a hospitalization for unstable 
angina.  For example, a patient with stable exertional angina whose admission for coronary 
angiography and PCI is prompted by a positive outpatient stress test should not be considered 
a 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.  
 


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DEFINITION OF TRANSIENT ISCHEMIC ATTACK AND STROKE  
 Transient Ischemic Attack  
  
Transient ischemic attack (TIA) is defined as a transient episode of neurological dysfunction 
caused by focal brain, spinal cord, or retinal ischemia, without acute infarction.  
  
Stroke  
  
Stroke is defined as an acute episode of neurological dysfunction caused by focal or global brain, 
spinal cord, or retinal vascular injury.  
  
Classification:  
  
A. Ischemic Stroke  
  
Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal 
dysfunction caused by an 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 a nontraumatic intraparenchymal, intraventricular, or subarachnoid 
hemorrhage.  
 
C. Undetermined Stroke  
  
Undetermined stroke is defined as a stroke with insufficient information to allow 
categorization as A or B.  
 
2. 
Stroke Disability 
  
Stroke disability should be measured by a reliable and valid scale in all cases.  For example, 
the modified Rankin Scale may be used to address this requirement:    
 
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; requiring some help, but able to walk without assistance 
3 
Moderate disability; requiring some help, but able to walk without assistance 
4 
Moderate 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 


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6 
Dead 
 
 
Additional Considerations  
  
In trials involving patients with stroke, evidence of vascular central nervous system injury 
without recognized neurological dysfunction may be observed.  Examples include 
microhemorrhage, silent infarction, and silent hemorrhage.  When encountered, the clinical 
relevance of these findings may be unclear.  If appropriate for a given clinical trial, however, they 
should be precisely defined and categorized.  
  
The distinction between a Transient Ischemic Attack and an Ischemic Stroke is the presence of 
infarction, not the transience of the symptoms.  In addition to laboratory documentation of 
infarction, persistence of symptoms is an acceptable indicator of infarction.  Thus, symptom 
transience should be defined for any clinical trial in which it will be used to distinguish between 
transient ischemia and infarction.  
 
DEFINITION OF HEART FAILURE REQUIRING HOSPITALIZATION  
 Heart failure (HF) requiring hospitalization is defined as an event that meets the following 
criteria:  
  
a. Requires hospitalization 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 date change if the time of 
admission/discharge is not available).  
 
*For this end point in any given clinical trial, there should be some flexibility in the required 
duration of stay, depending on the population and the adverse event profile of the drug to be 
studied.  For example, a clinical trial studying patients with NYHA Class III/IV heart failure 
may not wish to capture hospitalizations less than 24 hours in duration, because this 
population may have frequent hospital visits requiring short-term therapy.  On the contrary, 
clinical trials in patients with NYHA Class I/II heart failure may wish to capture shorter 
hospitalizations that may be predictive of subsequent decompensation.  
  
AND  
  
b. Clinical symptoms of heart failure, including at least one of the following: 
New or worsening  
• 
 dyspnea  
• 
 orthopnea  
• 
 paroxysmal nocturnal dyspnea  
• 
 increasing fatigue/worsening exercise tolerance  
 


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AND  
  
c. Physical signs of heart failure, including at least two of the following:  
1.  edema (greater than 2+ lower extremity)  
2.  pulmonary crackles greater than basilar (pulmonary edema must be sufficient to cause 
tachypnea and distress not occurring in the context of an acute myocardial infarction or 
as the consequence of an arrhythmia occurring in the absence of worsening heart failure)  
3.  jugular venous distension   
4.  tachypnea (respiratory rate > 20 breaths/minute)  
5.  rapid weight gain  
6.  S3 gallop  
7.  increasing abdominal distension or ascites  
8.  hepatojugular reflux  
9.  radiological evidence of worsening heart failure  
10.  A right heart catheterization within 24 hours of admission showing a pulmonary 
capillary wedge pressure (pulmonary artery occlusion pressure) ≥ 18 mm Hg or a cardiac 
output  < 2.2 L/min/m2  
 
NOTE:  Biomarker results (e.g., brain natriuretic peptide (BNP)) consistent with congestive 
heart failure will be supportive of this diagnosis, but the elevation in BNP cannot be due to 
other conditions such as cor pulmonale, pulmonary embolus, primary pulmonary 
hypertension, or congenital heart disease.  Increasing levels of BNP, although not exceeding 
the ULN, may also be supportive of the diagnosis of congestive heart failure in selected cases 
(e.g. morbid obesity).  
  
AND  
  
d. Need for additional/increased therapy  
1. Initiation of, or an increase in, treatment directed at heart failure or occurring in a patient 
already receiving maximal therapy for heart failure and including at least one of the 
following:  
• 
 Initiation of or a significant augmentation in oral therapy for the treatment of 
congestive heart failure  
• 
 Initiation of intravenous diuretic, inotrope, or vasodilator therapy  
• 
 Uptitration of intravenous therapy, if already on therapy  
• 
 Initiation of mechanical or surgical intervention (mechanical circulatory support, 
heart transplantation or ventricular pacing to improve cardiac function), or the use of 
ultrafiltration, hemofiltration, or dialysis that is specifically directed at treatment of 
heart failure.  
AND  


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e. No other non-cardiac etiology (such as chronic obstructive pulmonary disease, hepatic 
cirrhosis, acute renal failure, or venous insufficiency) and no other cardiac etiology (such as 
pulmonary embolus, cor pulmonale, primary pulmonary hypertension, or congenital heart 
disease) for signs or symptoms is identified.  
 
NOTE:  It is recognized that some patients may have multiple simultaneous disease processes.  
Nevertheless, for the end point event of heart failure requiring hospitalization, the diagnosis of 
congestive heart failure would need to be the primary disease process accounting for the above 
signs and symptoms.  
 
INTERVENTIONAL CARDIOLOGY DEFINITIONS  
  
1.  Coronary Revascularization Procedure:  A coronary revascularization procedure is a 
catheter-based or open surgical procedure designed to improve myocardial blood flow.  
Catheter-based tools (e.g., balloon catheters, cutting balloons, atherectomy devices, lasers, 
bare metal stents, and drug-eluting stents) improve myocardial blood flow by increasing the 
luminal area at a site of an obstructive coronary lesion.  Bypass grafts (arterial, venous, or 
synthetic) improve myocardial blood flow by providing a conduit for blood flow distal to an 
obstructive coronary lesion.  Insertion of a guidewire through a coronary guide catheter into a 
coronary vessel or bypass graft for the purpose of percutaneous coronary intervention (PCI) 
is considered intention for PCI.  However, in the assessment of the severity of intermediate 
lesions with the use of intravascular ultrasound, Doppler flow velocity, or fractional flow 
reserve, insertion of a guidewire will NOT be considered PCI.  
 
2.  Procedural Success:  Achievement of <30 % residual diameter stenosis of the target lesion 
assessed by visual inspection or quantitative coronary angiography (QCA) and no in-hospital 
major adverse cardiac events (MACE, a composite of death, MI, or repeat coronary 
revascularization of the target lesion).  Ideally, the assessment of the residual stenosis at the 
end of the procedure should be performed by an angiographic core laboratory.  
  
Comment:  For some devices or clinical settings (e.g., plain old balloon angioplasty 
(POBA) for patients undergoing non-cardiac surgery), achievement of < 50% diameter 
stenosis by visual inspection is an acceptable definition for procedural success.  
  
3. Elective and  Non-elective Procedures:  
  
Elective:  An elective procedure is one performed on a patient with stable cardiac function in 
the days or weeks prior to the procedure.  Elective cases are usually scheduled at least 1 day 
prior to the procedure.  
  
Non-Elective:  A non-elective procedure is one performed on a patient who has been 
stabilized following initial treatment of acute coronary ischemia, and there is clinical 
consensus that the procedure should occur within the next 24 hours.  
  
OR  


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A procedure that is performed without delay on a patient with evidence of ongoing refractory 
ischemia with or without hemodynamic instability.  
 
4. Target Lesion:  A target lesion is any lesion treated or attempted to be treated during the 
trial procedure with the study device.  The target lesion is the treated segment starting 5 mm 
proximal and ending 5 mm distal to the study device (stent, in most cases).  
  
5. Target Vessel:  A target vessel is any native coronary vessel (e.g., left main coronary artery  
(LMCA), left anterior descending coronary artery (LAD), left circumflex coronary artery 
(LCX), or right coronary artery (RCA)) or bypass graft to the LAD, LCX, or RCA containing 
the target lesion.  The target vessel includes the target lesion as well as segments of the vessel 
that are upstream and downstream to the target lesion, including side branches (native 
vessel).  
 
6. Non-Target Lesion:  A non-target lesion is one for which revascularization is not attempted 
or one in which revascularization is performed using a non-study device.  
 
7.  Non-Target Vessel:  A non-target vessel is one for which revascularization is not attempted 
or one in which revascularization is performed using a non-study device.  
 
8.  Target Vessel, Non-Target Lesion:  Any lesion or revascularization of a lesion in the target 
vessel other than the target lesion.  
 
9.  Target Lesion Revascularization (TLR):  Target lesion revascularization is any repeat  
percutaneous intervention of the target lesion (including 5 mm proximal and distal to the 
target lesion) or surgical bypass of the target vessel performed for restenosis or other 
complication involving the target lesion.  In the assessment of TLR, angiograms should be 
assessed by an angiographic core laboratory (if designated) and made available to the 
Clinical End Points Committee (CEC) for review.  
 
10.  Target Vessel Revascularization (TVR):  Target vessel revascularization is any repeat  
percutaneous intervention or surgical bypass of any segment of the target vessel.  In the 
assessment of TVR, angiograms should be assessed by an angiographic core laboratory (if 
designated) and made available to the CEC for review.  
 
11. Clinically-Driven Target Lesion Revascularization:  Revascularization is clinically-driven 
if the subject has a target lesion diameter stenosis ≥ 50% by QCA and clinical or functional 
ischemia which cannot be explained by another native coronary or bypass graft lesion.  
Clinical or functional ischemia includes any of the following:  
 
a. A history of angina pectoris, presumably related to the target vessel  
b. Objective signs of ischemia at rest (ECG changes) or during exercise test (or equivalent), 
presumably related to the target vessel  
c. Abnormal results of any invasive functional diagnostic test (e.g., Doppler flow velocity 
reserve or fractional flow reserve (FFR))  
d. A diameter stenosis ≥70% by QCA even in the absence of the above signs or symptoms.  
 


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Comment:  In the absence of QCA data or if a <50% stenosis is present, TLR may be 
considered clinically-driven by the CEC if severe ischemic signs and symptoms attributed 
to the target lesion are present.  
 
DEFINITION OF PERIPHERAL ARTERIAL REVASCULARIZATION 
PROCEDURE  
1. Peripheral Arterial Revascularization Procedure: A peripheral arterial revascularization  
procedure is a catheter-based or open surgical procedure designed to improve peripheral 
arterial blood flow. This procedure may include thrombectomy, embolectomy, atherectomy, 
dissection repair, angioplasty, and stent placement.  
 
The intention to perform percutaneous peripheral arterial intervention is denoted by the 
insertion of a guidewire through a guide catheter into a peripheral artery.  
 
The target vessel(s) should be specified (e.g., aorta, renal, mesenteric, iliac, femoral, tibial) 
and recorded as well as the type of revascularization procedure (e.g., surgical, angioplasty, 
stent placement, thromboembolectomy). For simplicity, this definition applies to non-cardiac 
and non-cerebrovascular vessels, including the aorta, but does not address aortic aneurysm 
repair.  
 
2. Procedural Success: In the case of percutaneous intervention for obstructive lesions, 
procedural success is defined as the achievement of a final residual diameter stenosis < 30% 
by angiography at the end of the procedure (and without flow limiting arterial dissection and 
hemodynamically significant translesional pressure gradient) without any in-hospital major 
adverse events (death, acute onset of limb ischemia, need for urgent/emergent vascular 
surgery). The balloon inflation and/or stent placement may be preceded by use of adjunctive 
devices (e.g., percutaneous mechanical thrombectomy, directional or rotational atherectomy, 
laser, chronic total occlusion crossing device).  
 
3. Elective and Non-Elective Procedures:  
 
Elective: An elective procedure is one that is scheduled and is performed on a patient with 
stable peripheral arterial disease.  
 
Non-Elective: A non-elective procedure is one performed on a patient who has been 
stabilized following initial treatment of acute peripheral limb ischemia, and there is clinical 
consensus that the procedure should occur within the next 24 hours.  
 
OR  
 
A procedure that is performed without delay because of urgency of the medical condition 
(e.g., acute limb ischemia, acute aortic dissection).  
 
4. Target Lesion: A target lesion is any lesion treated or attempted to be treated during the trial 
procedure with the index device. The target lesion is the treated segment starting 5 mm 
proximal and ending 5 mm distal to the index device (stent, in most cases).  


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5. Target Vessel:  A target vessel is any vessel (e.g., non-cardiac or non-cerebrovascular 
vessel) that contains the target lesion treated with the study device.  The target vessel 
includes the target lesion as well as the entire vessel upstream and downstream to the target 
lesion, including side branches (native vessel).  
 
6. Non-Target Lesion:  A non-target lesion is one for which revascularization is not attempted 
or one in which revascularization is performed using a non-study device.  
 
7.  Non-Target Vessel:  A non-target vessel is one for which revascularization is not attempted  
or one in which revascularization is performed using a non-study device.  
 
8. Target Vessel, Non-Target Lesion:  Any lesion or revascularization of a lesion in the target 
vessel other than the target lesion.  
 
9. Target Lesion Revascularization (TLR):  Target lesion revascularization is any repeat  
percutaneous intervention of the target lesions (including 5 mm proximal and distal to the 
index device) or surgical bypass of the target vessel performed for restenosis or other 
complication involving the target lesion.  In the assessment of TLR, angiograms should be 
assessed by an angiographic core laboratory (if designated) and made available to the 
Clinical End Points Committee (CEC) for review.  
 
10. Target Vessel Revascularization (TVR):  Target vessel revascularization is any repeat  
percutaneous intervention or surgical bypass of any segment of the target vessel.  In the 
assessment of TVR, angiograms should be assessed by an angiographic core laboratory (if 
designated) and made available to the CEC for review.  
 
11. Clinically-Driven Target Lesion Revascularization:  Clinically-driven target lesion  
revascularization is a target lesion revascularization prompted by recurrent ipsilateral limb 
symptoms (intermittent claudication, critical limb ischemia) or objective imaging evidence of 
target lesion restenosis (i.e., most commonly with duplex ultrasonography).  In the 
assessment of clinically driven TLR based on duplex ultrasonography, ultrasonographic 
images should be assessed by a duplex ultrasound core laboratory (if designated) and made 
available to the CEC for review.  
 
 
 


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APPENDIX C: CRITERIA FOR THE DIAGNOSIS OF DIABETES 
 
Reference: 
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 
2010; 33 Suppl 1:S62. 
 
1. HbA1c ≥6.5%. The test should be performed in a laboratory using a method that is National 
Glycohemoglobin Standardization Program (NGSP) certified and standardized to the 
Diabetes Control and Complications Trial (DCCT) assay.* 
OR 
2. Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric 
intake for at least 8 hr.* 
OR  
3. 2-hr plasma glucose ≥200 mg/dL (11.1 mmol/L) during an Oral Glucose Tolerance Test 
(OGTT). The test should be performed as described by the World Health Organization, 
using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in 
water.* 
OR  
4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random 
plasma glucose ≥200 mg/dL (11.1 mmol/L). 
 
* In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat 
testing. 
 


TM
 
 
 
CLINICAL STUDY PROTOCOL 
A Multi-Center, Prospective, Randomized, Double-Blind, 
Placebo-Controlled, Parallel-Group Study to Evaluate the Effect of AMR101 
on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients 
with Cardiovascular Disease or at High Risk for Cardiovascular Disease: 
REDUCE-IT (Reduction of Cardiovascular Events with EPA – Intervention Trial) 
 
Investigational Product: AMR101 (icosapent ethyl [ethyl-EPA]) 
Protocol Number: AMR-01-01-0019 
 
 
Sponsor: 
Amarin Pharma Inc. 
1430 Route 206 
Bedminster, NJ 07921 
Telephone: +1-908-719-1315 
Facsimile: +1-908-719-3012 
 
 
Amendment #1: Final 16 May 2013 
Amendment #1 Protocol Version Number: Final v 2.0 
Original Protocol: 2 August 2011 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the 
written consent of Amarin Pharma Inc., except to the extent that disclosure would be required 
by law and for the purpose of evaluating and/or conducting a clinical trial for Amarin Pharma 
Inc. You are allowed to disclose the contents of this document only to your Institutional 
Review Board or Independent Ethics Committee and study personnel directly involved with 
conducting this study. Persons to whom the information is disclosed must be informed that 
the information is confidential and proprietary to Amarin Pharma Inc. and that it may not be 
further disclosed to third parties. 


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SIGNATURE PAGE 
TRIAL TITLE: A Multi-Center, Prospective, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group Study to Evaluate the Effect of AMR101 on Cardiovascular 
Health and Mortality in Hypertriglyceridemic Patients with Cardiovascular Disease or at 
High Risk for Cardiovascular Disease: REDUCE-IT (Reduction of Cardiovascular Events 
with EPA – Intervention Trial) 
 
We, the undersigned, have reviewed and approved this protocol. 
 
Signature 
Date 
 
 
[Name / signature redacted]                            [Signed (16 May 2013)]       
Vice President, Clinical Development 
Amarin Pharma Inc. 
 
 
[Name / signature redacted]                            [Signed (16 May 2013)]       
Senior Director, Clinical Development  
Amarin Pharma Inc. 
 
 
[Name / signature redacted]                            [Signed (16 May 2013)]       
Vice President & Head of Regulatory Affairs 
Amarin Pharma Inc. 
 
 
[Name / signature redacted]                            [Signed (16 May 2013)]       
Principal Investigator 
 
 
 


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SYNOPSIS 
TITLE: 
A Multi-Center, Prospective, Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group Study to Evaluate the Effect of AMR101 on Cardiovascular Health and Mortality in 
Hypertriglyceridemic Patients with Cardiovascular Disease or at High Risk for 
cardiovascular Disease: REDUCE-IT (Reduction of Cardiovascular Events with EPA – 
Intervention Trial) 
PROTOCOL NUMBER: AMR-01-01-0019 
INVESTIGATIONAL PRODUCT: AMR101 (icosapent ethyl [ethyl-EPA]) 
PHASE: 3b 
INDICATION: 
Treatment with AMR101 to reduce the risk of cardiovascular events in patients with clinical 
cardiovascular disease or with multiple risk factors for cardiovascular disease. 
OBJECTIVES: 
The primary objective is, in patients at LDL-C goal while on statin therapy, with established 
cardiovascular disease (CVD) or at high risk for CVD, and hypertriglyceridemia (fasting 
triglycerides, TG, 200 mg/dL and <500 mg/dL [2.26 mmol/L and <5.64 mmol/L]), to 
evaluate the effect of 4 g/day AMR101 for preventing the occurrence of a first major 
cardiovascular event of the composite endpoint that includes: 
 Cardiovascular (CV)  death, 
 Nonfatal myocardial infarction (MI), 
 Nonfatal stroke, 
 Coronary revascularization,  
 Unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization. 
 
The secondary objectives of this study are the following: 
The key secondary objective is to evaluate the effect of therapy on the composite of death 
from CV causes, nonfatal MI, coronary revascularization, unstable angina determined to be 
caused by myocardial ischemia by invasive/non-invasive testing and requiring emergent 
hospitalization, nonfatal stroke, or peripheral CVD requiring intervention, angioplasty, 
bypass surgery, or aneurysm repair. 
 
Other secondary objectives: 
 To evaluate the effect of therapy on combinations of each of the key secondary 
objective clinical events in addition to the following clinical events: 
o Cardiac arrhythmia requiring hospitalization  
o Cardiac arrest 


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o Peripheral CVD requiring intervention, angioplasty, bypass surgery, or 
aneurysm repair 
o Total mortality 
 
The tertiary objectives of this study are the following: 
 Evaluate the effect of therapy on the occurrence of a second, third, fourth, and fifth 
major cardiovascular event (same as the primary composite endpoint but for events 
occurring after the first event); 
 To evaluate the effect of therapy on the primary endpoint in subgroups of patients 
including: 
o Diabetes mellitus 
o Metabolic syndrome as defined by the NCEP ATP III or future criteria as they 
may evolve; 
 To evaluate the effect of therapy on the individual endpoints of new congestive heart 
failure (CHF), on new CHF as a primary cause of hospitalization, on transient 
ischemic attack, on amputation for vascular disease and on carotid revascularization; 
 Elective coronary revascularization and emergent coronary revascularization;  
 To assess the effects regarding lipids, lipoproteins and inflammatory markers 
including triglycerides (TG), total cholesterol (TC), low-density lipoprotein 
cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, 
very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein B (apo B), high 
sensitivity C-reactive protein (hs-CRP) and high sensitivity troponin (hsTnT), as 
follows: 
o Assessment of the effect of AMR101 on each marker (on-treatment 
change of markers) 
o Assessment of the effect of the baseline value of each marker on 
treatment effects (baseline effect on outcomes) 
o To evaluate the effect of therapy for preventing clinical events, as 
defined above, among all patients in the study, and in subgroups such as 
patients with diabetes mellitus and patients with substantial on-treatment 
changes of any of the markers (on-treatment effect on outcomes). 
 To evaluate the effect of therapy on new onset diabetes (See appendix C); 
 To explore the effect of AMR101 on weight and waist circumference. 
 
ENDPOINTS: 
Primary endpoint: 
Time from randomization to the first occurrence of the composite of the following clinical 
events: 
 CV death, 


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 Nonfatal MI (including silent MI; ECGs will be performed annually for the detection 
of silent MIs), 
 Nonfatal stroke, 
 Coronary revascularization,  
 Hospitalization for unstable angina determined to be caused by myocardial ischemia 
by invasive/non-invasive testing.  
The first occurrence of any of these major adverse vascular events during the follow-up 
period of the study will be included in the incidence. 
 
Secondary endpoints: 
The key secondary efficacy endpoint is: 
 The composite of death from CV causes, nonfatal MI, coronary revascularization, 
unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization, nonfatal stroke, or peripheral 
CVD requiring intervention, angioplasty, bypass surgery, or aneurysm repair. 
Other secondary efficacy endpoints are as follows (to be tested in said order): 
 The composite of total mortality, nonfatal MI, or nonfatal stroke; 
 The composite of death from CV causes, nonfatal MI, coronary revascularization, 
unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization, peripheral CVD requiring 
intervention, or cardiac arrhythmia requiring hospitalization; 
 The composite of death from CV causes, nonfatal MI, coronary revascularization, or 
unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization; 
 The composite of death from CV causes or nonfatal MI; 
 Total mortality; 
 Fatal and nonfatal MI (including silent MI); 
 Coronary Revascularization;  
 Hospitalization for unstable angina determined to be caused by myocardial ischemia 
by invasive/non-invasive testing ; 
 Fatal and nonfatal stroke. 
For the secondary endpoints that count a single event, the first occurrence of this type of 
event will be counted in each patient. For secondary endpoints that are composites of two or 
more types of events, the first occurrence of any of the event types included in the composite 
will be counted in each patient. 
 
Tertiary endpoints: 
 The second, third, fourth, and fifth major CV event of the primary composite 
endpoint. The type of (nonfatal) events may occur in any order. 
 Primary endpoint in subset of patients with diabetes mellitus; 


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 Primary endpoint in subset of patients with metabolic syndrome; 
 Individual endpoints of new CHF, new CHF leading to hospitalization, transient 
ischemic attack, amputation for CVD and carotid revascularization; 
 Elective coronary revascularization and emergent coronary revascularization; 
 New onset diabetes; 
 Fasting TG, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apo B, hs-CRP, and hsTnT: 
effect of baseline and on-treatment change of biomarkers on primary and key 
secondary endpoints; 
 CV mortality; 
 Cardiac Arrhythmias requiring hospitalization; 
 Cardiac Arrest; 
 To explore the effect of AMR101 on weight and waist circumference. 
For the tertiary endpoints that count a single event, the first occurrence of this type of event 
will be counted in each patient. For tertiary endpoints that are composites of two or more 
types of events, the first occurrence of any of the event types included in the composite will 
be counted in each patient (except when stated otherwise, for the second, third, fourth, and 
fifth major CV event). 
 
POPULATION: 
Inclusion Criteria: 
1. Fasting TG levels of 200 mg/dL (2.26 mmol/L) and <500 mg/dL (5.64 mmol/L).  
2. LDL-C >40 mg/dL (1.04 mmol/L) and ≤100 mg/dL (2.60 mmol/L) and on stable therapy 
with a statin (with or without ezetimibe) for at least 4 weeks prior to the LDL-C/TG 
baseline qualifying measurements for randomization  
 
Stable therapy is defined as the same daily dose of the same statin for at least 28 
days before the lipid qualification measurements (TG and LDL-C) and, if applicable, 
the same daily dose of ezetimibe for at least 28 days before the lipid qualification 
measurements (TG and LDL-C). Patients who have their statin therapy or use of 
ezetimibe initiated at Visit 1, or have their statin, statin dose and/or ezetimibe dose 
changed at Visit 1, will need to go through a stabilization period of at least 28 days 
since initiation/change and have their qualifying lipid measurements measured (TG 
and LDL-C) after the washout period (at Visit 1.1).  
 
Statins may be administered with or without ezetimibe.   
NOTE: If patients qualify at the first qualification visit (Visit 1) for TG and LDL-C, and 
meet all other inclusion/exclusion criteria, they may be randomized at Visit 2. If patients 
do not qualify at the first qualifying visit (Visit 1), a second re-qualifying visit (Visit 1.1) 
is allowed. For some patients, because they need to stabilize medications and/or need to 
washout medications, the second re-qualifying visit (Visit 1.1) will be needed after the 
stabilization/washout period. 


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3. Either having established CVD (in CV Risk Category 1) or at high risk for CVD (in CV 
Risk Category 2). The CV risk categories are defined as follows: 
CV Risk Category 1: defined as men and women ≥45 years of age with one or more of 
the following: 
o Documented coronary artery disease (CAD; one or more of the following primary 
criteria must be satisfied): 
 Documented multi vessel CAD (>50% stenosis in at least two major epicardial 
coronary arteries – with or without antecedent revascularization); 
 Documented prior MI; 
 Hospitalization for high-risk NSTE ACS (with objective evidence of ischemia: 
ST-segment deviation or biomarker positivity). 
o Documented cerebrovascular or carotid disease (one of the following primary criteria 
must be satisfied): 
 Documented prior ischemic stroke; 
 Symptomatic carotid artery disease with ≥50% carotid arterial stenosis; 
 Asymptomatic carotid artery disease with ≥70% carotid arterial stenosis per 
angiography or duplex ultrasound; 
 History of carotid revascularization (catheter-based or surgical). 
o Documented peripheral arterial disease (PAD; one or more of the following primary 
criteria must be satisfied): 
 Ankle-brachial index (ABI) <0.9 with symptoms of intermittent claudication; 
 History of aorto-iliac or peripheral arterial intervention (catheter-based or 
surgical). 
OR 
CV Risk Category 2: defined as patients with: 
1. Diabetes mellitus (Type 1 or Type 2) requiring treatment with medication AND 
2. Men and women ≥50 years of age AND  
3. One of the following at Visit 1 (additional risk factor for CVD): 
 Men ≥55 years of age and Women ≥65 years of age; 
 Cigarette smoker or stopped smoking within 3 months before Visit 1; 
 Hypertension (blood pressure ≥140 mmHg systolic OR ≥90 mmHg diastolic) 
or on antihypertensive medication; 
 HDL-C ≤40 mg/dL for men or ≤50 mg/dL for women; 
 hs-CRP >3.00  mg/L (0.3 mg/dL); 


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 Renal dysfunction: Creatinine clearance (CrCL) >30 and <60 mL/min (>0.50 
and <1.00 mL/sec); 
 Retinopathy, defined as any of the following: non-proliferative retinopathy, 
preproliferative retinopathy, proliferative retinopathy, maculopathy, advanced 
diabetic eye disease or a history of photocoagulation; 
 Micro- or macroalbuminuria. Microalbuminuria is defined as either a positive 
micral or other strip test (may be obtained from medical records), an 
albumin/creatinine ratio ≥2.5 mg/mmol or an albumin excretion rate on timed 
collection ≥20 mg/min all on at least two successive occasions; 
macroalbuminuria, defined as albustix or other dipstick evidence of gross 
proteinuria, an albumin/creatinine ratio ≥25 mg/mmol or an albumin excretion 
rate on timed collection ≥200 mg/min all on at least two successive occasions; 
 ABI <0.9 without symptoms of intermittent claudication (patients with ABI 
<0.9 with symptoms of intermittent claudication are counted under CV Risk 
Category 1). 
Note: Patients with diabetes and vascular disease as defined above are eligible based 
on the vascular disease requirements and will be counted under CV Risk Category 1. 
Only patients with diabetes and no documented CV disease as defined above need at 
least one additional risk factor as listed, and will be counted under CV Risk 
Category 2. 
4. Women may be enrolled if all 3 of the following criteria are met: 
 They are not pregnant; 
 They are not breastfeeding; 
 They do not plan on becoming pregnant during the study. 
5. Women of child-bearing potential must have a negative urine pregnancy test before 
randomization. 
Note: Women are not considered to be of childbearing potential if they meet one of the 
following criteria as documented by the investigator: 
 They have had a hysterectomy, tubal ligation or bilateral oophorectomy prior to 
signing the informed consent form; 
 They are post-menopausal, defined as ≥1 year since their last menstrual period or 
have a follicle-stimulating hormone (FSH) level in a menopausal range. 
6. Women of childbearing potential must agree to use an acceptable method of avoiding 
pregnancy from screening to the end of the study, unless their sexual partner(s) is/are 
surgically sterile or the woman is abstinent. 
7. Understanding of the study procedures, willing to adhere to the study schedules, and 
agreement to participate in the study by giving informed consent prior to screening. 
8. Agree to follow a physician recommended diet, and to maintain it through the duration of 
the study. 
 


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Exclusion Criteria: 
1. Severe (class IV) heart failure. 
2. Any life-threatening disease expected to result in death within the next 2 years (other 
than CVD). 
3. Active severe liver disease (evaluated at Visit 1): cirrhosis, active hepatitis, ALT or AST 
>3 x ULN, or biliary obstruction with hyperbilirubinemia (total bilirubin >2 x ULN). 
4. Hemoglobin A1c >10.0% (or 86 mmol/mol IFCC units) at screening (Visit 1). If patients 
fail this criterion (HbA1c >10.0% or 86 mmol/mol IFCC units) at Visit 1, they may have 
their antidiabetic therapy optimized and be retested at Visit 1.1. 
5. Poorly controlled hypertension: blood pressure ≥200 systolic mmHg OR ≥100 mmHg 
diastolic (despite antihypertensive therapy). 
6. Planned coronary intervention (such as stent placement or heart bypass) or any non-
cardiac major surgical procedure. Patients can be (re)evaluated for participation in the 
trial (starting with Visit 1.1) after their recovery from the intervention/surgery. 
7. Known familial lipoprotein lipase deficiency (Fredrickson Type I), apolipoprotein C-II 
deficiency, or familial dysbetalipoproteinemia (Fredrickson Type III)]. 
8. Participation in another clinical trial involving an investigational agent within 90 days 
prior to screening (Visit 1). Patients cannot participate in any other investigational 
medication or medical device trial while participating in this study (participation in a 
registry or observational study without additional therapeutic intervention is allowed). 
9. Intolerance or hypersensitivity to statin therapy. 
10. Known hypersensitivity to any ingredients of the study product or placebo (refer to Table 
3); known hypersensitivity to fish and or shellfish. 
11. History of acute or chronic pancreatitis. 
12. Malabsorption syndrome and/or chronic diarrhea. (Note: patients who have undergone 
gastric/intestinal bypass surgery are considered to have malabsorption, hence are 
excluded; patients who have undergone gastric banding are allowed to enter the trial). 
13. Non-study drug related, non-statin, lipid-altering medications, supplements or foods: 
 Patients are excluded if they used niacin >200 mg/day or fibrates during the screening 
period (after Visit 1) and/or plan to use during the study; patients who are taking 
niacin >200 mg/day or fibrates during the last 28 days before Visit 1 need to go 
through washout of at least 28 days after their last use and have their qualifying lipids 
measured (TG and LDL-C) after the washout period (Visit 1.1); 
 Patients are excluded if they take any omega-3 fatty acid medications (prescription 
medicines containing EPA and/or DHA) during the screening period (after Visit 1) 
and/or plan to use during the treatment/follow-up period of the study. To be eligible 
for participation in the study, patients who are taking omega-3 fatty acid medications 
during the last 28 days before Visit 1 (except patients in The Netherlands), need to go 
through a washout period of at least 28 days after their last use and have their 


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qualifying lipid measurements measured (TG and LDL-C) after the washout period 
(at Visit 1.1); 
o For patients in The Netherlands only: patients being treated with omega-3 
fatty acid medications containing EPA and /or DHA are excluded; no washout 
is allowed.  
 Patients are excluded if they use dietary supplements containing omega-3 fatty acids 
(e.g., flaxseed, fish, krill, or algal oils) during the screening period (after Visit 1) 
and/or plan to use during the treatment/follow-up period of the study. To be eligible 
for participation in the study, patients who are taking >300 mg/day omega-3 fatty 
acids (combined amount of EPA and DHA) within 28 days before Visit 1 (except 
patients in The Netherlands), need to go through a washout period of at least 28 days 
since their last use  and have their qualifying lipid measurements measured (TG and 
LDL-C) after the washout period (at Visit 1.1); 
o For patients in The Netherlands only: patients being treated with dietary 
supplements containing omega-3 fatty acids of >300 mg/day EPA and/or 
DHA are excluded; no washout is allowed. 
 Patients are excluded if they use bile acid sequestrants during the screening period 
(after Visit 1) and/or plan to use during the treatment/follow-up period of the study. 
To be eligible for participation in the study, patients who are taking bile acid 
sequestrants within 7 days before Visit 1, need to go through a washout period of at 
least 7 days since their last use and have their qualifying lipid measurements 
measured (TG and LDL-C) after the washout period (at Visit 1.1); 
14. Other medications (not indicated for lipid alteration): 
 Treatment with tamoxifen, estrogens, progestins, thyroid hormone therapy, systemic 
corticosteroids (local, topical, inhalation, or nasal corticosteroids are allowed), HIV-
protease inhibitors that have not been stable for ≥28 days prior to the qualifying lipid 
measurements (TG and LDL-C) during screening. To be eligible for participation in 
the study, patients who are not taking a stable dose of these medications within 
28 days before Visit 1, need to go through a stabilization period of at least 28 days 
since their last dose change and have their qualifying lipid measurements measured 
(TG and LDL-C) after the washout period (at Visit 1.1); 
 Patients are excluded if they use cyclophosphamide or systemic retinoids during the 
screening period (after Visit 1) and/or plan to use during the treatment/follow-up 
period of the study. To be eligible for participation in the study, patients who are 
taking these medications within 28 days before Visit 1, need to go through a washout 
period of at least 28 days since their last use and have their qualifying lipid 
measurements measured (TG and LDL-C) after the washout period (at Visit 1.1). 
15. Known to have AIDS (patients who are HIV positive without AIDS are allowed). 
16. Requirement for peritoneal dialysis or hemodialysis for renal insufficiency or creatinine 
clearance (CrCL) <30 mL/min (0.50 mL/sec). 
17. Unexplained creatine kinase concentration >5 × ULN or creatine kinase elevation due to 
known muscle disease (e.g., polymyositis, mitochondrial dysfunction) at Visit 1. 


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18. Any condition or therapy which, in the opinion of the investigator, might pose a risk to 
the patient or make participation in the study not in the patient’s best interest. 
19. Drug or alcohol abuse within the past 6 months, and unable/unwilling to abstain from 
drug abuse and excessive alcohol consumption during the study or drinking 5 units or 
more for men or 4 units or more for women in any one hour (episodic excessive drinking 
or binge drinking). Excessive alcohol consumption is on average >2 units of alcohol per 
day. A unit of alcohol is defined as a 12-ounce (350 mL) beer, 5-ounce (150 mL) wine, 
or 1.5-ounce (45 mL) of 80‐proof alcohol for drinks. 
20. Mental/psychological impairment or any other reason to expect patient difficulty in 
complying with the requirements of the study or understanding the goal and potential 
risks of participating in the study (evaluated at Visit 1). 
 
STUDY DESIGN AND DURATION: 
This is a multi-center, multi-national, prospective, randomized, double-blind, placebo-
controlled, parallel-group study. 
This is an event-driven trial: It is expected that a minimum of 1612 primary efficacy endpoint 
events will be required during the study. Approximately 7990 patients will be randomized at 
multiple Research Sites worldwide over a planned period of 18 months. After randomization, 
patients will be treated and followed over 3.25-4.75 years with a planned median follow-up 
of 4 years. The study end date is determined to be when approximately 1612 primary efficacy 
events have occurred. 
Screening Period: 
During the screening period, patients will be evaluated for inclusion/exclusion criteria. 
Patients will be eligible for randomization if they meet all the inclusion/exclusion criteria. 
Prospectively, eligible patients with documented CVD or diabetes (with at least one 
additional risk factor for CVD) will undergo screening to establish suitability for inclusion in 
the trial. The qualifying lipid determination at Visit 1 requires that eligible patients must have 
a fasting TG level 200 mg/dL (2.26 mmol/L) and <500 mg/dL (5.64 mmol/L) in order to 
enter the treatment/follow-up period of the trial (and they need to meet all other 
inclusion/exclusion criteria). These patients will be randomized at Visit 2, which will occur 
soon after Visit 1 (there will be no Visit 1.1 for these patients). 
Patients who do not qualify at Visit 1, may return to the Research Site for a second qualifying 
visit (Visit 1.1) at which time procedures that caused failure of eligibility at Visit 1 will be 
repeated. In this case, patients will be eligible for randomization after Visit 1.1 if they meet 
all inclusion criteria and if they no longer fail the exclusion criteria. 
For some patients, Visit 1.1 will be mandatory at least 28 days after Visit 1 in order to check 
eligibility. These are patients who at Visit 1 started treatment with a statin, changed their 
statin, changed the daily dose of their statin, started to washout prohibited medications or 
started a stabilization period with certain medications. Any of these changes at Visit 1 may 
affect the qualifying lipid levels and therefore, patients will need to have Visit 1.1 to 
determine whether they qualify based on lipid level requirements (TG and LDL-C) 


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determined at Visit 1. Other procedures that caused failure of eligibility at Visit 1 will also be 
repeated at Visit 1.1. Details are listed in the main section of the protocol. 
Treatment/Follow-Up Period: 
At Visit 2 (Day 0), eligible patients will be randomly assigned 1:1 to one of the following 
treatment groups: 
 AMR101 4 g daily, or 
 Placebo. 
Stratification will be by CV risk category (established CVD or the presence of diabetes with 
≥1 risk factor for CVD), use of ezetimibe and by geographical region (Westernized, Eastern 
European, and Asia Pacific countries). 
 
During the treatment/follow-up period, patients will return to the Research Site at regular 
intervals for efficacy and safety evaluations, and drug supply and compliance checks. The 
visits after the randomization visit (Visit 2; Day 0) are scheduled for 4 months after Visit 2 
(for Visit 3); 8 months after Visit 3 (for Visit 4); and then every year thereafter. 
 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Eligible patients will be randomly assigned at Visit 2 to receive orally AMR101 4 g daily or 
matching placebo. AMR101 is provided in 1000 mg liquid-filled, oblong, gelatin capsules. 
The matching placebo capsule is filled with light liquid paraffin and contains 0 mg of 
AMR101. AMR101 or matching placebo capsules are to be taken with food (i.e. with or at 
the end of a meal). 
 
During the treatment period, the daily dose of study drug is 4 capsules per day taken as two 
capsules taken on two occasions per day (2 capsules given twice daily). 
 
STATISTICAL ANALYSES: 
 Intent-to-treat analysis. 
 Parameters will be summarized using mean, standard deviation, median, minimum, 
maximum, and interquartile range for continuous data and percentage for categorical 
data. 
 Survival analysis using the log-rank test for the primary efficacy outcome comparing the 
2 treatment groups (AMR101 and Placebo) and including the stratification factors CV 
risk category, use of ezetimibe and by geographical region (Westernized, Eastern 
European, and Asia Pacific countries). 
 All statistical analyses for the efficacy and safety outcomes will be performed at the 5% 
significance level using 2-sided tests unless otherwise noted. 
 One interim analysis is planned when approximately 60% of the planned total number of 
events has occurred. 
 


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The analysis is planned to: 
 Describe at baseline: Patient characteristics, including lipids and lipoproteins, stroke 
history, cardiovascular risk factors, diabetes mellitus, or metabolic syndrome, among 
others. 
 Compare the primary, secondary, and tertiary endpoints between treatment groups at the 
corresponding follow-up time points. 
 
SAMPLE SIZE DETERMINATION: 
Sample size estimation is based on the assumption that the primary composite endpoint (time 
from randomization to the first occurrence of CV death, non-fatal MI, non-fatal stroke, 
coronary revascularization, or unstable angina requiring hospitalization) would be relatively 
reduced by 15%, from an event rate by 4 years of 23.6% in the placebo group to 20.5% in the 
AMR101 group. It is expected that a minimum of 1612 primary efficacy endpoint events will 
be required during the study. A total of approximately 6990 patients are needed to be able to 
detect this difference at 4.76% significance level (decreased from 5.00% because of one 
interim analysis) and with 90% power, assuming an 18-month enrollment period and a 
median follow-up of 4 years. The current sample size calculation is based on an estimated 
placebo yearly event rate of 5.9% (23.6% over 4 years). To protect against the possibility that 
the actual placebo event rate is lower than estimated, an extra 1000 patients will be enrolled 
(approximately 7990 patients in total). By adding the extra 1000 patients, the event rate in the 
placebo group could be 5.2% per year (20.8% over 4 years) without having to modify the 
other sample size assumptions.  
 
Since this is an events-driven trial, the ‘sample size’ is the number of events rather than the 
number of patients. The number of events that occur depends primarily on three factors: how 
many patients are enrolled, the combined group event rate, and how long the patients are 
followed. Because of the difficulty in predicting the combined event rate, the sponsor will 
monitor that event rate as the trial progresses. If the combined event rate is less than 
anticipated, either increasing the number of patients, extending the length of follow-up, or a 
balance of adjusting both factors may be necessary to achieve the sample size of 1612 events. 
 
Before completing the enrollment phase of the trial, i.e. approximately 3- to 6-months prior 
to the projected enrollment of the 7990th patient, the actual event rate based on pooled, 
blinded accumulation of primary efficacy endpoint events will be calculated and plotted.  If 
those analyses suggest the number of patients with at least 1 adjudicated, primary event (and 
appropriately accounting for patients with potential primary events for which the 
adjudication process is then incomplete) is consistent with projections, then the study could 
continue toward the protocol-specified target enrollment of 7990 patients.  However, if the 
number of such events appears less than, and inconsistent with projections, the Sponsor will 
consider (under blinded conditions) re-calculating the number of patients needed to achieve 
the target number of events within the desired timeline or extend the follow-up period.  If the 
projected increase in number of patients is ≤ 25% of the original 7990 target population, the 
Sponsor may, with documented approval of both the REDUCE-IT Steering Committee and 
the Data Monitoring Committee, extend enrollment to the revised target number without 


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need for an additional protocol amendment.   Under those conditions, all principal 
investigators, ethics committees, and regulatory authorities associated with the protocol will 
be promptly notified of the action. Should the projected increase in number of patients be 
more than 25% above the original 7990 target (i.e. more than 1998 additional patients) a 
formal protocol amendment will be initiated. 
 
If the number of patients to be studied is increased, the enrollment phase will be extended to 
allow enrollment of the additional patients. 
 
At completion of study enrollment, the actual number of patients randomized may vary from 
the target number (either original or revised) as a result of the inherent lag between the date 
the last patient started screening and the date the last patient was randomized. 
 
SPONSOR: 
Amarin Pharma Inc. 
1430 Route 206 
Bedminster, NJ 07921 
Telephone: +1-908-719-1315 
Facsimile: +1-908-719-3012 
 
 


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TABLE OF CONTENTS 
1. 
INTRODUCTION AND BACKGROUND INFORMATION ...................................... 22 
1.1. 
Background ............................................................................................................. 22 
1.2. 
Summary of Amarin-Sponsored Clinical Studies with AMR101........................... 23 
1.3. 
Study AMR-01-01-0017 (ANCHOR Study) .......................................................... 23 
1.4. 
Clinical Safety ......................................................................................................... 26 
1.5. 
Rationale ................................................................................................................. 26 
1.6. 
Risk/Benefit ............................................................................................................ 33 
2. 
STUDY OBJECTIVES ................................................................................................... 34 
3. 
STUDY DESIGN............................................................................................................ 35 
3.1. 
Type of Study .......................................................................................................... 35 
3.2. 
Study Population ..................................................................................................... 35 
3.3. 
Study Periods .......................................................................................................... 35 
3.4. 
Study Duration ........................................................................................................ 37 
3.5. 
Study Groups .......................................................................................................... 37 
3.6. 
Number of Patients ................................................................................................. 37 
3.7. 
Number of Study Sites ............................................................................................ 37 
3.8. 
Randomization ........................................................................................................ 37 
3.9. 
Blinding................................................................................................................... 37 
3.10.  Stratification ............................................................................................................ 38 
4. 
STUDY POPULATION ................................................................................................. 38 
4.1. 
Inclusion Criteria .................................................................................................... 38 
4.2. 
Exclusion Criteria ................................................................................................... 41 
5. 
STUDY COMMITTEES ................................................................................................ 43 
5.1. 
Steering Committee ................................................................................................ 43 
5.2. 
Study Operations Committee (SOC) ...................................................................... 43 
5.3. 
Clinical Event Committee (CEC) ........................................................................... 43 
5.4. 
Data Monitoring Committee (DMC) ...................................................................... 44 
6. 
STUDY PROCEDURES ................................................................................................ 44 
6.1. 
Assessment Schedule .............................................................................................. 44 


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6.1.1. 
Screening Period ............................................................................................. 44 
6.1.2. 
Treatment/Follow-Up Period .......................................................................... 46 
6.2. 
Telephone Follow-up Contact................................................................................. 49 
6.3. 
Laboratory Procedures ............................................................................................ 50 
6.3.1. 
Clinical Laboratory Procedures ...................................................................... 50 
6.3.2. 
Medical Procedures ......................................................................................... 52 
7. 
TREATMENT AND RESTRICTIONS ......................................................................... 53 
7.1. 
Treatment ................................................................................................................ 53 
7.1.1. 
Treatment Regimen, Dosage, and Duration .................................................... 53 
7.1.2. 
Treatment Assignment .................................................................................... 54 
7.1.3. 
Compliance Control ........................................................................................ 55 
7.2. 
Study Restrictions ................................................................................................... 55 
7.2.1. 
Concomitant Medications during Treatment/Follow-Up Period .................... 55 
7.2.2. 
Patient Restrictions ......................................................................................... 56 
8. 
INVESTIGATIONAL PRODUCT ................................................................................. 56 
8.1. 
Clinical Trial Material ............................................................................................. 56 
8.2. 
Pharmaceutical Formulations .................................................................................. 57 
8.3. 
Labeling and Packaging .......................................................................................... 57 
8.4. 
Dispensing Procedures and Storage Conditions ..................................................... 57 
8.4.1. 
Dispensing Procedures .................................................................................... 57 
8.4.2. 
Storage Conditions .......................................................................................... 58 
9. 
EFFICACY ASSESSMENTS ........................................................................................ 58 
9.1. 
Specification of Variables and Procedures ............................................................. 58 
9.2. 
Efficacy Endpoints .................................................................................................. 58 
9.2.1. 
Primary Efficacy Endpoint ............................................................................. 58 
9.2.2. 
Secondary Efficacy Endpoints ........................................................................ 59 
9.2.3. 
Tertiary Efficacy Endpoints: ........................................................................... 59 
10. 
SAFETY ASSESSMENTS ......................................................................................... 60 
10.1.  Specification of Variables and Procedures ............................................................. 60 
10.2.  Adverse Events ....................................................................................................... 60 
10.2.1. 
Serious Adverse Events .................................................................................. 62 
10.3.  Serious Adverse Event Reporting – Procedure for Investigators ........................... 62 
10.3.1. 
Initial Reports .................................................................................................. 62 
10.3.2. 
Follow-Up Reports.......................................................................................... 63 
10.3.3. 
Reporting by the Sponsor................................................................................ 63 
10.4.  Exposure In Utero During Clinical Trials .............................................................. 63 


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11. 
TREATMENT DISCONTINUATION/PATIENT WITHDRAWAL ........................ 63 
11.1.  Reasons for Early Study Drug Discontinuation ...................................................... 63 
11.2.  Follow-Up after Early Study Drug Discontinuation/Lost to Follow-Up ................ 64 
12. 
STATISTICS .............................................................................................................. 65 
12.1.  Analysis Populations ............................................................................................... 65 
12.1.1. 
Randomized Population .................................................................................. 65 
12.1.2. 
Intent-to-Treat Population ............................................................................... 65 
12.1.3. 
Per-Protocol Population .................................................................................. 65 
12.1.4. 
Safety Population ............................................................................................ 65 
12.2.  Statistical Methods .................................................................................................. 65 
12.2.1. 
Patient Disposition and Demographic/Baseline Characteristics ..................... 65 
12.2.2. 
Study Medication Exposure and Compliance ................................................. 66 
12.2.3. 
Concomitant Therapies ................................................................................... 66 
12.2.4. 
Analysis of Efficacy ........................................................................................ 66 
12.2.5. 
Analysis of Safety ........................................................................................... 69 
12.3.  Sample Size Determination ..................................................................................... 69 
13. 
MONITORING, DATA MANAGEMENT, AND RECORD KEEPING .................. 70 
13.1.  Data Management ................................................................................................... 70 
13.1.1. 
Data Handling ................................................................................................. 70 
13.2.  Record Keeping ...................................................................................................... 70 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ......................................... 71 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 71 
16. 
ETHICS AND GOOD CLINICAL PRACTICE COMPLIANCE ............................. 71 
17. 
INFORMED CONSENT ............................................................................................ 72 
18. 
PUBLICATION POLICY .......................................................................................... 72 
19. 
Financing and Insurance ............................................................................................. 73 
19.1.  Finances .................................................................................................................. 73 
19.2.  Insurance Compensation ......................................................................................... 73 
20. 
Completion of Study ................................................................................................... 73 
21. 
STUDY ADMINISTRATIVE INFORMATION ....................................................... 73 
21.1.  Protocol Amendments ............................................................................................. 73 
22. 
REFERENCES ........................................................................................................... 74 


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23. 
INVESTIGATOR’S AGREEMENT .......................................................................... 79 
APPENDIX A: 
SCHEDULE OF PROCEDURES........................................................... 80 
Appendix B: Standardized definitions for end point events in cardiovascular trials .............. 82 
23.1.  Definition of Cardiovascular Death ........................................................................ 82 
23.2.  Definition of Non-Cardiovascular Death ................................................................ 84 
23.3.  Definition of Undetermined Cause of Death .......................................................... 86 
23.4.  Definition of Myocardial Infarction ........................................................................ 86 
23.5.  Common Classification Schemes for Myocardial Infarction Categories ............... 92 
23.6.  Definition of Hospitalization for Unstable Angina ................................................. 95 
23.7.  Definition of Transient Ischemic Attack and Stroke .............................................. 97 
23.8.  Definition of Heart Failure Event ........................................................................... 99 
23.9.  Interventional Cardiology Definitions .................................................................. 102 
23.10. 
Definition of Peripheral Vascular Intervention ................................................. 105 
23.11. 
Definition of Any Revascularization Procedure ............................................... 108 
23.12. 
Definition of Cardiac Arrhythmia Requiring Hospitalization .......................... 108 
23.13. 
Definition of Cardiac Arrest (Sudden Cardiac Death) ...................................... 109 
23.14. 
Definition of Resuscitated Cardiac Arrest  ....................................................... 109 
APPENDIX C: Criteria for the Diagnosis of Diabetes ......................................................... 110 
 
LIST OF TABLES AND FIGURES 
Figure 1. Median Placebo-Adjusted Baseline and Percent Change from Baseline in Lipid 
Parameters in 687 Patients (ITT population) with High Triglyceride Levels 
(≥200 mg/dL and <500 mg/dL) [ANCHOR] ..................................................... 25 
Table 1. Adverse Reactions Occurring at Incidence >2% and Greater than Placebo in 
 
Double-Blind, Placebo-Controlled Trials .......................................................... 26 
Table 2.  Dosing Schedule during the Treatment Period .................................................. 54 
Table 3.  Components of AMR101 Capsules .................................................................... 57 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AA 
Arachidonic acid 
ABI 
Ankle-brachial index 
ACC 
American College of Cardiology 
ACS 
Acute coronary syndrome 
AHA 
American Heart Association 
AIDS 
Acquired immune deficiency syndrome 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AP 
Angina pectoris 
apo B 
Apolipoprotein B 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CABG 
Coronary Artery Bypass Graft 
CAD 
Coronary artery disease 
CBC 
Complete blood count 
CEC 
Clinical Event Committee 
CI 
Confidence interval 
CHD 
Coronary heart disease 
CHF 
Congestive heart failure 
CK-MB 
Creatine kinase-MB fraction 
CrCL 
Creatinine clearance 
CNS 
Central nervous system 
CRF 
Case Report Form 
CT 
Computed tomography 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
%CV 
Percent coefficient of variation 
DART 
Diet and Reinfarction Trial 
DCCT 
Diabetes Control and Complications Trial 
DHA 
Docosahexaenoic acid 
DMC 
Data Monitoring Committee 
EDC 
Electronic data capture 
ECG 
Electrocardiogram 
EPA 
Eicosapentaenoic acid 
Ethyl-EPA 
Ethyl icosapentaenoate; icosapent ethyl 
FSH 
Follicle-stimulating hormone 
GC/FID 
Gas chromatograph with flame ionization detector 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GISSI 
Gruppo Italiano per lo Studio della Sopravvivenza 
nell’Infarto Miocardico 
Hct 
Hematocrit 


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HDL-C 
High-density lipoprotein cholesterol 
HF 
Heart failure 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
hs-CRP 
High-sensitivity C-reactive protein 
hsTnT 
High-sensitivity troponin T 
HR 
Hazard ratio 
ICAM-1 
Intercellular adhesion molecule-1 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
EC 
Independent Ethics Committee 
IFCC 
International Federation of Clinical Chemistry 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IWR 
Interactive Web Response  
JELIS 
Japan Eicosapentaenoic Acid Lipid Intervention Study 
LBBB 
Left bundle branch block 
LC-MS/MS 
Liquid chromatography with tandem mass spectrometry 
LDL-C 
Low-density lipoprotein cholesterol 
MACE 
Major adverse coronary event 
MI 
Myocardial infarction 
NCEP 
National Cholesterol Education Program 
NGSP 
National Glycohemoglobin Standardization Program 
NMR 
Nuclear magnetic resonance 
NO 
Nitric oxide 
NSTE-ACS 
Non-ST-Segment Elevation Acute Coronary Syndrome 
O3FA 
Omega-3 fatty acid 
OGTT 
Oral Glucose Tolerance Test 
PAD 
Peripheral arterial disease 
PCI 
Percutaneous coronary intervention 
PH 
Proportional hazard 
PI 
Principal Investigator 
PP 
Per protocol 
PROVE-IT 
Pravastatin or Atorvastatin Evaluation and Infection Therapy 
PTCA 
Percutaneous transluminal coronary angioplasty 
RBC 
Red blood cells 
RR 
Relative risk 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SCD 
Sudden cardiac death 
SD 
Standard deviation 
SOC 
Study Operations Committee 
SPC 
Summary of Product Characteristics 
ST 
Steering committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 


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T1/2 
Half-life 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TG 
Triglycerides 
TIMI 
Thrombolysis In Myocardial Infarction 
Tmax 
Time of maximum concentration 
ULN 
Upper limit of normal 
USPI 
United States Prescribing Information 
VCAM-1 
Vascular cell adhesion molecule-1 
VF 
Ventricular fibrillation 
WBC 
White cell blood count 


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1. 
INTRODUCTION AND BACKGROUND INFORMATION 
AMR101 (icosapent ethyl [ethyl-EPA]) is a highly purified ethyl ester of eicosapentaenoic 
acid (EPA) derived from fish oil, and is being developed by Amarin Pharma Inc. (hereafter 
referred to as Amarin or the Sponsor) for the treatment of hypertriglyceridemia. The purpose 
of this study is to evaluate whether the triglyceride-lowering drug AMR101, combined with a 
statin therapy, will be superior to the statin therapy alone, when used as a prevention in 
reducing long-term clinical events in patients with mixed dyslipidemia at high risk for 
cardiovascular (CV) events. 
1.1. 
Background 
Since the initial observation of a link between fish oil consumption and the reduced incidence 
of coronary heart disease in the Eskimos of Greenland (Bang 1972), a large body of evidence 
has accumulated showing that regular intake of omega-3 fatty acids (O3FAs) exerts 
cardioprotective effects in both primary and secondary coronary heart disease prevention 
(Harris 2008, Lee 2008). Several mechanisms have been proposed to account for these 
beneficial effects, including the reduction of triglycerides (TG), suppression of cardiac 
arrhythmias, decreased platelet aggregation, improved plaque composition and stabilization, 
and hemodynamic changes. This mounting body of evidence has led the American Heart 
Association (AHA) to recommend the consumption of O3FAs in dietary fish or in capsule 
form at a dose of 1 g/day for secondary prevention of cardiovascular disease (CVD) (Kris-
Etherton 2002). This recommendation has now been included in American College of 
Cardiology/American Heart Association (ACC/AHA) guidelines for the long-term 
management of patients with stable angina and acute coronary syndromes (Antman 2004, 
Fraker 2007, Anderson 2007). 
A large number of studies have also demonstrated the triglyceride-lowering effects of O3FAs 
(Harris 1997, Ginsberg 2001). The US FDA has approved a product containing 
approximately 90% esters of the O3FAs EPA and DHA for use at a dose of 4 g/day as an 
adjunct to diet for the treatment of patients with very high triglyceride levels (≥500 mg/dL) 
(Lovaza® USPI 2009). The same medicinal product under the name Omacor® (Omacor SPC 
2008) is approved in Europe for the treatment of endogenous hypertriglyceridemia at a dose 
of up to 4 grams daily as a supplement to diet when dietary measures alone are insufficient to 
produce an adequate response. Omacor® at a dose of 1 gram daily is also approved in key 
European and certain Asian markets for the secondary prevention of myocardial infarction 
(Post-MI). 
Epadel® capsules, which contain highly purified (>95%) ethyl-EPA, have been marketed by 
Mochida in Japan since 1991 for the treatment of arteriosclerosis obliterans and since 1994 
for the treatment of hyperlipidemia (Epadel SPC 2007). The recommended dose is 1.8 g/day 
for arteriosclerosis obliterans and 1.8 to 2.7 g/day for hyperlipidemia. Hypertriglyceridemia 
is a feature of many dyslipidemias and often occurs in persons who are obese and/or have 
Type 2 diabetes mellitus in isolation or as a component of the metabolic syndrome (Jacobson 
2007, Bays 2008). 
Elevation in TG confers dual risks of acute pancreatitis (most marked in patients with severe 
hypertriglyceridemia [TG >1500 mg/dL]) (Yadav 2003) and accelerated atherosclerosis 
leading to CV events, the latter even after correction for other lipid and non-lipid risk factors 


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(Jacobson 2007). With this in mind, Amarin is assessing the potential of AMR101 capsules, 
which contain highly purified icosapent ethyl (ethyl-EPA), for the treatment of patients, as an 
adjunct to diet, with very high TG levels (≥500 mg/dL) and those with high TG levels (≥200 
and <500 mg/dL) despite optimal statin therapy. Amarin-sponsored studies with AMR101 in 
patients with very high TGs (Study AMR-01-01-0016, the MARINE study) and in patients 
with high TGs on statins (Study AMR-01-01-0017, the ANCHOR study) are in progress. 
1.2. 
Summary of Amarin-Sponsored Clinical Studies with AMR101 
To date, Amarin has completed 8 double-blind, placebo-controlled clinical trials with 
AMR101 in patients with CNS disorders including Huntington’s disease, depression, 
schizophrenia and age-associated memory impairment. Males and females were almost 
equally represented. The majority of patients were Caucasian, but the studies also included, 
among the patients receiving AMR101, 14 Blacks, 6 Asians and 11 patients of another race.  
The patients received 0.5-4 g/day AMR101 or placebo. The duration of the double-blind 
treatment period ranged from 6 weeks to 1 year. In addition, 24 healthy volunteers have 
received AMR101 2 g/day for up to 28 days in a pharmacokinetic study (LA01.01.0009). In 
these studies, AMR101 was administered in the form of 500-mg soft gelatin capsules, orally 
with meals as a twice-daily regimen with half of the daily dose in the morning and half in the 
evening. 
Across all 9 completed Amarin-sponsored studies (1 in healthy volunteers and 8 in patients), 
a total of 1243 patients were randomized (24 healthy volunteers and 1219 patients with CNS 
disorders). From the 1243 patients, 724 (24 healthy patients and 700 patients) were 
randomized to receive AMR101 and 519 to receive placebo. See the Investigator’s Brochure 
for more information. 
In 4 of the Amarin-sponsored studies in patients with CNS disorders, patients who completed 
the double-blind period were rolled-over into an open-label extension phase and received 1-
2 g/day AMR101 (most received 2 g/day). The treatment period in the open-label extensions 
ranged from 6 months to 1 year. Across all studies, including patients from the double-blind 
periods receiving AMR101 and also those switched from placebo to AMR101 in the open-
label extensions, a total of 1071 patients have been exposed to ethyl-EPA from AMR101 
capsules. 
In addition, two Phase 3 studies in patients with hypertriglyceridemia have been completed. 
These trials have investigated the efficacy of AMR101 in lowering triglycerides: 
 Study AMR-01-01-0016 (the MARINE study) in 229 patients with very high 
triglycerides (>500 mg/dL). 
 Study AMR-01-01-0017 (the ANCHOR study) in approximately 702 patients 
with mixed dyslipidemia (high triglycerides: ≥200 to <500 mg/dL) who are taking 
statins 
 
1.3. 
Study AMR-01-01-0017 (ANCHOR Study) 
The results from the ANCHOR study are particularly relevant for the dose selection of the 
present study since the ANCHOR study was conducted in a very similar patient population. 
The primary objective in the ANCHOR study was to determine the efficacy of AMR101 2 g 


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daily and 4 g daily, compared to placebo, in lowering fasting TG levels in patients with high 
risk for cardiovascular disease (CVD) and fasting TG levels ≥200 mg/dL and <500 mg/dL, 
despite treatment to low density lipoprotein cholesterol (LDL-C) goal (>40 mg/dL and <100 
mg/dL) on statin therapy. 
After a 6- to 8-week screening period which included diet and lifestyle stabilization, a 
washout period for excluded non-statin lipid-altering medications (if needed), and a TG 
qualifying period, patients were randomized to one of 3 treatment groups and received study 
medication during a 12-week, double-blind treatment period. Patients had to be treated with 
one of 3 statins (simvastatin, atorvastatin or rosuvastatin) to reach their LDL-C goal of 100 
mg/dL (+15% allowed for variability) and had to be on a stable dose for a minimum period 
of 4 weeks before the TG qualifying measurements. The TG target for enrollment was for 
patients to have qualifying fasting TG levels of ≥200 mg/dL and <500 mg/dL based on the 
mean of 2 measurements. During the 12-week double-blind treatment period, patients 
received orally AMR101 2 g/day, AMR101 4 g/day, or placebo. 
Patients were randomized to either 2 or 4 g/day of AMR101 or placebo for 12 weeks.  The 
primary endpoint was the reduction in triglyceride levels compared to placebo.  Secondary 
endpoints were percent change in LDL-C compared to placebo, non-HDL-C, apoB, LpPLA2, 
and VLDL-C. 
The median placebo-adjusted changes in the major lipid parameters for the groups receiving 
statin plus AMR101 are shown in Figure 1.   
 


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Figure 1. Median Placebo-Adjusted Baseline and Percent Change from Baseline in 
Lipid Parameters in 687 Patients (ITT population) with High Triglyceride Levels (≥200 
mg/dL and <500 mg/dL) [ANCHOR] 
 
**** p<0.0001; *** p<0.001; ** p<0.01; * p<0.05; NS = Not Significant (p≥0.05) 
 
Median Baseline TG: 259 (placebo, N=227), 265 (4 g/day, N=226), 254 (2 g/day, N=234) mg/dL 
Median Baseline LDL-C: 84 (placebo, N=226), 82 (4 g/day, N=225), 82 (2 g/day, N=233) mg/dL 
Median Baseline non-HDL-C: 128 mg/dL for all treatment groups. 
Median Baseline apoB: 91 (placebo, n=219), 93 (4 g/day, n=217), 91 (2 g/day, n=227) mg/dL 
Medians are Hodges-Lehmann medians; p-values are from the Wilcoxon rank-sum test. 
 
Apo B = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol; hsCRP = high sensitivity C-reactive protein; ITT=intent to treat; 
LDL-C = low-density lipoprotein cholesterol; Lp-PLA2 = lipoprotein-associated phospholipase A2; non-HDL-C = non-high-density 
lipoprotein cholesterol; TC = total cholesterol; TG = triglyceride; VLDL-C = very low density lipoprotein cholesterol; VLDL-TG = very 
low-density lipoprotein triglycerides. 
 
AMR101 4g/day reduced median placebo-adjusted triglyceride levels by 13.1% (p=0.5467) 
in the lowest statin potency regimen (simvastatin 5-10 mg/day); by 20.1% (p<0.0001) in the 
medium potency statin regimen (rosuvastatin 5-10 mg, atorvastatin 10-20 mg, simvastatin 
20-40 mg, simvastatin 10-20 mg + ezetimibe 5-10 mg); and by 26% (p<0.0001) in the 
highest statin potency regimen (rosuvastatin 20-40 mg, atorvastatin 40-80 mg, simvastatin 80 
mg or simvastatin with ezetimibe 5-10 mg).  The statin potency regimens were pre-defined. 
Of the 702 patients with high triglycerides enrolled in this study, 514 had diabetes mellitus. 
Efficacy results in patients with diabetes were similar to those of the non-diabetics, and no 
significant changes in fasting plasma glucose or HbA1c with AMR101 vs. placebo were 
observed. 
The reduction in triglycerides observed with AMR101 was also associated with a placebo-
adjusted decrease in median LDL-C levels at both doses.  Median baseline LDL-C levels 
were 82.0 mg/dL (4 g/day), 82.0 mg/dL (2 g/day), and 84.0 mg/dL (placebo).  AMR101        
4 g/day decreased median placebo-adjusted LDL-C by 6.2% (p=0.0067) which was superior 
to placebo, based on a pre-specified +6% margin.   
 


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1.4. 
Clinical Safety 
In the MARINE and ANCHOR trials, a total of 622 patients have been exposed to ethyl-EPA 
from AMR101 capsules. AMR101 has been well tolerated (with incidence of adverse events 
similar to placebo) and there have been no major safety concerns. See the Investigator’s 
Brochure for more information. 
The types (by preferred term) of common treatment-emergent adverse events (TEAEs) and 
their incidence in the MARINE and ANCHOR trials are listed in Table 1. 
Table 1. Adverse Reactions Occurring at Incidence >2% and Greater than Placebo in 
Double-Blind, Placebo-Controlled Trials* 
Adverse Reaction 
Placebo 
(N=309) 
AMR101  
(N=622) 
 
N 
% 
N 
% 
Arthralgia 
3 
1.0 
14 
2.3 
*Studies included patients with triglycerides values of  200 to 2000 mg/dL. 
 
An additional adverse reaction from clinical studies was oropharyngeal pain. 
Source: Vascepa PI, Table 1 
 
In a large study with Japanese patients (Japan EPA Lipid Intervention Study [JELIS]), long-
term administration of 1.8 g/day ethyl-EPA (Epadel®) was associated with an excellent safety 
and tolerability profile (Yokoyama 2007). Most AEs attributable to ethyl-EPA were regarded 
as mild. The most common adverse events were gastro-intestinal (nausea, diarrhea, epigastric 
discomfort) or dermatologic (eruption, itching, exanthema, eczema) in nature. 
1.5. 
Rationale 
Hypothesis 
The hypothesis is that combination anti-dyslipidemic therapy of a LDL-C lowering drug 
(statin therapy) with the triglyceride-lowering drug AMR101 will be superior to the LDL-C 
lowering therapy alone when used as prevention in reducing long-term clinical events in 
patients with mixed dyslipidemia at high risk for cardiovascular events. 
TG-Lowering as a Therapeutic CV Target 
Studies have shown that elevated levels of total cholesterol (TC) and low-density lipoprotein 
cholesterol (LDL-C) are associated with increased risk of coronary heart disease (CHD) 
(LaRosa 2003), and therapeutic strategies that lead to a statistically significant reduction in 
LDL-C lower CHD event rates (Baigent 2005). One potential impediment, limiting further 
reduction in CHD events despite low on-treatment LDL-C, is residual elevation in serum TG 
levels (Miller 2000). Indeed, even after adjustment for HDL-C, detailed evaluation of 
population-based prospective studies has disclosed an independent effect of TG on CHD 
events (Sarwar 2007). Coupled with the knowledge that combined hyperlipidemia (i.e., 
elevated LDL-C and TG) promotes CHD to a significantly greater extent than either high 
LDL-C or TG alone (Manninen 1992), the hypothesis is strong that low on-treatment levels 
of TG when added to low LDL-C would be superior to low LDL-C alone in reducing 
subsequent CHD events. Supporting evidence for this hypothesis was obtained in a post hoc 
analysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In 


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Myocardial Infarction 22 Trial (PROVE IT-TIMI 22) (Miller 2008) wherein among patients 
receiving statin therapy after acute coronary syndrome (ACS), on treatment TG <150 mg/dL 
was associated with a lower risk of recurrent CHD events independently of the level of LDL-
C. For each 10% lowering of TG attained during the first 30 days of treatment after an ACS 
event, the risk for death, myocardial infarction, or recurrent acute coronary syndrome was 
reduced by 2.3% (p =0.035) after adjustment for high LDL-C (>70 mg/dL) and HDL-C (<40 
and 50 mg/dL in men and women, respectively). 
Omega-3 Fatty Acids in Fish Oils 
There is a growing body of evidence, encompassing molecular, cellular, animal and human 
studies defining the roles for O3FAs as bioactive agents for reducing the risks of and treating 
CVD (Torrejon 2007). Many epidemiological studies have demonstrated inverse associations 
between fish intake and CV mortality, and more specifically between the intake and blood 
levels of O3FAs and CV mortality. For example, when comparing blood levels of O3FAs 
among men who had died of sudden cardiac death with controls matched for age and 
smoking status, it was found that participants with the highest blood levels of EPA and DHA 
had a 90% risk reduction for sudden cardiac death compared with those with the lowest 
levels (Albert 2002). 
Clinical trials and experimental studies, suggest important antiatherogenic and antithrombotic 
effects of O3FAs. These result from wide-ranging biological effects, including benefits on 
lipoprotein metabolism, blood pressure, endothelial function and vascular reactivity, 
inflammation, platelet and fibrinolytic function, cytokine production, coagulation and 
oxidative stress (Mori and Woodman 2006). Evidence suggests that increased consumption 
of O3FAs from fish or fish-oil supplements reduces the rates of all-cause mortality, cardiac 
and sudden death, and possibly stroke (Wang 2006). The effect was evident in both primary-
prevention (general population without a history of CVD) and secondary-prevention (patients 
with a history of CVD) studies with a stronger effect in secondary prevention. 
The Diet and Reinfarction Trial (DART) was one of the first randomized, controlled studies 
to demonstrate the beneficial effects of O3FAs in secondary prevention of CHD and reported 
a 29% reduction in all-cause mortality over a 2-year period in 2033 male MI survivors 
advised to increase their intake of oily fish (200 to 400 g of fatty fish per week, which 
provided 500 to 800 mg/day of O3FAs) (Burr 1989). While not statistically significant, there 
was also a trend toward a reduction in recurrent ischemic heart disease events with increased 
fatty fish consumption. A post hoc analysis of patients receiving fish oil capsules 
(900 mg/day of EPA+DHA) in DART suggested that the protective effect was attributable to 
O3FAs (Burr 1994). The greatest benefit was seen in fatal MIs, and this observation led to 
the hypothesis that O3FAs might protect the myocardium against the adverse sequela of 
acute ischemic stress. 
A cardioprotective effect for O3FAs derived from fish oil is supported by prospective studies 
demonstrating inverse associations between fish intake and coronary heart disease mortality, 
especially amongst high-risk individuals (Mori and Woodman 2006). Early separation of 
survival curves in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto 
Miocardico (GISSI)-Prevenzione study (GISSI-Prevenzione Investigators 1999) and the 
DART trial support a reduction in ventricular fibrillation and a decreased incidence of 


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myocardial infarction (Leaf 1996) as the primary mechanisms through which O3FAs prevent 
CVD (Mori and Woodman 2006). 
Many international bodies including the AHA, American College of Cardiology, and the 
European Society of Cardiology have found the overall evidence for benefit sufficiently 
strong to make public recommendations for increased O3FA intake for both primary and 
secondary prevention (Harris 2007). 
Omega-3 Fatty Acid Ethyl Esters 
The largest prospective, randomized, controlled trial to test the efficacy of O3FAs for 
secondary prevention of CHD is the GISSI study (GISSI-Prevenzione Investigators 1999). In 
this study, 11,324 patients with preexisting CHD (experienced an MI and were receiving 
conventional cardiac pharmacotherapy) were randomized to either 300 mg of vitamin E, 
850 mg of O3FA ethyl esters (as EPA and DHA), both, or neither. After 3.5 years of follow-
up, the group given the O3FAs alone experienced a 15% reduction in the primary end point 
of death, nonfatal MI, and nonfatal stroke (p <0.02). There was a 20% reduction in all-cause 
mortality (p =0.01) and a 45% reduction in sudden death (p <0.001) compared with the 
control group; vitamin E provided no additional benefit. Triglycerides decreased by 4% and 
LDL cholesterol levels increased by 2.5% after six months in the O3FA treatment groups 
compared with controls. This trial, although very large and carried out in a relatively "usual-
care" setting, was not placebo controlled, and dropout rates were high (>25%). A follow-up 
study (Marchioli 2002) assessed the time-course of the benefit of O3FAs on mortality in 
subjects in the GISSI-P Study and found that survival curves diverged early after 
randomization. Total mortality was significantly lowered by 28% after 3 months of treatment 
(RR =0.59), and by 4 months, the risk of sudden cardiac death was reduced by 45% 
(RR =0.47). 
Ethyl-EPA 
In another larger trial, the Japan EPA Lipid Intervention Study (JELIS), 18,645 patients with 
hypercholesterolemia (70% women; mean age, 61 years) were randomly assigned to either 
statin alone or statin and pure ethyl-EPA (1.8 g/day). Of all patients, 15,000 patients (80%) 
were without existing CAD and 3,645 (20%) with existing CAD (Matsuzaki 2009). The 
primary endpoint was any major adverse coronary event (MACE including SCD, fatal and 
nonfatal MI, and other nonfatal events including unstable angina pectoris (determined to be 
caused by myocardial ischemia by invasive/non-invasive testing), angioplasty, stenting, and 
coronary artery bypass grafting).  
In the overall analysis (Yokoyama 2007), during the 4.6-year follow-up, ethyl-EPA reduced 
major adverse coronary events by 19% (p =0.011). EPA treatment was also associated with a 
significant 24% reduction in the incidence of unstable angina and a 19% decrease in nonfatal 
coronary events. This treatment also produced nonsignificant reductions of 21%, 25%, and 
14% in fatal MI, nonfatal MI, and revascularizations, respectively. 
In a subgroup analysis of primary prevention cases, compared to patients with normal serum 
TG and HDL-C levels, those with abnormal levels (TG ≥150 mg/dL; HDL-C <40 mg/dL) 
had a significantly higher major adverse coronary event (MACE) rate by 71% (p=0.014). In 
this higher risk group, ethyl-EPA treatment suppressed the MACE risk by 53% (p=0.043) 
(Saito 2008). 


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While there was no significant difference in the incidence of first stroke between ethyl-EPA 
and control groups, the incidence of stroke recurrence was significantly lower in the EPA 
group at 6.8% versus the control group at 10.5%, a reduction of 20% (p<0.05; Tanaka 2008). 
Further, while there was no difference in the incidence of recurrent hemorrhagic cerebral 
events between the two groups, ethyl-EPA was effective in reducing the recurrence of 
ischemic cerebral vascular events such as cerebral infarction (Harris 2009).  
O3FA supplementation lowered CV risk in both the GISSI-Prevenzione study and JELIS, 
despite aggressive therapy with standard pharmacotherapy (e.g., statins, aspirin, β-blockers 
and angiotensin-converting enzyme inhibitors). Additionally, the JELIS trial established the 
safety and efficacy of combination therapy with ethyl-EPA and a statin vs statin therapy 
alone for improving CV prognosis. The JELIS trial was conducted with Epadel that contains 
the same active ingredient, ethyl-EPA, as AMR101. Ethyl-EPA was shown in the JELIS 
study to reduce CAD events even in a Japanese population with very high intakes of O3FAs 
due to the high fish consumption. The evidence supporting a benefit in primary prevention 
comes from an observed 18% decrease in CV events in the 80% of patients in the JELIS trial 
without documented CAD (p =0.13); this effect size was essentially the same as that 
observed in the secondary prevention cohort (19%, p <0.05) (Lee 2008). 
Medical Need 
CVD resulting from progressive atherosclerosis remains the most common cause of 
morbidity and mortality all over the world. Based on 2006 US statistics (American Heart 
Association 2010), an estimated 81 million American adults (more than one in three) have 
one or more types of CVD. Of these, 38 million are estimated to be age 60 or older. Total 
CVD includes coronary heart disease (CHD): 17.6 million, heart failure (HF): 5.8 million and 
stroke: 6.4 million. CHD further divided includes myocardial infarction (MI): 8.5 million, 
and angina pectoris (AP): 10.2 million. Final mortality data show that CVD as the underlying 
cause of death accounted for 34.4% of all deaths (about 830,000 of all 2.4 million deaths in 
2006). CHD is the leading cause of death in all Western industrialized countries, despite 
considerable improvement since the mid-1960s. In developing countries, the incidence of 
CVD is increasing alarmingly. In addition to death, CVD also causes many serious non-fatal 
events and is the major cause of disability. Therefore, additional therapies for prevention of 
CVD would have a considerable public health benefit. 
A large number of studies have demonstrated the TG-lowering effects of O3FAs (Ginsberg 
2001; Harris 1997). Hypertriglyceridemia is a common lipid abnormality and often occurs in 
persons who are obese and have insulin resistance, Type 2 diabetes mellitus, or the metabolic 
syndrome (Jacobson 2007; Bays 2008). Elevation in TG is positively associated with 
accelerated atherosclerosis leading to CV events, the latter even after correction for other 
lipid and non-lipid risk factors (Jacobson 2007). In the US (American Heart Association 
2010), the mean TG level for American adults age 18 and older is 144.2 mg/dL (men, 
156.5 mg/dL; women, 132.1 mg/dL).  
Lifestyle modification is important for the management of patients with 
hypertriglyceridemia; however, for patients who do not adequately respond to dietary and 
lifestyle restrictions, relatively few classes of drugs are available to treat 
hypertriglyceridemia, and each is associated with risks that may limit their use alone or in 
combination. Currently available pharmacological treatments for hypertriglyceridemia 


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include fibric acid derivatives (such as gemfibrozil and fenofibrate), niacin in various 
formulations, prescription omega-3-acid ethyl esters (Lovaza/Omacor) and statins (3 hydroxy 
3 methylglutaryl coenzyme A reductase inhibitors).  
Although the above agents have robust TG-lowering effects in patients with 
hypertriglyceridemia, the degree of TG-lowering is highly variable; generally greater TG-
lowering effects are observed for fibrates and niacin compared with statins. Many patients 
will be satisfactorily treated with one or more of the above range of drugs (combined with 
appropriate diet and attention to other CV risk factors and lifestyle). 
Lovaza, comprised predominantly of ethyl-EPA and the ethyl ester of docosahexaenoic acid 
(ethyl-DHA), is indicated only in patients with very high TG levels (>500 mg/dL), raises 
LDL-C even when combined with statins in patients with high TGs (200-499 mg/dL), and is 
approved at 4 g/day (equivalent to 4 capsules/day) resulting in poor patient compliance. A 
non-compliance rate of 35% was reported in one clinical trial (Leaf 2005). 
Fibrates are clearly effective at raising HDL-C and lowering TG concentrations. However, 
their effects on vascular events remain uncertain. Several large-scale trials of fibrate therapy 
have been completed in the past few years. Although some of these trials have suggested 
benefit, others have shown no effect, leading to uncertainty about the presence and 
magnitude of any cardiovascular protective effects and difficulties for clinicians in 
interpretation of the results (Jun 2010). The ACCORD study (Ginsberg 2010) reported no 
overall benefit for fenofibrate, raising further questions about the usefulness of these agents. 
There are also safety issues with the above agents that limit their clinical use. Statins, 
particularly at high doses, may cause increases in hepatic transaminases and are also known 
to cause myopathy and occasionally rhabdomyolysis, which may lead to death from acute 
renal failure. This risk may be increased when fibrates and statins are co-administered and 
many clinicians will avoid co-prescribing these 2 medications. Fibrates are also associated 
with interactions with warfarin and hepatic transaminase elevations. The utility of niacin is 
limited by the occurrence of severe flushing and associated symptoms which can be difficult 
to manage even with careful dose titration and pre administration of aspirin or other non-
steroidal anti-inflammatory drugs. Niacin is also associated with impairment of glucose 
tolerance and precipitation of attacks of gout in susceptible patients. 
The DYSlipidemia International Study (DYSIS) assessed the prevalence of dyslipidemia 
among patients taking statins. This epidemiological observational study included more than 
22,000 patients in Europe and Canada aged 45 and older who received statin therapy for at 
least three months, and had a clinical diagnosis of coronary or other atherosclerotic disease, 
or were at high risk of developing CVD. The study found 48% of patients had LDL-C not at 
goal; 26% had low HDL-C levels; and 38% had elevated triglycerides. This study 
demonstrates that persistent dyslipidemia is highly prevalent in statin-treated patients. 
Patients with dyslipidemia, particularly those with established CVD or diabetes, have 
therapeutic needs that cannot be met by statin monotherapy. It is hypothesized that achieving 
target values for LDL-C/non-HDL-C in these patients using a therapeutic approach of the 
combination of AMR101 and a statin will benefit these patients. Such a combination therapy 
might increase the likelihood of therapeutic success in these patients with regards to future 
risk of CVD, based on meeting of both LDL-C/non-HDL-C goals and TG goals according to 
the ACC/AHA guidelines (Anderson 2007). Approximately 40 million Americans have high 


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TG levels (>200 mg/dL), however only a minority (3.6%) are currently treated with 
prescription medication (Ford 2009). Patients with elevated TGs are currently under-served 
and would benefit from a new, safe and effective product that can provide the following 
attributes: 
 Robust efficacy to lower TGs 
 Safe to use with other lipid-lowering agents, including statins 
 Does not increase LDL-C when used in patients on statin therapy (TG = 200-499 
mg/dL) 
 Has convenient dosing regimen 
 Has class-specific positive outcomes data 
 
Pleiotropic Effects 
There is ample evidence that O3FAs decrease TGs in patients with hypertriglyceridemia 
which is a beneficial effect related to the fact that elevated TGs have been identified as an 
independent risk factor for CVD. Lowering TGs in patients with hypertriglyceridemia would 
lead to a slowing of the development of atherosclerosis. However O3FAs including EPA 
have a wide range of additional pharmacological effects that most likely contribute to a 
beneficial effect in patients with CVD. 
Beneficial effects in clinical trials have been attributed in part to reducing arrhythmias (Lee 
2003; Goel 2002; Calo 2005). The case for an antiarrhythmic effect of O3FAs comes from 
clinical trials and from animal studies. Clinical trials have shown that the risk of sudden 
death in patients who have survived myocardial infarction is greatly reduced by inclusion of 
O3FAs in the diet (Siscovick 2000). Thus it seems that fatal ventricular fibrillation is less 
likely to occur during sufficient intake of O3FAs. Animal studies support this. Coronary 
ligation studies in a variety of species (rats, dogs and marmosets) have shown that the 
incidence of ventricular fibrillation is lower in animals fed a diet rich in O3FAs before 
ligation (McLennan 1992; Leaf 1996). In isolated cells, the story is similar (Li 1997, Engler 
2000; Omura 2001). In neonatal rat cardiac myocytes, EPA prevents the arrhythmogenic 
action of many interventions, including high external Ca2+ and ouabain (Kang 1994). The 
antiarrhythmic effect is caused by a reduction in electrical excitability caused by partitioning 
O3FAs into the phospholipid cell membranes of the cardiac myocytes, which modulates 
membrane ion channels. This is the postulated direct mechanism that refers to the 
antiarrhythmic effect of O3FAs which inhibits the fast, voltage-dependent sodium current 
along with the L-type calcium currents. This reduces the action potential of cardiac 
myocytes, reducing the susceptibility to arrhythmia. These cellular alterations are likely to 
reduce the severity of ventricular arrhythmias by inhibiting the rapid accumulation of 
intracellular Ca2+ following ischemia. It was also shown in patients with coronary artery 
disease that long-term treatment with EPA augments both NO-mediated and non-NO-
mediated endothelium-dependent forearm vasodilatation (Tagawa 1999). 
Another, indirect mechanism refers to the effect of O3FAs on cardiac arrhythmias by 
modifying the balance of different eicosanoids which are produced as end-products from 
chain elongation of their parent polyunsaturated fatty acids (Nair 1997). Most investigations 
of the link between O3FAs and heart disease have demonstrated the competition between AA 


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and O3FAs to become substrates in the production of eicosanoids. O3FAs compete with AA 
in several ways, but EPA in particular competes with AA as the substrate for the 
cyclooxygenase enzyme inhibiting the production of thromboxane A2 (TXA2) and in 
endothelial cells, prostaglandin I3 (PGI3) is synthesized from EPA (Nair 1997). The net result 
of these actions is vasodilatation. A reduced ratio of AA/EPA shifts the spectrum of 
eicosanoid production toward an increase in thromboxane A3 (TXA3) and PGI3 at the 
expense of TXA2 and PGI2, respectively. This shift was found to reduce the risk of 
ventricular fibrillation (VF) and sudden cardiac death (SCD) (Coker 1982). Excessive 
production of eicosanoids derived from omega-6 fatty acids have been associated with heart 
attacks, thrombotic stroke, and arrhythmia, while those from O3FAs are antiarrhythmic. 
Probably one of the most important pharmacologic properties of EPA is its anti-inflammatory 
and immune-modulating activity (Calder 2006; Calder 2010). Because of the inflammatory 
events underlying plaque rupture, the variety of anti-inflammatory effects of O3FAs may be 
of relevance to atherosclerosis and its clinical manifestations of myocardial infarction, 
sudden death, and stroke (Mori 2004; Thies 2003). A randomized controlled study, in 
patients awaiting surgery to remove atherosclerotic plaques in the carotid artery, has shown 
that an anti-inflammatory response might be involved, by demonstrating an association 
between the intake of O3FAs as a supplement (1.4 g/day) and the stability of atherosclerotic 
plaques (Thies 2003). This improved stability was achieved by incorporation of the O3FAs 
into the plaque. 
The omega-6 fatty acid AA gives rise to eicosanoid mediators that have established roles in 
inflammation and AA metabolism is a long recognized target for commonly used anti-
inflammatory therapies. O3FAs are incorporated into inflammatory cell phospholipids in a 
time- and dose-dependent manner. They are incorporated partly at the expense of AA, but 
also other omega-6 fatty acids. EPA and DHA inhibit AA metabolism. Thus production of 
AA-derived eicosanoids is decreased by these O3FAs. EPA gives rise to an alternative family 
of eicosanoids (e.g. PGE3), which frequently have lower anti-inflammatory potency than 
those produced from AA, and to resolvins (E- and D-series) which have potent anti-
inflammatory and inflammation resolving properties (Serhan 2006; Dona 2008). The plasma 
AA/EPA ratio has been used as a marker of the inflammatory status in patients with CVD 
(Rupp 2004; Holub 2009). In favor of the concept that less pro-inflammatory processes can 
be observed already at lower AA/EPA ratios is the finding that 1.4 g/day ethyl-EPA reduced 
the incidence of plaque rupture (Thies 2003). The AA/EPA ratio had a strong relationship 
with the incidence of CV events such as MACE in patients undergoing elective PCI (Domei 
2009). 
In addition to modifying the profile of lipid-derived mediators, O3FAs can also influence 
peptide mediator (i.e. cytokine) production. Pro-inflammatory cytokines, or cytokines 
reflecting inflammatory processes, e.g. IL-1beta, IL-2, IL-6, TNFalpha, platelet-derived 
growth factor (PDGF)-A and -B and monocyte chemoattractant protein-1 (MCP-1), are 
reduced by EPA and DHA in human subjects (von Schacky 2007), and soluble cytokines 
reflecting interactions between blood cells and the vessel wall, such as intercellular adhesion 
molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) (Yamada 2008). 
EPA and DHA intake also resulted in a decreased expression of genes involved in 
inflammatory- and atherogenic-related pathways, such as nuclear transcription factor B 


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signaling, eicosanoid synthesis, scavenger receptor activity, adipogenesis, and hypoxia 
signaling (Bouwens 2009). 
In conclusion, the pleiotropic effects of EPA may contribute to the overall beneficial effects 
on the risk of CVD, in addition to the TG-lowering effect. Therefore, it is possible that the 
efficacious dose of EPA that decreases the CV event rate is lower than the dose needed to 
exert the maximum TG-lowering effect, and/or that a modest decrease of TGs after EPA 
treatment could still lead to a significant decrease in the risk for CVD. 
Dose Selection 
This trial will be conducted with a dose of AMR101 of 4 g/day (4 capsules/day). 
To date, only one study was published investigating the effects of combination treatment 
with an O3FA plus statins on clinical cardiovascular events. This is the Japan EPA Lipid 
Intervention Study (JELIS) (Yokoyama 2007), as previously discussed, wherein ethyl-EPA 
combined with low-dose pravastatin or simvastatin compared with statin therapy alone 
reduced major coronary events without altering rates of sudden cardiac death. These effects 
were achieved without any significant changes in total, LDL- or HDL-C and a statistically 
significant (p <0.0001) decrease in triglycerides, suggesting that EPA can lower CVD risk by 
mechanisms other than LDL-C lowering (Yokoyama 2007). In a subanalysis of this study, 
the addition of ethyl-EPA to pravastatin or simvastatin reduced also the incidence of 
coronary heart disease events in high-risk patients with metabolic syndrome and atherogenic 
dyslipidemia characterized by high triglycerides and low HDL-C (Saito 2008). The JELIS 
study was performed in a large patient population wherein an ethyl-EPA dose of 1.8 g/day 
translated to significant benefits on CV events. 
In the ANCHOR study (Amarin-sponsored), both the 2 and 4 g/day dosing regimens of 
AMR101 resulted in statistically significant reductions of TGs (see Section 1.3). However, 
since the 4 g/day dose caused a larger reduction in TG and other lipid, lipoprotein and 
inflammatory markers, the AMR101 4 g/day dose was selected for the present study. 
1.6. 
Risk/Benefit 
Across all completed Amarin-sponsored studies, the proportion of patients (based on the 
safety population from the randomized, double-blind periods of the studies) experiencing any 
adverse events was similar for patients on placebo (light paraffin oil) and patients on 
AMR101 (57.1% and 57.4% for placebo and AMR101, respectively). The proportion of 
patients experiencing a serious adverse event (SAE) was also similar for both treatment 
groups (5.2% and 6.0% for placebo and AMR101, respectively). The safety profile in the 
open-label extensions was similar to that observed in the double-blind treatment periods. 
There were no SAEs attributed to AMR101 during the open-label extension periods of the 
studies. 
In summary, AMR101 is very well tolerated at daily doses up to 4 g. The side effects 
reported by the patients taking AMR101 were generally similar to those reported by the 
patients taking placebo. Ethyl-EPA is a pro-drug, and is rapidly and completely hydrolyzed 
to EPA. EPA is a natural substance found universally as a component of all cell membranes. 
It is classified as an essential fatty acid. Because of the nature of EPA, as an essential 
component of normal tissue and its part in normal metabolism, human studies have 
demonstrated that it is safe. See the Investigator’s Brochure for more information. 


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2. 
STUDY OBJECTIVES 
The primary objective is, in patients at LDL-C goal while on statin therapy, with established 
cardiovascular disease (CVD) or at high risk for CVD, and hypertriglyceridemia (fasting 
triglycerides, TG, 200 mg/dL and <500 mg/dL [2.26 mmol/L and <5.64 mmol/L]), to 
evaluate the effect of 4 g/day AMR101 for preventing the occurrence of a first major 
cardiovascular event of the composite endpoint that includes: 
 Cardiovascular (CV)  death, 
 Nonfatal myocardial infarction (MI), 
 Nonfatal stroke, 
 Coronary revascularization,  
 Unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization.  
 
Refer to Appendix B for cardiovascular event definitions. 
 
The secondary objectives of this study are the following: 
The key secondary objective is to evaluate the effect of therapy on the composite of death 
from CV causes, nonfatal MI, coronary revascularization, unstable angina determined to be 
caused by myocardial ischemia by invasive/non-invasive testing and requiring emergent 
hospitalization, nonfatal stroke, or peripheral CVD requiring intervention, angioplasty, 
bypass surgery, or aneurysm repair. 
 
Other secondary objectives: 
 To evaluate the effect of therapy on combinations of each of the key secondary 
objective clinical events in addition to the following clinical events: 
o Cardiac arrhythmia requiring hospitalization  
o Cardiac arrest 
o Peripheral CVD requiring intervention, angioplasty, bypass surgery, or 
aneurysm repair 
o Total mortality 
 
The tertiary objectives of this study are the following: 
 Evaluate the effect of therapy on the occurrence of a second, third, fourth, and fifth 
major cardiovascular event (same as the primary composite endpoint but for events 
occurring after the first event); 
 To evaluate the effect of therapy on the primary endpoint in subgroups of patients 
including: 
o Diabetes mellitus 
o Metabolic syndrome as defined by the NCEP ATP III or future criteria as they 
may evolve; 


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 To evaluate the effect of therapy on the individual endpoints of new congestive heart 
failure (CHF), on new CHF as a primary cause of hospitalization, on transient 
ischemic attack, on amputation for vascular disease and on carotid revascularization; 
 Elective coronary revascularization and emergent coronary revascularization;  
 To assess the effects regarding lipids, lipoproteins and inflammatory markers 
including triglycerides (TG), total cholesterol (TC), low-density lipoprotein 
cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, 
very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein B (apo B), high 
sensitivity C-reactive protein (hs-CRP) and high sensitivity troponin (hsTnT), as 
follows: 
o Assessment of the effect of AMR101 on each marker (on-treatment 
change of markers) 
o Assessment of the effect of the baseline value of each marker on 
treatment effects (baseline effect on outcomes) 
o To evaluate the effect of therapy for preventing clinical events, as 
defined above, among all patients in the study, and in subgroups such as 
patients with diabetes mellitus and patients with substantial on-treatment 
changes of any of the markers (on-treatment effect on outcomes). 
 To evaluate the effect of therapy on new onset diabetes (See appendix C); 
 To explore the effect of AMR101 on weight and waist circumference. 
3. 
STUDY DESIGN 
3.1. 
Type of Study 
Phase 3b, multi-Center, multinational, prospective, randomized, double-blind, placebo-
controlled, parallel-group study 
3.2. 
Study Population 
The population for this study is men and women ≥45 years of age with established CVD, or 
men and women ≥50 years of age with diabetes in combination with one additional risk 
factor for CVD. In addition, all patients will have atherogenic dyslipidemia defined as on 
treatment for hypercholesterolemia (but at treatment goal for LDL-C, by treatment with a 
statin) and hypertriglyceridemia. More details are listed in the inclusion criteria. 
The patients will need to provide consent to participate in the study and be willing and able 
to comply with the protocol and the study procedures. 
3.3. 
Study Periods 
This study consists of the following study periods: 
 Screening Period: During the screening period, patients will be evaluated for 
inclusion/exclusion criteria. 
At the first visit to the Research Unit (Visit 1), study procedures will be performed for 
evaluation of patient’s eligibility in the study. At this screening visit, patients will sign an 


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informed consent form before any study procedure is performed; the informed consent 
form will cover the treatment/follow-up period. Based on the evaluation from Visit 1, the 
following situations may occur: 
o 
Patients who are eligible for participation based on the study procedures on Visit 1 
will return to the Research Unit for Visit 2 (randomization visit) to start the 
treatment/follow-up period. This case includes, for example, patients at Visit 1who 
are on a stable dose of a statin, are planning to stay on the same statin and the same 
dose of the statin, and who not need to wash out any non-statin lipid-altering 
medications. 
o 
Patients who are not eligible for participation based on the study procedures on 
Visit 1 and are unlikely to become eligible in the next 28 days (for example: 
unlikely to stabilize statin dose, unable to wash out non-statin lipid-altering 
medications, etc.): these patients will be screen failed after Visit 1. 
o 
Patients not eligible for participation in the study based on the study procedures on 
Visit 1 may possibly become eligible in the next 28 days: these patients may return 
at the discretion of the investigator for a second optional screening visit (Visit 1.1) 
at which time the procedures needed for re-evaluation of the previously failed 
inclusion/exclusion criteria will be repeated. This case includes, for example, 
patients who are started on a statin at Visit 1, whose statin dose is changed at Visit 1, 
and/or needed to wash out non-statin lipid-altering medications. The following 
applies for these patients: 
 
Patients with a change in the statin or statin dose on Visit 1 will need to be on a 
stable statin dose for at least 28 days before the lipid qualifying measurements 
at Visit 1.1. Other concomitant medications (antidiabetic therapy, for example) 
can be optimized or stabilized during this period. 
 
Patients starting a washout at Visit 1 will have a washout period of at least 
28 days (only 7 days for bile acid sequestrants) before the lipid qualifying 
measurements at Visit 1.1. 
 
Patients at Visit 1 who are on a stable dose of a statin, are planning to stay on 
the same statin at the same dose, and who do not need any medication washout, 
but were asked to return for Visit 1.1 to repeat one or more of the other study 
procedures not related to concomitant medications  
o 
Patients who become eligible for participation based on the additional study 
procedures at Visit 1.1 will return to the Research Unit for Visit 2 (randomization 
visit) to start the treatment/follow-up period. 
At the end of the screening period, patients will need to meet all inclusion/exclusion criteria 
before they can be randomized. Patients who are not eligible for participation after the 
screening period (based on study procedures at Visit 1 and/or Visit 1.1) may return at a later 
date for rescreening. These patients will need to re-start with all procedures starting with 
Visit 1. This includes patients who need more time to stabilize one or more conditions or 
therapies (for example: statin, antidiabetic, antihypertensive, thyroid hormone, HIV-protease 
inhibitor therapy). 
 Treatment/Follow-Up Period: Within 42 days after the first screening visit (Visit 1) or 
within 60 days after the first screening visit (Visit 1) for those patients that have a second 


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screening visit (Visit 1.1), eligible patients will enter the treatment/follow-up period. 
During this period, the patients will receive study drug during the planned visits at the 
Research Site and take the study drug while away from the Research Site. 
During the visits, study procedures will be performed for evaluation of efficacy and safety. A 
detailed schedule of procedures is provided in Appendix A. 
3.4. 
Study Duration 
The estimated study duration includes a planned 18-month enrollment period followed by a 
follow-up period of approximately 3.5 years in expected duration (approximately 5 years in 
total). Patients will be randomized at different times during the enrollment period but will all 
end the study at the same date (study end date). It is planned that all randomized patients will 
receive study medication and be followed-up until the study end date. This is an event-driven 
trial and patients will continue in the trial if the trial runs longer than expected, or will 
terminate earlier if the trial runs shorter than expected. 
The total duration of the trial is based on a median 4-year follow-up period across patients. 
The first patient randomized would be followed for 4.75 years (the longest individual follow-
up duration), and the last patient randomized would be followed for 3.25 year (the shortest 
individual follow-up duration). 
3.5. 
Study Groups 
At Visit 2 (Day 0), eligible study patients will be randomly assigned to the following 
treatment groups: 
 Group 1: AMR101 4 g daily (four 1000 mg capsules daily) 
 Group 2: placebo (four capsules daily) 
The four AMR101 or placebo capsules daily will be taken as two capsules in the morning 
and two capsules in the evening (twice-per-day dosing regimen). 
3.6. 
Number of Patients 
This is an event-driven trial: It is expected that a minimum of 1612 primary efficacy endpoint 
events will be required during the study. A total of approximately 7990 patients will be 
entered into the study to either receive AMR101 or placebo (approximately 3995 patients per 
treatment group) in order to observe an estimated 1612 events that make up the primary 
composite endpoint for efficacy. 
3.7. 
Number of Study Sites 
Participants will be enrolled at multiple Research Sites in multiple countries. 
3.8. 
Randomization 
On Day 0, eligible patients will be randomized to one of 2 study groups using a computer-
generated randomization schema. Randomized treatment assignment to either AMR101 or 
placebo in a 1:1 ratio will be provided using the internet (IWR). 
3.9. 
Blinding 
This is a double-blind study. Patients, investigators, pharmacists and other supporting staff at 
the Research Sites, personnel and designees of the Sponsor, study administrators and 


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personnel at the organization(s) and vendors supporting the study will be unaware of the 
randomization code (i.e., they will not know which study participants are receiving the 
experimental drug and which are receiving the placebo drug). The study medication 
AMR101 and placebo capsules will be similar in size and appearance to maintain blinding. 
During the double-blind treatment/follow-up period, everyone (patients, investigators, 
pharmacists and other supporting staff at the Research Sites, personnel and designees of the 
Sponsor, study administrators and personnel at the organization(s) and vendors 
managing/supporting the study), with the exception of the laboratory personnel performing 
the analysis, will be blinded to individual results of the efficacy laboratory measurements 
(including lipid values). Individual results from the lipid profile may be unblinded in the 
event of an emergency for a patient. 
3.10. 
Stratification 
Participants will be assigned to treatment groups stratified by CV risk category, use of 
ezetimibe and by geographical region (Westernized, Eastern European, and Asia Pacific 
countries). There are two CV risk categories: 
 
CV Risk Category 1: patients with established CVD defined in the inclusion criteria. 
Patients with diabetes and established CVD are included in this category. 
 
CV Risk Category 2: patients with diabetes and at least one additional risk factor for 
CVD, but no established CVD. 
Stratification will be recorded in the IWR at the time of enrollment. Approximately 70% of 
randomized patients will be in the CV Risk Category 1 and approximately 30% of 
randomized patients will be in the CV Risk Category 2. Enrollment with patients of a CV 
risk category will be stopped when the planned number of patients in that risk category is 
reached. 
4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Patients meeting the following criteria will be eligible to participate in the study: 
1. Fasting TG levels of ≥200 mg/dL (2.26 mmol/L) and <500 mg/dL (5.64 mmol/L). 
2. LDL-C >40 mg/dL (1.04 mmol/L) and ≤100 mg/dL (2.60 mmol/L) and on stable therapy 
with a statin (with or without ezetimibe) for at least 4 weeks prior to the LDL-C/TG 
baseline qualifying measurements for randomization  
 
Stable therapy is defined as the same daily dose of the same statin for at least 28 
days before the lipid qualification measurements (TG and LDL-C) and, if applicable, 
the same daily dose of ezetimibe for at least 28 days before the lipid qualification 
measurements (TG and LDL-C). Patients who have their statin therapy or use of 
ezetimibe initiated at Visit 1, or have their statin, statin dose and/or ezetimibe dose 
changed at Visit 1, will need to go through a stabilization period of at least 28 days 
since initiation/change and have their qualifying lipid measurements measured (TG 
and LDL-C) after the washout period (at Visit 1.1).  
 
Statins may be administered with or without ezetimibe.  


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NOTE: If patients qualify at the first qualification visit (Visit 1) for TG and LDL-C, and 
meet all other inclusion/exclusion criteria, they may be randomized at Visit 2. If patients 
don’t qualify at the first qualifying visit (Visit 1), a second re-qualifying visit (Visit 1.1) 
is allowed. For some patients, because they need to stabilize medications and/or need to 
washout medications, the second re-qualifying visit (Visit 1.1) will be needed after the 
stabilization/washout period. 
3. Either having established CVD (in CV Risk Category 1) or at high risk for CVD (in CV 
Risk Category 2). The CV risk categories are defined as follows: 
CV Risk Category 1: defined as men and women ≥45 years of age with one or more of 
the following: 
o Documented coronary artery disease (CAD; one or more of the following primary 
criteria must be satisfied): 
 Documented multivessel CAD (>50% stenosis in at least two major epicardial 
coronary arteries – with or without antecedent revascularization) 
 Documented prior MI 
 Hospitalization for high-risk NSTE-ACS (with objective evidence of 
ischemia: ST-segment deviation or biomarker positivity) 
o Documented cerebrovascular or carotid disease (one of the following primary 
criteria must be satisfied): 
 Documented prior ischemic stroke 
 Symptomatic carotid artery disease with ≥50% carotid arterial stenosis 
 Asymptomatic carotid artery disease with ≥70% carotid arterial stenosis per 
angiography or duplex ultrasound 
 History of carotid revascularization (catheter-based or surgical) 
o Documented peripheral arterial disease (PAD; one or more of the following 
primary criteria must be satisfied):  
 ABI <0.9 with symptoms of intermittent claudication 
 History of aorto-iliac or peripheral arterial intervention (catheter-based or 
surgical) 
OR 
CV Risk Category 2: defined as patients with: 
1. Diabetes mellitus (Type 1 or Type 2) requiring treatment with medication AND 
2. Men and women ≥50 years of age AND  
3. One of the following at Visit 1 (additional risk factor for CVD): 
 Men ≥55 years of age or women ≥65 years of age; 
 Cigarette smoker or stopped smoking within 3 months before Visit 1; 
 Hypertension (blood pressure ≥140 mmHg systolic OR ≥90 mmHg diastolic) 
or on antihypertensive medication; 
 HDL-C ≤40 mg/dL for men or ≤50 mg/dL for women; 


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 Hs-CRP >3.00 mg/L (0.3 mg/dL); 
 Renal dysfunction: CrCL >30 and <60 mL/min (>0.50 and <1.00 mL/sec); 
 Retinopathy, defined as any of the following: non-proliferative retinopathy, 
preproliferative retinopathy, proliferative retinopathy, maculopathy, advanced 
diabetic eye disease or a history of photocoagulation; 
 Micro- or macroalbuminuria. Microalbuminuria is defined as either a positive 
micral or other strip test (may be obtained from medical records), an albumin 
creatinine ratio ≥2.5 mg/mmol or an albumin excretion rate on timed 
collection ≥20 mg/min all on at least two successive occasions; 
macroalbuminuria, defined as albustix or other dipstick evidence of gross 
proteinuria, an albumin:creatinine ratio ≥25 mg/mmol or an albumin excretion 
rate on timed collection ≥200 mg/min all on at least two successive occasions; 
 ABI <0.9 without symptoms of intermittent claudication (patients with ABI 
<0.9 with symptoms of intermittent claudication are counted under CV Risk 
Category 1). 
Note: Patients with diabetes with CVD as defined above are eligible based on the 
CVD requirements and will be counted under CV Risk Category 1. Only patients 
with diabetes and no documented CVD as defined above need at least one 
additional risk factor as listed, and will be counted under CV Risk Category 2. 
4. Women may be enrolled if all 3 of the following criteria are met: 
 
They are not pregnant; 
 
They are not breastfeeding; 
 
They do not plan on becoming pregnant during the study. 
5. Women of child-bearing potential must have a negative urine pregnancy test before 
randomization. 
Note: Women are not considered to be of childbearing potential if they meet one of the 
following criteria as documented by the investigator: 
 
They have had a hysterectomy, tubal ligation or bilateral oophorectomy prior to 
signing the informed consent form; 
 
They are post-menopausal, defined as 1 year since their last menstrual period or 
have a follicle-stimulating hormone (FSH) level in a menopausal range. 
6. Women of childbearing potential must agree to use an acceptable method of avoiding 
pregnancy from screening to the end of the study, unless their sexual partner(s) is/are 
surgically sterile or the woman is abstinent. 
7. Understanding of the study procedures, willing to adhere to the study schedules, and 
agreement to participate in the study by giving informed consent prior to screening. 
8. Agree to follow a physician recommended diet and to maintain it through the duration of 
the study. 


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4.2. 
Exclusion Criteria 
Patients are excluded from participation in the study if any of the following criteria apply: 
1. Severe (class IV) heart failure. 
2. Any life-threatening disease expected to result in death within the next 2 years (other than 
CVD). 
3. Active severe liver disease (evaluated at Visit 1): cirrhosis, active hepatitis, ALT or AST 
>3 x ULN, or biliary obstruction with hyperbilirubinemia (total bilirubin >2 x ULN). 
4. Hemoglobin A1c >10.0% (or 86 mmol/mol IFCC units) at screening (Visit 1). If patients 
fail this criterion (HbA1c >10.0% or 86 mmol/mol IFCC units) at Visit 1, they may have 
their antidiabetic therapy optimized and be retested at Visit 1.1. 
5. Poorly controlled hypertension: blood pressure ≥200 systolic mmHg OR ≥100 mmHg 
diastolic (despite antihypertensive therapy). 
6. Planned coronary intervention (such as stent placement or heart bypass) or any non-
cardiac major surgical procedure. Patients can be (re)evaluated for participation in the 
trial (starting with Visit 1.1) after their recovery from the intervention/surgery. 
7. Known familial lipoprotein lipase deficiency (Fredrickson Type I), apolipoprotein C-II 
deficiency, or familial dysbetalipoproteinemia (Fredrickson Type III)]. 
8. Participation in another clinical trial involving an investigational agent within 90 days 
prior to screening (Visit 1). Patients cannot participate in any other investigational 
medication or medical device trial while participating in this study (participation in a 
registry or observational study without an additional therapeutic intervention is allowed). 
9. Intolerance or hypersensitivity to statin therapy. 
10. Known hypersensitivity to any ingredients of the study product or placebo (refer to Table 
3); known hypersensitivity to fish and or shellfish. 
 
11. History of acute or chronic pancreatitis. 
12. Malabsorption syndrome and/or chronic diarrhea (Note: patients who have undergone 
gastric/intestinal bypass surgery are considered to have malabsorption, hence are 
excluded; patients who have undergone gastric banding are allowed to enter the trial). 
 
13. Non-study drug related, non-statin, lipid-altering medications, supplements or foods: 
 
Patients are excluded if they used niacin >200 mg/day or fibrates during the during 
the screening period (after Visit 1) and/or plan to use during the study; patients who 
are taking niacin >200 mg/day or fibrates during the last 28 days before Visit 1 need 
to go through washout of at least 28 days after their last use and have their qualifying 
lipids measured (TG and LDL-C) after the washout period (Visit 1.1); 
 
Patients are excluded if they take any omega-3 fatty acid medications (prescription 
medicines containing EPA and/or DHA) during the screening period (after Visit 1) 
and/or plan to use during the treatment/follow-up period of the study. To be eligible 
for participation in the study, patients who are taking omega-3 fatty acid medications 


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during the last 28 days before Visit 1 (except patients in The Netherlands), need to 
go through a washout period of at least 28 days after their last use and have their 
qualifying lipids measured (TG and LDL-C) after the washout period (at Visit 1.1);  
o For patients in The Netherlands only: patients being treated with omega-3 
fatty acid medications containing EPA and/or DHA are excluded; no 
washout is allowed.  
 
Patients are excluded if they use dietary supplements containing omega-3 fatty acids 
(e.g., flaxseed, fish, krill, or algal oils) during the screening period (after Visit 1) 
and/or plan to use during the treatment/follow-up period of the study. To be eligible 
for participation in the study, patients who are taking >300 mg/day omega-3 fatty 
acids (combined amount of EPA and DHA) within 28 days before Visit 1 (except 
patients in The Netherlands), need to go through a washout period of at least 28 days 
since their last use and have their qualifying lipid measurements measured (TG and 
LDL-C) after the washout period (at Visit 1.1); 
o For patients in The Netherlands only: patients being treated with dietary 
supplements containing omega-3 fatty acids of >300 mg/day EPA and/or 
DHA are excluded; no washout is allowed. 
 
Patients are excluded if they use bile acid sequestrants during the screening period 
(after Visit 1) and/or plan to use during the treatment/follow-up period of the study. 
To be eligible for participation in the study, patients who are taking bile acid 
sequestrants within 7 days before Visit 1, need to go through a washout period of at 
least 7 days since their last use and have their qualifying lipid measurements 
measured (TG and LDL-C) after the washout period (at Visit 1.1); 
14. Other medications (not indicated for lipid alteration): 
 
Treatment with tamoxifen, estrogens, progestins, thyroid hormone therapy, systemic 
corticosteroids (local, topical, inhalation, or nasal corticosteroids are allowed), HIV-
protease inhibitors that have not been stable for ≥28 days prior to the qualifying lipid 
measurements (TG and LDL-C) during screening. To be eligible for participation in 
the study, patients who are not taking a stable dose of these medications within 
28 days before Visit 1, need to go through a stabilization period of at least 28 days 
since their last dose change and have their qualifying lipid measurements measured 
(TG and LDL-C) after the washout period (at Visit 1.1). 
 
Patients are excluded if they use cyclophosphamide or systemic retinoids during the 
screening period (after Visit 1) and/or plan to use during the treatment/follow-up 
period of the study. To be eligible for participation in the study, patients who are 
taking these medications within 28 days before Visit 1, need to go through a washout 
period of at least 28 days since their last use and have their qualifying lipid 
measurements measured (TG and LDL-C) after the washout period (at Visit 1.1). 
15. Known to have AIDS (patients who are HIV positive without AIDS are allowed). 
16. Requirement for peritoneal dialysis or hemodialysis for renal insufficiency or if 
creatinine clearance (CrCL) <30 mL/min (0.50 mL/sec). 


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17. Unexplained creatine kinase concentration >5 × ULN or creatine kinase elevation due to 
known muscle disease (e.g., polymyositis, mitochondrial dysfunction) at Visit 1. 
18. Any condition or therapy which, in the opinion of the investigator, might pose a risk to 
the patient or make participation in the study not in the patient’s best interest. 
19. Drug or alcohol abuse within the past 6 months, and unable/unwilling to abstain from 
drug abuse and excessive alcohol consumption during the study or drinking 5 units or 
more for men or 4 units or more for women in any one hour (episodic excessive drinking 
or binge drinking). Excessive alcohol consumption is on average >2 units of alcohol per 
day. A unit of alcohol is defined as a 12-ounce (350 mL) beer, 5-ounce (150 mL) wine, or 
1.5-ounce (45 mL) of 80-proof alcohol for drinks. 
20. Mental/psychological impairment or any other reason to expect patient difficulty in 
complying with the requirements of the study or understanding the goal and potential 
risks of participating in the study (evaluated at Visit 1). 
5. 
STUDY COMMITTEES 
5.1. 
Steering Committee 
The Steering Committee (SC) will include the chairperson, the Principal Investigator (PI), 
key representatives from the Sponsor and its designees (for example, from the 
organization(s) conducting the study as delegated by the Sponsor), and key representatives 
from each region who are deemed to have clinical and methodological expertise (national 
coordinators). 
The SC has overall responsibility for: 
 
Scientific and strategic direction for the trial. The SC must address and resolve all 
scientific issues regarding the conduct of the trial. All sub-studies must be approved 
by the SC. 
 
The execution of the study protocol, and the reporting and publication of the study 
results. 
 
Logistical coordination of the different study committees. 
The SC will meet at least twice per year. 
5.2. 
Study Operations Committee (SOC) 
The Study Operations Committee (SOC) is responsible for ensuring that study execution and 
management is of the highest quality, and will monitor recruitment, compliance, and the 
adjudication process and address the day to day issues arising from the trial. The SOC will be 
composed of representatives from the Sponsor and the organization(s) conducting the study 
(as delegated by the sponsor). This committee will meet by telephone and/or in person on a 
monthly or bimonthly basis, and each meeting will be documented with minutes. 
5.3. 
Clinical Event Committee (CEC) 
The CEC is composed of multidisciplinary medical experts. This committee will be 
responsible for blindly validating all the primary and secondary efficacy outcome events 


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reported by the investigators (event adjudication). The committee will create a charter with 
details of the adjudication process and methods based on the definitions of the events. 
5.4. 
Data Monitoring Committee (DMC) 
A DMC will be instituted for this study in order to ensure its ongoing safety and to oversee 
and review the interim analysis. Recommendation for trial continuation will be guided by 
monitoring boundaries at an interim analysis at which a formal efficacy analysis is performed 
as well as safety evaluations at all safety data reviews. Members of the DMC will not 
otherwise be participating in the trial. The committee will include at least one cardiologist 
and one independent statistician. A DMC Charter will be drafted and approved by the DMC 
and the Steering Committee. The Charter will provide details regarding the interim analysis 
and monitoring plan. 
6. 
STUDY PROCEDURES 
6.1. 
Assessment Schedule  
A detailed schedule of procedures is provided in Appendix A. 
6.1.1. 
Screening Period 
6.1.1.1. 
Screening Visit (Visit 1) 
Patients will come to the Research Site for Visit 1. They will be instructed to fast for at least 
10 hours before their visit. 
If patients qualify for randomization based on the procedures at Visit 1, they need to be 
randomized within 42 days after Visit 1. The following procedures will be performed at the 
screening visit: 
 
Obtain signed informed consent 
 
Assign the patient a patient number 
 
Obtain medical, surgical and family history 
 
Record demographics 
 
Obtain height, weight, and body mass index 
 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and body temperature) 
 
Obtain a 12-lead electrocardiogram 
 
Evaluate inclusion/exclusion criteria 
 
This includes procedures and (fasting) blood samples (for example, hs-CRP, 
calculated creatinine clearance) as needed to determine the CV risk category (see 
inclusion criteria) 
 
Obtain fasting blood samples for chemistry and hematology testing 
 
Obtain a fasting blood sample for the lipid profile (TG, TC, HDL-C, LDL-C, non-
HDL-C, VLDL-C) 


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 
Perform a urine pregnancy test on women of childbearing potential 
 
Record concomitant medication(s) 
 
Instruct patient to fast for 10 hours prior to the next visit 
6.1.1.2. 
Screening Visit (Visit 1.1) 
Some patients will skip Visit 1.1: Patients who qualify for study participation after Visit 1 
because they meet all inclusion criterion and none of the exclusion criteria, may return to the 
Research Site for Visit 2 to be randomized and to start the treatment/follow-up period of the 
study. For these patients, Visit 2 will occur soon after Visit 1. 
Patients, who do not qualify at Visit 1, may return to the Research Site for a second 
qualifying visit (Visit 1.1) at the discretion of the investigator. At Visit 1.1, procedures that 
caused failure of eligibility at Visit 1 will be repeated. Patients will be eligible for 
randomization after Visit 1.1 if they meet all inclusion criteria and if they no longer fail the 
exclusion criteria. If patients are evaluated at Visit 1.1 and qualify for randomization based 
on the repeated procedures at Visit 1.1, they need to be randomized within 60 days after 
Visit 1. 
For some patients, Visit 1.1 will be mandatory at least 28 days after Visit 1 in order to check 
eligibility. These are patients who at Visit 1 started treatment with a statin, changed their 
statin, changed the daily dose of their statin, started to washout prohibited medications or 
started a stabilization period with certain medications (see inclusion/exclusion criteria for 
details). Any of these changes at Visit 1 may affect the qualifying lipid levels and therefore, 
patients will need to have Visit 1.1 to determine whether they qualify based on lipid level 
requirements (TG and LDL-C) determined at Visit 1. Other procedures that caused failure of 
eligibility at Visit 1 will also be repeated at Visit 1.1. 
The following procedures will be performed at the screening visit: 
 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and body temperature) 
 
Evaluate inclusion/exclusion criteria; only those evaluations will be repeated that 
deemed the patient not eligible on Visit 1. 
 
Obtain fasting blood samples for chemistry and hematology testing. Only those 
samples will be obtained that deemed the patient not eligible on Visit 1. 
 
Obtain a fasting blood sample for the lipid profile (TG, TC, HDL-C, LDL-C, non-
HDL-C, VLDL-C) if the patient was deemed not eligible on Visit 1. This includes 
patients who at Visit 1 started treatment with a statin, changed their statin, changed 
the daily dose of their statin, started to washout prohibited medications or started a 
stabilization period with certain medications (see inclusion/exclusion criteria for 
details). These patients will have a fasting blood sample collected at Visit 1.1 for the 
qualifying lipid values (TG and LDL-C), and the TG and LDL-C inclusion criteria 
will be evaluated. 
 
Record concomitant medication(s) 


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6.1.2. 
Treatment/Follow-Up Period 
Every attempt should be made to complete the follow-up visits during the defined window 
periods. 
6.1.2.1. 
Randomization visit (Visit 2; Day 0) 
Qualified patients will return to the Research Site for Visit 2. 
The following procedures will be performed at Visit 2: 
 
Perform physical examination 
 
Obtain weight 
 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and body temperature) 
 
Measure waist circumference (one of the factors to diagnose metabolic syndrome) 
 
Obtain a 12-lead electrocardiogram 
 
Evaluate inclusion/exclusion criteria 
 
Obtain fasting blood samples for: 
o 
Chemistry and hematology testing 
o 
Lipid profile (baseline) 
o 
Biomarker assays (baseline) 
o 
Genetic testing (optional blood sample) 
o 
Archiving (in countries and at sites approved by IRB/IEC and dependent on 
country regulations) 
 
Perform a urine pregnancy test on women of childbearing potential (must be 
negative for randomization) 
 
Dispense study drug and record randomization number 
 
Instruct patient on how to take study drug 
 
Administer study drug - Note: Study drug should be taken orally with food following 
the collection of all fasting blood samples 
 
Assess for and record adverse events 
 
Record concomitant medication(s) 
 
Instruct patient: 
o 
To bring all study supplies with them to the next visit 
o 
Not to take study drug on the morning of their next visit 
o 
To fast for 10 hours prior to the next visit 
6.1.2.2. 
Visit 3 (Day 120; ~4 Months) 
Patients will return to the Research Site for Visit 3 on Day 120 ±10 days. 


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The following procedures will be performed: 
 
Perform physical examination 
 
Obtain weight 
 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and body temperature) 
 
Obtain fasting blood samples for: 
o 
Chemistry and hematology testing 
o 
Lipid profile 
 
Review study drug compliance by unused capsule count; discuss with and counsel 
patients about compliance if needed 
 
Administer study drug - Note: Study drug should be taken orally with food following 
the collection of all fasting blood samples 
 
Assess and record efficacy events 
 
Assess for and record adverse events 
 
Record concomitant medication(s) 
 
Instruct patient: 
o 
To bring all study supplies with them to the next visit 
o 
Not to take study drug on the morning of their next visit 
o 
To fast for 10 hours prior to the next visit 
6.1.2.3. 
Visits 4, 5, 6 and 7 
At Visit 4: Day 360 ± 10; Visit 5: Day 720 ± 10; Visit 6: Day 1080 ± 10; and Visit 7: 
Day 1440 ± 10, the following procedures will be performed: 
 
Perform physical examination 
 
Obtain weight 
 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and body temperature) 
 
Measure waist circumference (collected at Visit 5 only) 
 
Obtain a 12-lead electrocardiogram 
 
Obtain fasting blood samples for: 
o 
Chemistry and hematology testing 
o 
Lipid profile 
o 
Biomarker assays (collected at Visit 5 only) 
o 
Archiving (in countries and at sites approved by IRB/IEC and dependent on 
country regulations) 


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 
Review study drug compliance by unused capsule count; discuss with and counsel 
patients about compliance if needed 
 
Administer study drug - Note: Study drug should be taken orally with food following 
the collection of all fasting blood samples 
 
Assess and record efficacy events 
 
Assess for and record adverse events 
 
Record concomitant medication(s) 
 
Instruct patient: 
o 
To bring all study supplies with them to the next visit 
o 
Not to take study drug on the morning of their next visit 
o 
To fast for 10 hours prior to the next visit 
6.1.2.4. 
Additional Visits 
The end date of the study is expected for Day 1800 but the actual end date will be dependent 
on the determination of the study end date by the DMC. The study end date is determined to 
be when approximately 1612 primary efficacy events have occurred. If the actual study end 
date is later than the expected end date, additional visits will be planned between Visit 7 and 
the Last Visit with a maximum of 360 ±10 days between visits. If the actual study end date is 
sooner than the expected end date, fewer visits will occur, and the last visit (See Section 
6.1.2.5) will occur sooner. 
On additional visits the same procedures will be performed as listed in Section 6.1.2.3. 
Irrespective of the number of additional visits, after the DMC has established the end of the 
study date, there will be a last visit with procedures as listed in Section 6.1.2.5. 
6.1.2.5. 
Last Visit – End of Study 
All patients will complete the study at the same time (within a 30-day window after the study 
end date), irrespective of the date that they were randomized. The end date of the study is 
planned for Day 1800 but the actual end date will be dependent on the determination of the 
study end date by the DMC when approximately 1612 primary efficacy events have occurred 
(event-driven trial). For each patient, the last visit may occur within 30 day after the actual 
study end date as determined by the DMC. However, for the efficacy endpoints based on CV 
events, only events occurring up to and including the scheduled actual study end date will be 
included in the efficacy analyses. 
A final follow-up visit is required for all patients. In the rare cases that a final follow-up visit 
cannot occur within the 30-day timeframe following the study end date, any attempt to 
contact the patient must be recorded on a special contact form, until/unless appropriate 
information is obtained. 
At the Last Visit, the following procedures will be performed: 
 
Perform physical examination 
 
Obtain weight 


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 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and body temperature) 
 
Measure waist circumference  
 
Obtain a 12-lead electrocardiogram 
 
Obtain fasting blood samples for: 
o 
Chemistry and hematology testing 
o 
Lipid profile 
o 
Biomarker assays 
o 
Archiving (in countries and at sites approved by IRB/IEC and dependent on 
country regulations) 
 
Determine study drug compliance by unused capsule count 
 
Assess and record efficacy events 
 
Assess for and record adverse events 
 
Record concomitant medication(s) 
6.2. 
Telephone Follow-up Contact 
Site personnel will contact each patient by telephone on the following study days: 
 
Day 60 ±3 days 
 
Day 180 ±5 days 
 
Day 270 ±5 days 
 
Day 450 ±5 days 
 
Day 540±5 days 
 
Day 630 ±5 days 
 
Day 810 ±5 days 
 
Day 900 ±5 days 
 
Day 990 ±5 days 
 
Day 1170 ±5 days 
 
Day 1260 ±5 days 
 
Day 1350 ±5 days 
 
Day 1530 ±5 days 
 
Day 1620 ±5 days 
 
Day 1710 ±5 days 
If the treatment/follow-up period of the study is extended beyond the expected end date 
(Day 1800), additional follow-up phone calls will be made every 3 months in-between 


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additional visits ±5 days. See Section 6.1.2.4 for the timing of the additional visits. If the 
treatment/follow period of the study is shorter than the expected end date, less follow-up 
phone calls will be needed. 
Every attempt will be made to talk to each patient within this time frame. 
The following information will be collected from the patient: 
 
Possible efficacy endpoints related to CV events. Patients will be asked to return to 
the Research Site to assess for any endpoints or events identified. 
 
Adverse events 
 
Concomitant medications 
 
Current address and contact information (update if changed or will be changing) 
Patients will be reminded about the following items: 
 
To take the study medication according to the dosing schedule assigned, with food 
 
When to return to the Research Center for the next visit 
 
To bring the unused study medication to the next visit 
 
To not take study drug on the morning of their next visit 
 
To fast for at least 10 hours prior to the next visit 
6.3. 
Laboratory Procedures 
6.3.1. 
Clinical Laboratory Procedures 
All clinical laboratory determinations for screening and safety will be performed by a 
certified clinical laboratory under the supervision of the Sponsor or its designee. 
Whenever possible and appropriate, samples for the clinical laboratory procedures will be 
collected after fasting for at least 10 hours. For the purposes of this study, fasting is defined 
as nothing by mouth except water (and any essential medications). 
The investigator must review and sign all laboratory test reports. At screening, patients who 
have laboratory values that are outside the exclusionary limits specified in the exclusion 
criteria may not be enrolled in the study (patients can be considered for the study if values 
are classified as not clinically significant by the investigator). After randomization, the 
investigator will be notified if laboratory values are outside of their normal range. In this 
case, the investigator will be required to conduct clinically appropriate follow-up procedures. 
6.3.1.1. 
Safety Laboratory Tests 
The safety laboratory tests include: 
 
Hematology with complete blood count (CBC), including RBC, hemoglobin (Hgb), 
hematocrit (Hct), white cell blood count (WBC), white cell differential, and platelet 
count 
 
Biochemistry panel including total protein, albumin, alkaline phosphatase, alanine 
aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), total 


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bilirubin, glucose, calcium, electrolytes (sodium, potassium, chloride), blood urea 
nitrogen (BUN), serum creatinine, uric acid, creatine kinase, and HbA1c. 
6.3.1.2. 
Fasting Lipid Profile 
The fasting lipid panel includes: TG, TC, LDL-C, HDL-C, non-HDL-C, and VLDL-C.  
At all visits, LDL-C will be calculated using the Friedewald equation. At Visit 1 and Visit 
1.1 Direct LDL-C will be used if at the same visit TG >400 mg/dL (4.52 mmol/L). These 
LDL-C values will be used for the evaluation of the LDL-C inclusion criterion (LDL-C 
qualifying measurements for randomization) and for the assessment of changes in the statin 
therapy when LDL-C is not at goal. At all remaining visits (except Visit 2 and Visit 4) LDL-
C will be measured by Direct LDL Cholesterol or by Preparative Ultracentrifugation if at the 
same visit TG >400 mg/dL (4.52 mmol/L). In addition, irrespective of the TG levels, at Visit 
2 (0 Months of Follow-up, baseline) and at Visit 4 (12 Months of Follow-up), LDL-C will be 
measured by Preparative Ultracentrifugation. These Preparative Ultracentrifugation LDL-C 
measurements will be used in the statistical analysis including the calculation of the percent 
change from baseline (1 year versus baseline). 
6.3.1.3. 
Genetic testing 
A fasting blood sample will be stored for future genetic testing at the discretion of the 
sponsor. The specifics of this test will be determined at a later date. This sample is optional 
as local regulations may prohibit genetic samples to be collected or shipped outside the 
country, or patients may not consent. 
Research on genetic testing will look for links between genes and certain diseases, including 
their treatment(s) such as medicines and medical care.  The blood samples will be collected 
in the study center with the regular protocol-required labs. Each patient tube with sample for 
genetic testing will be labeled with patient number only.  The site will maintain a Subject 
Code Identification List for cross-reference.  The patient number does not contain any 
identifiable information (i.e. Patient initials, date of birth, etc). Un-analyzed samples will be 
stored frozen by the sponsor for a period of up to 2 years following the end of the study, at 
which time they will be destroyed. If samples are tested, results will not be reported to the 
patient, parents, relatives, or attending physician and will not be recorded in the patient’s 
medical records. There will be no follow-up contact with the sites or patients regarding this 
sample. The subject can withdraw their consent for genetic testing at any time up to analysis, 
even after the sample has been obtained.  The subject can notify the site in writing that they 
withdraw their consent for the genetic testing portion of the study, and it will be documented 
by the site in the subject chart, as well as captured in the CRF.  The lab will be notified to 
pull the sample and destroy it.  
6.3.1.4. 
Biomarkers Assays 
The biomarker assays include: hs-CRP, Apo B and hsTnT. 
6.3.1.5. 
Additional laboratory tests 
Additional laboratory tests include: 
 
A urine pregnancy test will be administered to women of childbearing potential at 
certain visits as listed in schedule of procedures (Appendix A). The urine pregnancy 


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tests will be performed at the Research Site utilizing marketed test kits, or at a 
certified clinical laboratory. 
 
A fasting blood sample (12 mL) for archiving. This sample will be collected only at 
sites in countries where allowed by local regulations and at sites for which approved 
by the IRB or IEC. The plasma from the archiving sample will be stored frozen in 2 
separate equal aliquots, and will be used at the Sponsor’s discretion to perform 
repeat analyses described in the protocol or to perform other tests related to 
cardiovascular health. 
6.3.1.6. 
Blinding of Laboratory Results 
All efficacy laboratory results during the double-blind period of the trial will be blinded 
(values not provided) to patients, investigators, pharmacists and other supporting staff at the 
Research Sites, personnel and designees of the Sponsor, study administrators and personnel 
at the organization(s) and vendors managing and/or supporting the study, with the exception 
of the laboratory personnel conducting the assays. To ensure patient safety, hsTnT values 
will be reported to the site. 
6.3.1.7. 
Flagging of Critical Lab Values 
Critical lab values are values that may warrant medical intervention to avoid possible harm to 
a patient. Critical lab values will be defined in the Laboratory Manual for the study, and the 
Research Site will be notified of the occurrence of a critical lab value (critical high or critical 
low) by a special annotation (flag) in the laboratory reports provided to the Research Sites. 
Although laboratory values that are part of the efficacy endpoints during the double-blind 
period of the study will not be provided to the Research Site (see Section 6.3.1.6), the sites 
will be notified when the TG value of a patient sample is >1000 mg/dL (11.29 mmol/L) 
(critical high TG value) or if the LDL-C values of a patient sample is >130 mg/dL (3.37 
mmol/L) (critical high LDL-C value). These critical high values will need to be confirmed by 
a repeat measurement (new fasting blood sample) within 7 days. TG value of >2000 mg/dL 
(22.58 mmol/L) will also be flagged, so that appropriate medical action can be taken by the 
investigator as soon as possible. 
If TG values are confirmed critically high, patients may be discontinued from study drug 
with the option to remain on study (see Section 11.1 ODIS). The investigator should use the 
best clinical judgment for each patient which could include the use of approved TG-lowering 
medications after patients have been discontinued from study drug. 
If LDL-C values are confirmed critically high, the investigator may need to take appropriate 
medical action which could include: reinforce/intensify therapeutic lifestyle changes 
(including diet and physical activity), increase the dose of the present statin therapy, add 
ezetimibe, or prescribe a more potent statin to lower LDL-C. The investigator should use the 
best clinical judgment for each patient. 
6.3.2. 
Medical Procedures 
6.3.2.1. 
Medical, Surgical and Family History 
Medical history, including family history and details regarding all illnesses and allergies, 
date(s) of onset, status of current condition, and smoking and alcohol use will be collected on 
all patients. 


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6.3.2.2. 
Demographics 
Demographic information including day, month, and year of birth, race, and gender will be 
collected for all patients. 
6.3.2.3. 
Vital Signs 
Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature. Blood pressure will be measured using a standardized process: 
 
Patient should sit for 5 minutes with feet flat on the floor and measurement arm 
supported so that the midpoint of the manometer cuff is at heart level. 
 
Use a mercury sphygmomanometer or automatic blood pressure device with an 
appropriately sized cuff with the bladder centered over the brachial artery. 
Blood pressure should be recorded to the nearest 2 mmHg mark on the manometer or to the 
nearest whole number on an automatic device. A blood pressure reading should be repeated 1 
to 2 minutes later, and the second reading should also be recorded to the nearest 2 mmHg 
mark. 
6.3.2.4. 
Physical Examination 
A physical examination must include source documentation of general appearance, skin, and 
specific head and neck, heart, lung, abdomen, extremities, and neuromuscular assessments.  
6.3.2.5. 
Height, Weight and Body Mass Index 
Height and weight will be measured. Measurement of weight should be performed with the 
patient dressed in indoor clothing, with shoes removed, and bladder empty.  
6.3.2.6. 
Waist Circumference 
Waist circumference will be measured with a tape measure, as follows: Start at the top of the 
hip bone then bring the tape measure all the way around – level with the navel. Make sure the 
tape measure is snug, but without compressing the skin, and that it is parallel with the floor.  
Patients should not hold their breath while measuring waist circumference. 
6.3.2.7. 
Electrocardiogram (ECG) 
ECGs (standard 12-lead) will be obtained annually. Site personnel should make every 
attempt to perform a patient’s ECG using the same equipment at each visit. ECGs will be 
reviewed by the site for the detection of silent MI. Silent MIs will be sent for event 
adjudication.  
7. 
TREATMENT AND RESTRICTIONS 
7.1. 
Treatment 
7.1.1. 
Treatment Regimen, Dosage, and Duration 
Eligible study patients will be randomly assigned on Day 0 to one of the 2 treatment groups. 
Patients in each group will receive either 4 g/day AMR101 or placebo for up to 4.75 years 
(4 years planned median treatment duration) according to Table 2. 


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The daily dose of study drug is 4 capsules per day taken as two capsules taken on two 
occasions per day (2 capsules given twice daily). 
Table 2. 
Dosing Schedule during the Treatment Period 
 
 
 
 
 
Patients will be instructed to take study drug with food (i.e., with or at the end of their 
morning and evening meals). On days that patients are scheduled for study visits, the daily 
dose of study drug will be administered by site personnel with food provided by the site 
following collection of all fasting blood samples. For the purposes of this study, fasting is 
defined as nothing by mouth except water (and any essential medications) for at least 10 
hours. 
7.1.2. 
Treatment Assignment 
7.1.2.1. 
Identification number 
A unique patient identification number (patient number) will be established for each patient 
at each site. The patient number will be used to identify the patient throughout the study and 
will be entered on all documentation. If a patient is not eligible to receive treatment, or if a 
patient discontinues from the study, the patient number cannot be reassigned to another 
patient. The patient number will be used to assign patients to one of the 2 treatment groups 
according to the randomization schedule. 
7.1.2.2. 
Drug Randomization 
Only qualified patients who meet all of the inclusion criteria and none of the exclusion 
criteria will be randomized and will receive study medication starting at Visit 2 (Day 0). 
Eligible patients will be randomly assigned to one of the 2 treatment groups. Randomization 
will be stratified by CV risk category, use of ezetimibe and by geographical region 
(Westernized, Eastern European, and Asia Pacific countries) (See Section 3.10). 
Approximately 70% of randomized patients will be in the CV Risk Category 1, including 
patients with established CVD, and approximately 30% of randomized patients will be in the 
CV Risk Category 2, including patients with diabetes and at least one additional risk factor 
but no established CVD. Enrollment with patients of a CV risk category will be stopped 
when the planned number of patients in that risk category is reached. 
7.1.2.3. 
Emergency Unblinding 
In an emergency, when knowledge of the patient’s treatment assignment is essential for the 
clinical management or welfare of the patient, the investigator may request the patient’s 
treatment assignment for unblinding. Prior to unblinding the patient’s individual treatment 
assignment, the investigator should assess the relationship of an adverse event to the 
administration of the study drug (Yes or No). If the blind is broken for any reason, the 
investigator must record the date and reason for breaking the blind on the appropriate Case 
Report Form (CRF) and source documents. 
Treatment 
Group 
Daily Dose 
Number of Capsules per Day 
1 
4 g 
4 capsules of 1000 mg AMR101 
2 
Placebo 
4 capsules of matching placebo 


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7.1.3. 
Compliance Control 
It is recommended that, unless clear contraindications arise, patients be strongly encouraged 
to adhere to their treatment regimen with the study drug for the duration of the trial. Any 
interruptions of therapy should, if possible, be brief (e.g., <4 weeks) and only for clinically 
indicated reasons, such as adverse events. Discontinuations will be discouraged as much as 
possible. Any discontinuations should be based on compelling clinical reasons. 
For every patient, an assessment of compliance to the study drug treatment regimen must be 
obtained at each scheduled visit. Study medication will be dispensed in amounts exceeding 
the amount required for the study. Patients will be instructed to return all unused study 
medication at the next visit. Compliance to the study drug regimen will be evaluated at each 
visit by counting unused capsules. Discrepancies will be evaluated and discussed with each 
patient to assess compliance. If compliance is unsatisfactory, the patient will be counseled 
about the importance of compliance to the dosing regimen. At the end of the study, the final 
study medication compliance will be determined by unused capsule count (see Section 
12.2.2). 
7.2. 
Study Restrictions 
7.2.1. 
Concomitant Medications during Treatment/Follow-Up Period 
Any medications administered during the study period must be documented on the 
Concomitant Medication CRF. Patients must not have taken any investigational agent within 
90 days prior to screening. Patients cannot participate in any other investigational medication 
trial while participating in this study.  
The following non-study drug related, non-statin, lipid-altering medications and supplements, 
and foods are prohibited during the study (from Visit 1 until after the Last Visit-End of 
Study), except for compelling medical reasons in ODIS patients (see description of ODIS in 
section 11.1): 
 
niacin >200 mg/day; 
 
fibrates; 
 
prescription omega-3 fatty acid medications; 
 
dietary supplements containing omega-3 fatty acids (e.g., flaxseed, fish, krill, or 
algal oils); 
 
bile acid sequestrants; 
 
cyclophosphamide; 
 
systemic retinoids 
If any of these products would be used during the treatment/follow-up period of the study, it 
should be for compelling medical reasons in ODIS patients, and it should be documented in 
the Concomitant Medication CRF. If the ODIS patient agrees to restart study medication, the 
use of excluded medication must be discontinued. 
Foods enriched with omega-3 fatty acids are strongly discouraged after Visit 1 for the 
duration of the study (does not apply to The Netherlands or Canada only. Therefore, all 
centers in The Netherlands and Canada must ignore this request).  


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The following products are allowed: statins, ezetimibe, and herbal products & dietary 
supplements not containing omega-3 fatty acids. 
Statins: 
 
The same statin at the same dose should be continued until the end of the study, 
unless deemed medically necessary to change because of an adverse event or lack of 
efficacy (LOE).  It is preferred that if LOE is the determining factor that ezetimibe 
be added to the present dose. 
 
Switching between a brand name statin and the generic version of the same statin is 
allowed at any time during the study. 
 
 Statins may be administered with or without ezetimibe. 
 
Based on the FDA recommendation, simvastatin 80 mg be used only in patients who 
have been taking this dose for 12 months or more and have not experienced any 
muscle toxicity. (See reference:  FDA Drug Safety Communication: Ongoing safety 
review of high-dose Zocor (simvastatin) and increased risk of muscle injury. 
(http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatient
sandProviders/ucm204882.htm)  
 
Changing of the type of statin or the statin dose during the treatment/follow-up 
period of the study should only be done for compelling medical reasons and must be 
documented in the CRF. 
LDL-C Rescue: 
 If the level of LDL-C exceeds 130 mg/dL (3.37 mmol/L) during the study (initial 
measurement and confirmed by a second determination at least 1 week later), the 
investigator may either increase the dose of the present statin therapy or may add 
ezetimibe to lower LDL-C. The investigator should use the best clinical judgment for 
each patient.  
No data are available with regard to potential interactions between ethyl-EPA and oral 
contraceptives. There are no reports suggesting that omega-3 fatty acids, including ethyl-
EPA, would decrease the efficacy of oral contraceptives. 
7.2.2. 
Patient Restrictions 
Beginning at the screening visit, all patients should be instructed to refrain from excessive 
alcohol consumption, to follow a physician recommended diet and to maintain it through the 
duration of the study. Excessive alcohol consumption is on average 2 units of alcohol per 
day or drinking 5 units or more for men or 4 units or more for women in any one hour 
(episodic excessive drinking or binge drinking). A unit of alcohol is defined as a 12-ounce 
(350 mL) beer, 5-ounce (150 mL) wine, or 1.5-ounce (45 mL) of 80‐proof alcohol for drinks. 
8. 
INVESTIGATIONAL PRODUCT 
8.1. 
Clinical Trial Material 
The following will be supplied by the Sponsor: 
 AMR101 1000 mg capsules 


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 Placebo capsules 
The Sponsor will supply sufficient quantities of AMR101 1000 mg capsules and placebo 
capsules to allow for completion of the study. The lot numbers of the drugs supplied will be 
recorded in the final study report. 
Records will be maintained indicating the receipt and dispensation of all drug supplies. At 
the conclusion of the study, any unused study drug will be destroyed. 
8.2. 
Pharmaceutical Formulations 
AMR101 1000 mg and placebo capsules are provided in liquid-filled, oblong, gelatin 
capsules. Each capsule is filled with a clear liquid (colorless to pale yellow in color). The 
capsules are approximately 25.5 mm in length with a diameter of approximately 9.5 mm.  
Table 3 summarizes the components of each capsule. 
Table 3. 
Components of AMR101 Capsules 
Component 
AMR101 
1000 mg capsules
Quantity 
(mg/capsule) 
Placebo 
capsules 
Quantity 
(mg/capsule) Function 
Capsule fill 
 
 
 
 
Icosapent ethyl 
998 
- 
Active 
 
Paraffin, light liquid 
- 
932 
 
 
All-rac-α-tocopherol 
2 
1.86 
Antioxidant 
Capsule shell 
 
 
 
 
Gelatin 
279 
279 
Capsule shell material
 
Sorbitol, liquid 
 
(non-crystallizing) 
78 
78 
Plasticizer 
 
Glycerol 
44 
44 
Plasticizer 
 
Purified water 
37 
37 
Solvent 
 
Maltitol, liquid 
28 
28 
Plasticizer 
 
8.3. 
Labeling and Packaging 
Study medication will be packaged in high-density polyethylene bottles. Labeling and 
packaging will be performed according to GMP guidelines and all applicable country-
specific requirements. The bottles will be numbered for each patient based on the 
randomization schedule. The patient randomization number assigned by IWR or a designee 
of the Sponsor for the study (if no IWR system is used), will correspond to the number on the 
bottles. The bottle number for each patient will be recorded in the Electronic Data Capture 
(EDC) system for the study. 
8.4. 
Dispensing Procedures and Storage Conditions 
8.4.1. 
Dispensing Procedures 
At Visit 2 (Day 0), patients will be assigned study drug according to their treatment group 
determined by the randomization schedule. Once assigned to a treatment group, patients will 
receive study drug supplies. At each visit, patients will bring unused drug supplies dispensed 


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to them earlier. From the drug supplies assigned to each patient, site personnel will 
administer drug while the patients are at the Research Site. 
The investigator or designee must contact the IWR system or a designee of the Sponsor for 
the study (if no IWR system is used) when any unscheduled replacements of study 
medication are needed. 
During the last visit during the treatment period, patients will bring the unused drug supplies 
for site personnel to calculate the final study medication compliance by unused capsule count 
(see Section 12.2.2). 
8.4.2. 
Storage Conditions 
At the Research Sites, study drugs must be stored at room temperature, 68°F to 77°F (20°C 
to 25°C). Do not allow storage temperature to go below 59°F (15°C) or above 86°F (30°C). 
Store in the original package. 
Study drugs must be stored in a pharmacy or locked and secure storage facility, accessible 
only to those individuals authorized by the investigator to dispense the drug. The investigator 
or designee will keep accurate dispensing records. At the conclusion of the study, study site 
personnel will account for all used and unused study drug. Any unused study drug will be 
destroyed. The investigator agrees not to distribute study drug to any patient, except those 
patients participating in the study. 
9. 
EFFICACY ASSESSMENTS 
9.1. 
Specification of Variables and Procedures 
The primary endpoint and the majority of the secondary and tertiary endpoints are based on 
clinical events related to CVD and mortality. All events occurring between randomization 
and the study end date (inclusive) must be recorded. Only adjudicated events will be included 
in the final analyses. Further details on the assessment of clinical events and their definitions 
will be found in the CEC charter. Important definitions are listed in Appendix B of this 
protocol. 
9.2. 
Efficacy Endpoints 
9.2.1. 
Primary Efficacy Endpoint 
Time from randomization to the first occurrence of the composite of the following clinical 
events: 
 CV death, 
 Nonfatal MI (including silent MI; ECGs will be performed annually for the detection 
of silent MIs), 
 Nonfatal stroke, 
 Coronary revascularization  
 Hospitalization for unstable angina determined to be caused by myocardial ischemia 
by invasive/non-invasive testing. 
The first occurrence of any of these major adverse vascular events during the follow-up 
period of the study will be included in the incidence. 


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9.2.2. 
Secondary Efficacy Endpoints 
The key secondary efficacy endpoint is: 
 The composite of death from CV causes, nonfatal MI, coronary revascularization, 
unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization, nonfatal stroke, or peripheral 
CVD requiring intervention, angioplasty, bypass surgery, or aneurysm repair. 
Other secondary efficacy endpoints are as follows (to be tested in said order): 
 The composite of total mortality, nonfatal MI, or nonfatal stroke; 
 The composite of death from CV causes, nonfatal MI, coronary revascularization, 
unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization, peripheral CVD requiring 
intervention, or cardiac arrhythmia requiring hospitalization; 
 The composite of death from CV causes, nonfatal MI, coronary revascularization, or 
unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization; 
 The composite of death from CV causes or nonfatal MI; 
 Total mortality; 
 Fatal and nonfatal MI (including silent MI); 
 Coronary Revascularization;  
 Hospitalization for unstable angina determined to be caused by myocardial ischemia 
by invasive/non-invasive testing ; 
 Fatal and nonfatal stroke. 
For the secondary endpoints that count a single event, the first occurrence of this type of 
event will be counted in each patient. For secondary endpoints that are composites of two or 
more types of events, the first occurrence of any of the event types included in the composite 
will be counted in each patient. 
9.2.3. 
Tertiary Efficacy Endpoints: 
 The second, third, fourth, and fifth major CV event of the primary composite 
endpoint. The type of (nonfatal) events may occur in any order. 
 Primary endpoint in subset of patients with diabetes mellitus; 
 Primary endpoint in subset of patients with metabolic syndrome; 
 New CHF, new CHF leading to hospitalization, transient ischemic attack, amputation 
for CVD and carotid revascularization; 
 Elective coronary revascularization and emergent coronary revascularization; 
 New onset diabetes; 
 Fasting TG, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apo B, hs-CRP, and hsTnT: 
effect of baseline and on-treatment change of biomarkers on primary and key 
secondary endpoints; 


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 CV mortality; 
 Cardiac Arrhythmias requiring hospitalization; 
 Cardiac Arrest; 
 To explore the effect of AMR101 on weight and waist circumference. 
For the tertiary endpoints that count a single event, the first occurrence of this type of event 
will be counted in each patient. For tertiary endpoints that are composites of two or more 
types of events, the first occurrence of any of the event types included in the composite will 
be counted in each patient (except when stated otherwise, for the second, third, fourth, and 
fifth major CV event). 
10. 
SAFETY ASSESSMENTS 
10.1. 
Specification of Variables and Procedures 
Safety assessments will include adverse events, clinical laboratory measurements (chemistry, 
hematology), 12-lead ECGs, vital signs (systolic and diastolic blood pressure, heart rate, 
respiratory rate, and body temperature), and physical examinations as per Study 
Procedures/Appendix A. 
A complete medical, surgical and family history will be completed at Visit 1. 
A list of the analytes to be measured for the safety evaluation is found in Section 6.3.1.1. All 
laboratory test results must be evaluated by the investigator as to their clinical significance. 
Any observations at physical examinations or laboratory values considered by the 
investigator to be clinically significant should be considered an adverse event. 
10.2. 
Adverse Events 
An adverse event is defined as any untoward medical occurrence, which does not necessarily 
have a causal relationship with the medication under investigation. An adverse event can 
therefore be any unfavorable and/or unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an investigational 
medication product, whether or not related to the investigational medication product. All 
adverse events, including observed or volunteered problems, complaints, or symptoms, are to 
be recorded on the appropriate CRF. Each adverse event is to be evaluated for duration, 
intensity, and causal relationship with the study medication or other factors. 
Adverse events, which include clinical laboratory test variables, will be monitored from the 
time of informed consent until study participation is complete. Patients should be instructed 
to report any adverse event that they experience to the investigator. Beginning with Visit 2, 
investigators should assess for adverse events at each visit and record the event on the 
appropriate adverse event CRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the investigator and recorded on the CRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the investigator, it should be recorded as a separate adverse event on the CRF. 
Any medical condition that is present when a patient is screened or present at baseline that 
does not deteriorate should not be reported as an adverse event. However, medical conditions 


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or signs or symptoms present at baseline and that change in severity or seriousness at any 
time during the study should be reported as an adverse event. 
Clinically significant abnormal laboratory findings or other abnormal assessments that are 
detected during the study or are present at baseline and significantly worsen will be reported 
as adverse events or SAEs. The investigator will exercise his or her medical and scientific 
judgment in deciding whether an abnormal laboratory finding or other abnormal assessment 
is clinically significant. 
The investigator will rate the severity (intensity) of each adverse event as mild, moderate, or 
severe, and will also categorize each adverse event as to its potential relationship to study 
drug using the categories of Yes or No. 
Severity: 
 Mild – An event that is usually transient in nature and generally not interfering with 
normal activities. 
 Moderate – An event that is sufficiently discomforting to interfere with normal 
activities. 
 Severe – An event that is incapacitating with inability to work or do usual activity or 
inability to work or perform normal daily activity. 
Causality Assessment: 
The relationship of an adverse event to the administration of the study drug is to be assessed 
according to the following definitions: 
 No (unrelated, not related, no relation) – The time course between the administration 
of study drug and the occurrence or worsening of the adverse event rules out a causal 
relationship and another cause (concomitant drugs, therapies, complications, etc.) is 
suspected. 
 Yes – The time course between the administration of study drug and the occurrence 
or worsening of the adverse event is consistent with a causal relationship and no other 
cause (concomitant drugs, therapies, complications, etc.) can be identified. 
The following factors should also be considered: 
 The temporal sequence from study medication administration 
 The event should occur after the study medication is given. The length of time from 
study medication exposure to event should be evaluated in the clinical context of the 
event. 
 Underlying, concomitant, intercurrent diseases 
 Each report should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have. 
 Concomitant medication 
 The other medications the patient is taking or the treatment the patient receives 
should be examined to determine whether any of them might be recognized to cause 
the event in question. 
 Known response pattern for this class of study medication 
 Clinical and/or preclinical data may indicate whether a particular response is likely to 
be a class effect. 


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 Exposure to physical and/or mental stresses 
 The exposure to stress might induce adverse changes in the patient and provide a 
logical and better explanation for the event. 
 The pharmacology and pharmacokinetics of the study medication 
 The known pharmacologic properties (absorption, distribution, metabolism, and 
excretion) of the study medication should be considered. 
Unexpected Adverse Events – An unexpected adverse event is an adverse event either not 
previously reported or where the nature, seriousness, severity, or outcome is not consistent 
with the current Investigator’s Brochure. 
10.2.1. 
Serious Adverse Events 
A serious adverse event (SAE) is defined as an adverse event that meets any of the following 
criteria: 
 Results in death 
 Is life-threatening- Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the patient was at risk of death at the time of the event. It 
does not refer to an event, which hypothetically might have caused death, if it were 
more severe. 
 Requires hospitalization or prolongation of existing hospitalization- Note: In general, 
hospitalization for treatment of a pre-existing condition(s) that did not worsen from 
baseline is not considered adverse events and should not be reported as SAEs. 
 Results in disability/incapacity 
 Is a congenital anomaly/birth defect; 
 Is an important medical event- Note: Important medical events that may not result in 
death, be life threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalizations, or the development of drug dependency. 
By design of this study SAEs that are endpoint events will only be recorded for the endpoint 
determination and not captured as SAEs. The intention is that the endpoint events are not 
reported to IRBs as SAEs, unless the IRB requires that these are reported. Investigators 
should specifically inform their institution/IRB of this plan and confirm whether or not they 
want the endpoint events reported. By agreement with the US FDA, these endpoints will also 
not be reported to the US FDA as SAEs; rather they will be reported as endpoint events. 
Following adjudication if the event is determined to not meet the criteria for an event, the 
event will be evaluated as an SAE beginning with that day as Day 0. 
10.3. 
Serious Adverse Event Reporting – Procedure for Investigators 
10.3.1. 
Initial Reports 
All SAEs occurring from the time of informed consent until 28 days following the last 
administration of study medication must be reported to the Sponsor or designee within 24 
hours of the knowledge of the occurrence (this refers to any adverse event that meets any of 


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the aforementioned serious criteria). SAEs that the investigator considers related to study 
medication occurring after the 28-day follow-up period will also be reported to the Sponsor 
or designee.  
The investigator is required to submit SAE reports to the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) in accordance with local requirements. All 
investigators involved in studies using the same investigational medicinal product (IMP) will 
receive any Suspected Unexpected Serious Adverse Reaction (SUSAR) reports for onward 
submission to their local IRB as required. All reports sent to investigators will be blinded. 
In addition, regulatory agencies will be notified of SAEs per the requirements of the specific 
regulatory jurisdiction regulations and laws. 
10.3.2. 
Follow-Up Reports 
The investigator must continue to follow the patient until the SAE has subsided, or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
patient dies. Within 24 hours of receipt of follow-up information, the investigator must 
update the SAE form electronically in the EDC system for the study and submit any 
supporting documentation (e.g., laboratory test reports, patient discharge summary, or 
autopsy reports) to the Sponsor or designee via fax or email. 
10.3.3. 
Reporting by the Sponsor 
IRBs and IECs will be informed of SUSARs according to local requirements. Cases will be 
unblinded for reporting purposes as required. 
10.4. 
Exposure In Utero During Clinical Trials 
If a patient becomes pregnant during the study, the investigator should report the pregnancy 
to the Sponsor or designee within 24 hours of being notified. The Sponsor or designee will 
then forward the Exposure In Utero form to the investigator for completion. 
The patient should be followed by the investigator until completion of the pregnancy. If the 
pregnancy ends for any reason before the anticipated date, the investigator should notify the 
Sponsor or designee. At the completion of the pregnancy, the investigator will document the 
outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, 
neonatal death, or congenital anomaly), the investigator should follow the procedures for 
reporting an SAE. 
11. 
TREATMENT DISCONTINUATION/PATIENT WITHDRAWAL 
Patients may withdraw from the study at any time and for any reason. Study drug 
administration may also be discontinued at any time, at the discretion of the investigator. In 
any case, follow-up for efficacy and safety should be continued. 
11.1. 
Reasons for Early Study Drug Discontinuation 
Study drug discontinuation should be avoided as much as possible, but may be done for any 
of the following reasons: 


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 Patient withdraws consent or requests early discontinuation from the study for any 
reason. Patients should be encouraged to continue to participate in the study for the 
entire duration of the study even if they choose not to take study medication any 
longer. 
 Occurrence of a clinical or laboratory adverse event, either serious or non-serious, at 
the discretion of the investigator. The Sponsor or designee should be notified if a 
patient is discontinued because of an adverse event or laboratory abnormality. It is 
recommended that, unless clear contraindications arise, patients be strongly 
encouraged to adhere to their treatment regimen with the study drug for the duration 
of the trial. Any interruptions of therapy should, if possible, be brief (e.g., <4 weeks) 
and only for clinically indicated reasons, such as adverse events. The following 
should be considered reason for discontinuation: 
o ALT > 3x ULN and bilirubin > 1.5x ULN 
o ALT >5x ULN 
o ALT >3x ULN and appearance or worsening of hepatitis 
o ALT > 3x ULN persisting for >4weeks 
o ALT > 3x ULN and cannot be monitored weekly for 4 weeks 
 Any medical condition or personal circumstance that, in the opinion of the 
investigator, exposes the patient to risk by continuing in the study or precludes 
adherence to the protocol. 
 Sponsor discontinues the study. 
 A TG value that is flagged as critically high, i.e., >1000 mg/dL (11.29 mmol/L), and 
confirmed as critically high by a repeat measurement (new fasting blood sample) 
within 7 days. In this case, a patient may be discontinued from study drug (with the 
option to remain ODIS) and other lipid-altering medications may be (re)initiated. If 
the TG value is flagged as >2000 mg/dL (22.58 mmol/L) then appropriate medical 
action can be taken by the investigator as soon as possible. 
Occurrence of an outcome event according to the judgment of the investigator is not 
considered a valid reason for study drug discontinuation. 
Patients whose treatment with study medication is discontinued early, and have not 
withdrawn consent, will stay in study and will be monitored until the end of the study. 
Patients that continue in the study after indefinite cessation of therapy will be characterized 
as Off Drug In Study (ODIS). ODIS patients should be asked to return to the study site for an 
interim visit once the patient has been off study drug for >30 days. Procedures at this visit are 
consistent with those at Visit 5. If not contraindicated, patients will also have the option to 
restart study medication at any point once characterized as ODIS.  
The reason for study drug discontinuation or interruption will be recorded on the CRF. 
11.2. 
Follow-Up after Early Study Drug Discontinuation/Lost to Follow-Up 
 Patients who prematurely discontinue study drug are not to be replaced. 
 All randomized patients must be followed up according to the study flowchart until 
the study end date or death, regardless of whether they discontinue study drug 
prematurely or not. Any event occurring after early study drug discontinuation will be 
recorded up through the study end date. 


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 In order to follow the medical status of the patients, especially when they 
discontinued the study, investigators are encouraged to obtain information from the 
patient’s primary care practitioner (physician or any other medical care provider). 
Investigators are also requested to try as much as possible to re-contact those patients 
at the end of the trial to obtain at least their vital status as well as their status with 
respect to the primary endpoint, and thus avoid lost to follow-up for the efficacy 
assessment. 
 If patients are lost to follow-up, the CRF must be completed up to the last visit or 
contact.  
12. 
STATISTICS 
12.1. 
Analysis Populations 
12.1.1. 
Randomized Population 
The randomized population will include all patients who sign the informed consent form and 
are assigned a randomization number at Visit 2 (Day 0). 
12.1.2. 
Intent-to-Treat Population  
The Intent-to-Treat (ITT) population will consist of all randomized patients who take at least 
one dose of study drug. The ITT population is the primary analysis population. All efficacy 
analyses will be performed on the ITT population. 
12.1.3. 
Per-Protocol Population 
The per-protocol (PP) population will include all ITT patients without any major protocol 
deviations, and who had ≥80% compliance with study drug while on treatment (up to 
discontinuation for patients whose treatment is terminated early). The per-protocol efficacy 
analysis for CV events will be restricted to each patient’s time on study drug plus 30 days 
thereafter. 
12.1.4. 
Safety Population 
All safety analyses will be conducted based on the safety population, which is defined as all 
randomized patients who receive at least one dose of study drug. This is the same as the ITT 
population. 
12.2. 
Statistical Methods 
Safety and efficacy variables will be analyzed using appropriate statistical methods to be 
described in detail in a separate Statistical Analysis Plan (SAP). The SAP will be finalized 
before study unblinding. 
12.2.1. 
Patient Disposition and Demographic/Baseline Characteristics 
The numbers of patients screened, the number of patients randomized per treatment group 
(randomized population), and the number of patients in the ITT and PP populations by 
treatment group will be listed. 
For randomized patients who discontinued treatment with study drug, the primary reason for 
discontinuation will be listed and summarized by treatment group. 


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Summary statistics (mean, standard deviation, median, minimum and maximum) will be 
provided by treatment group for demographic characteristics (e.g., age, sex, race, and 
ethnicity) and baseline characteristics (e.g., body weight, height, and body mass index) in the 
ITT and PP populations. 
Demographic data and baseline characteristics will be compared among treatment groups for 
the ITT and PP population. Differences in demographic and baseline characteristics will be 
tested using a chi-square test (for categorical variables) or a 1-way analysis of variance 
model with treatment as a factor (for continuous variables). The p-values will be used as 
descriptive statistics, primarily as an assessment of the adequacy of randomization. 
12.2.2. 
Study Medication Exposure and Compliance 
The final compliance to study drug will be calculated as the percent of doses taken relative to 
doses scheduled to be taken. Overall percent compliance will be calculated per patient in the 
ITT and PP populations and summarized by treatment group using summary statistics (n, 
mean, standard deviation, median, minimum, and maximum). 
12.2.3. 
Concomitant Therapies 
Concomitant medication/therapy verbatim terms will be coded using the latest version of the 
World Health Organization Drug Dictionary. The numbers and percentages of patients in 
each treatment group taking concomitant medications will be summarized by anatomic and 
therapeutic chemical classification and preferred term. 
12.2.4. 
Analysis of Efficacy 
For efficacy endpoints including CV events, only adjudicated events will be included in the 
final statistical analyses. 
12.2.4.1. 
Summary Statistics 
Summary statistics (n, mean, standard deviation, median, minimum, and maximum) for the 
baseline and post-baseline measurements, the percent changes, or changes from baseline will 
be presented by treatment group and by visit for all efficacy variables to be analyzed. The 
summary statistics will include changes in body weight and body mass index from baseline 
by treatment group and by visit. 
12.2.4.2. 
Primary Endpoint 
The primary efficacy endpoint is the time from randomization to the first occurrence of any 
component of the composite of the following clinical events: 
 CV death, 
 Nonfatal MI (including silent MI), 
 Nonfatal stroke, 
 Coronary revascularization,  
 Hospitalization for unstable angina determined to be caused by myocardial ischemia 
by invasive/non-invasive testing. 
The analysis of the primary efficacy endpoint will be performed using the log-rank test 
comparing the 2 treatment groups (AMR101 and placebo) and including the stratification 
factor “CV risk category”, use of ezetimibe and geographical region (Westernized, Eastern 
European, and Asia Pacific countries) (each as recorded in the IWR at the time of 


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enrollment) as covariates. Treatment difference will be tested at alpha level of 0.0476 
accounting for one interim efficacy analysis. The hazard ratio for treatment group (AMR101 
vs. placebo) from a Cox proportional hazard model that includes the stratification factor will 
also be reported, along with the associated 95% confidence interval. Kaplan-Meier estimates 
from randomization to the time to the primary efficacy endpoint will be plotted.  
The size and direction of the treatment effects of the individual components of the composite 
endpoint and their relative contribution to the composite endpoint will be determined as well. 
12.2.4.3. 
Secondary Endpoints 
The statistical analyses of the secondary endpoints will be analyzed by the same log-rank test 
specified above for the primary efficacy endpoint. Treatment differences will be tested at 
alpha level of 0.05 using a sequential procedure for controlling type 1 error starting with the 
key secondary variable.  The remaining secondary variables will be tested in the order 
specified in Section 9.2.2. Estimates of the hazard ratios from the Cox proportional hazard 
model and the associated 95% confidence intervals will also be provided. Kaplan-Meier 
estimates from randomization the time to the secondary efficacy endpoints will be plotted. 
12.2.4.4. 
Tertiary Endpoints 
For event rates, the statistical analyses of the tertiary endpoints (see section 9.2.3) will be 
similar to the analysis of the secondary efficacy endpoints. All tertiary analyses will be 
conducted for the ITT population. No adjustments for multiple testing will be made. 
For measurements of lipids, lipoproteins and inflammatory markers the change from baseline 
will be analyzed in the units of each marker, and the percent change from baseline. Since 
these biomarkers are typically not normally distributed, the Wilcoxon rank-sum test will be 
used for treatment comparisons of the percent change from baseline, and medians and 
quartiles will be provided for each treatment group. The medians of the differences between 
the treatment groups and 95% confidence intervals will be estimated with the Hodges-
Lehmann method. 
New onset diabetes is defined as Type 2 diabetes newly diagnosed during the 
treatment/follow-up period (i.e. patients with no history of diabetes at randomization, with 
the test as listed in Appendix C). 
12.2.4.5. 
Exploratory Subgroup Analyses  
Subgroup analyses of the primary and key secondary endpoints (as defined in the Statistical 
Analysis Plan) will be performed. All subgroup analyses will be conducted for the ITT 
population. No adjustments for multiple testing will be made.  
Log-rank tests, treatment effects and the associated 95% confidence intervals for the primary 
and key secondary efficacy endpoints within each subgroup will be provided using the Cox 
proportional hazard model with treatment (AMR101 or placebo), and stratification as a factor 
(with the exception of the subgroup analyses of those subgroup variables related to the 
stratification factors, i.e., CV risk category that will not have stratification as a factor). 
Subgroups including, but not limited to the following, will be explored.  A complete list will 
be prospectively defined in the Statistical Analysis Plan. 
 


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Demographics: 
 Gender, 
 age (<65 yr and ≥65 yr), 
 race (white and nonwhite, or any other subset with at least 10% of the total number of 
patients), 
 geography (western vs. non-western) 
 
Disease Parameters: 
 CV risk category, 
 the presence/absence of diabetes at baseline, 
 renal impairment 
 
Treatment Parameters: 
 by statin intensity (statin type and regimen), 
 relevant concomitant medications, 
 
Baseline Lipid and Lipoprotein Parameters: 
 LDL-C (by tertile), 
 HDL-C (by tertile), 
 TG (by tertile), 
 TG ≥150 mg/dL, 
 TG ≥200 mg/dL and TG <200 mg/dL, 
 combined highest tertile for TG and lowest tertile for HDL-C, 
 hs-CRP (≤3 mg/L and >3 mg/L), 
 Apo B (by tertile), 
 non-HDL-C (by tertile) 
The consistency of the treatment effects in subgroups will be assessed for the primary and 
key secondary efficacy endpoints. For each subgroup variable, a Cox proportional hazard 
model with terms for treatment, stratification factors (with the exception of those subgroup 
variables related to the stratification factors, i.e., CV risk category), subgroup, and treatment-
by-subgroup interaction will be performed. The main treatment effect will not be tested with 
this model. P-values for testing the interaction terms will be provided. 
12.2.4.6. 
Interim Efficacy Analysis 
One interim analysis will be performed for the primary efficacy endpoint using best available 
data (adjudicated events and site reported endpoints) based on data when approximately 60% 
of the total number of primary endpoint events is reached. The interim analysis will be based 
on a group sequential design that includes early stopping rules for benefit while preserving 
the overall Type I error rate (O’Brien-Fleming). This allows for interim analysis and 
preserves the overall Type I error probability of α=0.05 for the primary endpoint. 
Approximately 1612 primary efficacy endpoint events are planned to be observed during the 
trial, based on sample size calculation assumptions. Therefore, the interim analysis will occur 
after at least 967 primary efficacy endpoint events have been observed. According to this 


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boundary, the critical p-value at the interim analysis has to be p<=0.0076, resulting in the 
final evaluation p-value of 0.0476.  
The interim results of the study will be monitored by an independent DMC. The analyses will 
be performed by the independent statistical group unblinded to the treatment assignment. The 
results will be reported only to the DMC. The unblinded information will not be released to 
sponsor under any circumstance before the completion of the study. Specific statistical 
guidelines for data monitoring will be discussed and formalized in a separate Interim 
Statistical Analysis Plan and DMC Charter. 
12.2.5. 
Analysis of Safety 
All analyses of safety will be conducted on the safety population, which is defined as all 
randomized patients who receive at least one dose of study drug. The safety assessment will 
be based on the frequency of adverse events, physical exams, vital signs and safety 
laboratory tests. 
Adverse events with new onset during the study between the initiation of study drug and 
30 days after the last dose of study drug for each patient will be considered treatment-
emergent (TEAEs). This will include any AE with onset prior to initiation of study drug and 
increased severity after the treatment initiation. 
Treatment-emergent adverse events will be summarized by system organ class and preferred 
term, and by treatment. This will include overall incidence rates (regardless of severity and 
relationship to study drug), and incidence rates for moderate or severe adverse events. A 
summary of SAEs and adverse events leading to early discontinuation from the study will be 
presented through data listings. 
Safety laboratory tests and vital signs will be summarized by post-treatment change from 
baseline for each of the parameters using descriptive statistics by treatment group. Those 
patients with significant laboratory abnormalities will be identified in data listings. 
Additional safety parameters will be summarized in data listings. 
12.3. 
Sample Size Determination 
Sample size estimation is based on the assumption that the primary composite endpoint (time 
from randomization to the first occurrence of CV death, non-fatal MI, non-fatal stroke, 
coronary revascularization, or unstable angina requiring hospitalization) would be relatively 
reduced by 15%, from an event rate by 4 years of 23.6% in the placebo group to 20.5% in the 
AMR101 group. It is expected that a minimum of 1612 primary efficacy endpoint events will 
be required during the study. A total of approximately 6990 patients are needed to be able to 
detect this difference at 4.76% significance level (because of the interim analysis described in 
Section 12.2.4.6) and with 90% power, assuming an 18-month enrollment period and a 
median follow-up of 4 years. The current sample size calculation is based on an estimated 
placebo yearly event rate of 5.9% (23.6% over 4 years). To protect against the possibility that 
the actual placebo event rate is lower than estimated, an extra 1000 patients will be enrolled 
(approximately 7990 patients in total). By adding the extra 1000 patients, the event rate in the 
placebo group could be 5.2% per year (20.8% over 4 years) without having to modify the 
other sample size assumptions. 
 


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Since this is an events-driven trial, the ‘sample size’ is the number of events rather than the 
number of patients. The number of events that occur depends primarily on three factors: how 
many patients are enrolled, the combined group event rate, and how long the patients are 
followed. Because of the difficulty in predicting the combined event rate, the sponsor will 
monitor that event rate as the trial progresses. If the combined event rate is less than 
anticipated, either increasing the number of patients, extending the length of follow-up, or a 
balance of adjusting both factors may be necessary to achieve the sample size of 1612 events. 
Before completing the enrollment phase of the trial, i.e. approximately 3- to 6-months prior 
to the projected enrollment of the 7990th patient, the actual event rate based on pooled, 
blinded accumulation of primary efficacy endpoint events will be calculated and plotted.  If 
those analyses suggest the number of patients with at least 1 adjudicated, primary event (and 
appropriately accounting for patients with potential primary events for which the 
adjudication process is then incomplete) is consistent with projections, then the study could 
continue toward the protocol-specified target enrollment of 7990 patients.  However, if the 
number of such events appears less than, and inconsistent with projections, the Sponsor will 
consider (under blinded conditions) re-calculating the number of patients needed to achieve 
the target number of events within the desired timeline or extend the follow-up period.  If the 
projected increase in number of patients is ≤ 25% of the original 7990 target population, the 
Sponsor may, with documented approval of both the REDUCE-IT Steering Committee and 
the Data Monitoring Committee, extend enrollment to the revised target number without 
need for an additional protocol amendment.   Under those conditions, all principal 
investigators, ethics committees, and regulatory authorities associated with the protocol will 
be promptly notified of the action. Should the projected increase in number of patients be 
more than 25% above the original 7990 target (i.e. more than 1998 additional patients) a 
formal protocol amendment will be initiated. 
If the number of patients to be studied is increased, the enrollment phase will be extended to 
allow enrollment of the additional patients. 
At completion of study enrollment, the actual number of patients randomized may vary from 
the target number (either original or revised) as a result of the inherent lag between the date 
the last patient started screening and the date the last patient was randomized.  
13. 
MONITORING, DATA MANAGEMENT, AND RECORD KEEPING 
13.1. 
Data Management 
13.1.1. 
Data Handling 
Data will be recorded at the site on CRFs. All entries on a CRF are ultimately the 
responsibility of the Investigator, who is expected to review each form for completeness and 
accuracy before signing. A CRF must be completed for each randomized patient. The CRFs 
and source documents must be made available to the Sponsor and/or its designee. 
13.2. 
Record Keeping 
The Investigator must maintain all documents and records, originals or certified copies of 
original records, relating to the conduct of this trial, and necessary for the evaluation and 
reconstruction of the clinical trial. This documentation includes, but is not limited to 
protocol, CRFs, AE reports, patient source data (including records of patients, patient visit 


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Amendment #1 16 May 2013 
Page 71 of 110 
logs, clinical observations and findings), correspondence with health authorities and IRB, 
consent forms, inventory of study product, Investigator’s curriculum vitae, monitor visit logs, 
laboratory reference ranges and laboratory certification or quality control procedures, and 
laboratory director curriculum vitae. 
The Investigator and affiliated institution should maintain the trial documents as required by 
the applicable regulations. The Investigator and affiliated institution should take measures to 
prevent accidental or premature destruction of documents. Clinical trial documents must be 
kept in the clinical site’s archives indefinitely, unless written authorization is obtained from 
the Sponsor. 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator and research institution agree that the Sponsor, their representatives and 
designees, the IRB or IEC, and representatives from worldwide regulatory agencies will have 
the right, both during and after the clinical trial, to review and inspect pertinent medical 
records related to the clinical trial. 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor and/or its designee(s) will perform quality control and quality assurance checks 
of all clinical trials that it sponsors. Before the enrollment of any patient in this study, the 
Sponsor or its designee will review with the investigator and site personnel the following 
documents: protocol, Investigator’s Brochure, CRFs and procedures for their completion, the 
informed consent process, and the procedure for reporting SAEs. Site visits will be 
performed by the Sponsor and/or its designees. During these visits, information recorded on 
the CRFs will be verified against source documents and requests for clarification or 
correction may be made. After the CRF data is entered by the site, the Sponsor or designee 
will review for safety information, completeness, accuracy, and logical consistency. 
Computer programs that identify data inconsistencies may be used to help monitor the 
clinical trial. If necessary, requests for clarification or correction will be sent to investigators. 
By signing the protocol, the Sponsor agrees directly or through its designee(s) to be 
responsible for implementing and maintaining quality control and quality assurance systems 
with written standard operating procedures to ensure that trials are conducted and data are 
generated, documented, and reported in compliance with the protocol, accepted standards of 
Good Clinical Practice (GCP), International Conference on Harmonization (ICH) and other 
applicable regulations. 
16. 
ETHICS AND GOOD CLINICAL PRACTICE COMPLIANCE 
Good Clinical Practice is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting trials that involve human patients. 
Compliance with this standard provides public assurance that the rights, safety, and well 
being of trial patients are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki, and that the clinical trial data are credible. In this study, 
 
 


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Amendment #1 16 May 2013 
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 the 2008 version of the Declaration of Helsinki will be adhered to. It can be found on the 
website of The World Medical Association: 
http://www.wma.net/en/30publications/10policies/b3/17c.pdf 
17. 
INFORMED CONSENT 
Prior to participation in a study, the participant, or participant’s legal representative/impartial 
witness must sign an IRB/IEC-approved written informed consent form (ICF). The approved 
written informed consent must abide to all applicable laws in regards to the safety and 
confidentiality of the patients. To obtain and document informed consent, the Investigator 
should comply with applicable regulations; adhere to GCP standards and the ethical 
principles in the Declaration of Helsinki (see Section 16). 
The language in the oral and written information about the trial, including the written 
informed consent form should be as non-technical as practical and should be understandable 
to the participant or participant’s legal representative/impartial witness, where applicable. 
Before informed consent is obtained, the Investigator should provide the participant, or 
participant’s legal representative/impartial witness ample time and opportunity to inquire 
about the trial and to decide whether or not to participate. 
All questions about the trial should be answered to the satisfaction of the participant, or the 
participant’s legal representative/impartial witness. The written ICF should be signed and 
personally dated by the participant or participant’s legal representative/impartial witness, and 
by the person who conducted the informed consent discussion. Participants will be informed 
that participation is voluntary and that he/she can withdraw from the study at any time. A 
signed copy of the consent form must be given to the participant, and this fact will be 
documented in the CRF. 
Of special concern regarding informed consent is the collection of blood samples for genetic 
analysis. Local regulations may not allow the collection of blood samples for genetic testing 
or the shipment of blood samples for genetic testing outside the region. In these cases, blood 
samples for genetic testing will not be collected, and the portion of the ICF describing the 
genetic component of the study will not be included. If blood samples for genetic testing will 
be collected, the ICF will clearly indicate that a sample will be drawn for this purpose, but 
that the participant has the right to refuse this procedure. 
18. 
PUBLICATION POLICY  
The Steering Committee (SC) is responsible for the reporting and publication of the study 
results. The Sponsor will be provided a reasonable opportunity to review such manuscripts 
prior to journal submission. The results of the study will be published irrespective of whether 
the endpoints are met, or whether the results are regarded positive or negative. 
 
Confidentiality, publication, and patent applications related to unpublished study-related 
information and unpublished information given to the site investigators by the Sponsor 
and/or its designee(s) shall be handled as set forth in the Clinical Trial Agreement. 


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Amendment #1 16 May 2013 
Page 73 of 110 
19. 
FINANCING AND INSURANCE 
19.1. 
Finances 
Prior to starting the study, the Principal Investigator and/or institution will sign a Clinical 
Trial Agreement with the Sponsor and/or its designee(s). This agreement will include the 
financial information agreed upon by the parties. 
19.2. 
Insurance Compensation 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical 
trials under its sponsorship. This insurance policy is in accordance with local laws and 
requirements. The insurance of the Sponsor does not relieve the investigator and the other 
collaborators from maintaining their own liability insurance policy. An insurance certificate 
will be provided to the IRB/IEC and Competent Authority according to country specific 
regulatory requirements. 
20. 
COMPLETION OF STUDY 
The end of the study will be at the time of the last patient-last visit of the follow-up period of 
the study. The IRB and IEC will be notified about the end of the study according to country-
specific regulatory requirements. 
21. 
STUDY ADMINISTRATIVE INFORMATION 
21.1. 
Protocol Amendments 
Any amendments to the study protocol considered to be a substantial amendment will be 
communicated to the investigator by the Sponsor or its designee. All substantial protocol 
amendments will undergo the same review and approval process as the original protocol and 
may be implemented after it has been approved by the IRB/IEC and Competent Authority, 
unless immediate implementation of the change is necessary for patient safety. In this case, 
the situation must be documented and reported to the IRB/IEC and Competent Authority 
according to all relevant country-specific regulatory requirements. 
A protocol amendment is considered to be a substantial amendment if it is likely to affect the 
safety, physical, or mental integrity of patients in the study; the scientific value of the study; 
the conduct or management of the study; or the quality or safety of any IMP used in the 
study. 
Any other minor changes to the protocol not considered to be substantial amendments will 
not need prior approval of the IRB/IEC and Competent Authority and will be communicated 
to the investigator by the Sponsor or its designee. 
 


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22. 
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Antman E, Anbe D, Amstrong P, et al. ACC/AHA guidelines for the management of patients 
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Baigent C, Keech A, Kearney PM, et al., Cholesterol Treatment Trialists’ (CTT) 
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Serum Eicosapentaenoic Acid(EPA) to Arachidonic Acid(AA) With Major Adverse 
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Harris WS. International recommendations for consumption of longchain omega-3 fatty acids. 
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phospholipid from 2053 human blood samples with key fatty acid ratios. Nutr J 8:58, 
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23. 
INVESTIGATOR’S AGREEMENT 
This document is a confidential communication of Amarin. The authorized investigators 
agree to personally conduct or supervise the conduct of this investigational study in 
compliance with the current protocol, good clinical practices, and all applicable laws, 
regulations, and guidelines. No changes will be made to the protocol without prior 
notification to Amarin, except to protect the safety, rights, and welfare of the study patients, 
and always in compliance with all applicable laws, regulations, and guidelines. Acceptance 
of this document constitutes the agreement by the Investigator that no unpublished 
information contained herein or related to the study will be published or disclosed without 
prior written approval from Amarin. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly. 
 
 
 
 
_____________________________  
____________________ 
Signature 
 
 
 
 
Date 
Principal Investigator 
 
 
_____________________________ 
Printed Name 
 


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APPENDIX A: SCHEDULE OF PROCEDURES 
 
Screening 
Follow-Up (FU) 13 
Study Day 
Up to 42  days 
before Day 0 
If a Visit 1.1 
takes place, 
Visit 1 may 
occur up to 60 
days before 
Day 02 
0 
 
120 
± 10 
360 
± 10 
720 
± 10 
1080 
± 10 
1440 
± 10 
1800 
+ 30 
Months of FU 
 
 
0 
4 
12 
24 
36 
48 
60 
Years of FU 
 
 
0 
0.33 
1 
2 
3 
4 
5 
Visit # 
1 
1.1 
2 
3 
4 
5 
6 
7 
LV 14 
Study Procedures: 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical, Surgical & 
Family History 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Evaluate inclusion / 
exclusion criteria 
X 1 
X 3 
X 
 
 
 
 
 
 
Physical Examination 
 
 
X 
X 
X 
X 
X 
X 
X 
Weight, Height 4 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Waist Circumference 
 
 
X 
 
 
X 
 
 
X 
12-Lead ECG 
X 
 
X 
 
X 
X 
X 
X 
X 
Urine pregnancy test 6 
X 
 
X 
 
 
 
 
 
 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
Dosing 
at the Research Site 7 
 
 
X 
X 
X 
X 
X 
X 
 
Efficacy events 
 
 
 
X 
X 
X 
X 
X 
X 
AE Evaluations 
 
 
X 
X 
X 
X 
X 
X 
X 
Compliance Check 8 
 
 
 
X 
X 
X 
X 
X 
X 
Chemistry and 
hematology 9 
X 
X 3 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid profile 10 
X 
X 3 
X 
X 
X 
X 
X 
X 
X 
Genetic testing 11 
 
 
X 
 
 
 
 
 
 
Biomarkers: hs-CRP,  apo 
B, hsTNT 
 
 
X 
 
 
X 
 
 
X 
Fasting blood sample 
for archiving 12 
 
 
X 
 
X 
X 
X 
X 
X 


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1. Includes procedures and (fasting) blood samples (for example, hs-CRP, calculated creatinine clearance) as needed to determine the CV risk category (see 
inclusion criteria). 
2. Screening visit to re-evaluate inclusion/exclusion criteria for patients who are not eligible for participation based on data from Visit 1. 
3. Inclusion/exclusion criteria will be re-evaluated for selected study procedures that are performed on Visit 1.1 because patients failed to meet them at Visit 1. 
4. Height at first screening visit only. 
5. Vital signs, including systolic and diastolic blood pressure (mmHg), heart rate, respiratory rate and body temperature. Participants must be seated for at least 
5 minutes before assessments of vital signs. 
6. For women of childbearing potential. 
7. The patients will fast of at least 10 hours before arriving at the Research Site, when all fasting blood samples will be obtained. After blood samples are 
obtained, patients will be given drug with food. 
8. Review study drug compliance by unused capsule count, discuss with and counsel patients about compliance if needed; final study compliance at last visit. 
9. Safety Laboratories — Complete Blood Count: Includes RBC, Hgb, Hct, WBC and differential, and platelet count. Biochemistry includes total protein, 
albumin, alkaline phosphatase, ALT, AST, total bilirubin, glucose, calcium, electrolytes (sodium, potassium, chloride), blood urea nitrogen (BUN), serum 
creatinine, uric acid, creatine kinase, HbA1c. Safety labs may be repeated as deemed necessary by the Investigator. 
10. TG, TC, HDL-C, LDL-C, non-HDL-C, and VLDL-C. 
11. Fasting blood sample that will be stored for future genetic testing at the discretion of the sponsor. This sample is optional as local regulations may prohibit 
genetic samples to be collected or shipped outside the country, or patients may not consent. 
12. Used at the sponsor’s discretion to perform repeat analyses described in the protocol or to perform other tests related to cardiovascular health. 
13. Site personnel will contact each patient by telephone in-between Visit 2 and Visit 3 and between Visit 3 and Visit 4. After Visit 4 contact will be made every 
3 months. The purpose of the contact is to collect information about efficacy events, adverse events, concomitant medications, confirm patient’s current 
address and contact information and remind patients about taking their study medication and logistics for the next visit. 
14. The last visit (LV) may occur within 30 day after the study end date as determined by the DMC; the study end date is tentatively schedule for Day 1800 but 
the actual date as determined by the DMC may be different.


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APPENDIX B: STANDARDIZED DEFINITIONS FOR END POINT 
EVENTS IN CARDIOVASCULAR TRIALS 
 
References: 
http://www.cdisc.org/stuff/contentmgr/files/0/2356ae38ac190ab8ca4ae0b222392b37/misc/cdisc_
november_16__2010.pdf 
 
Karen A. Hicks, H. M. James Hung, Kenneth W. Mahaffey, Roxana Mehran, Steven E. 
Nissen, Norman L. Stockbridge, Shari L. Targum, Robert Temple; on behalf of the 
Standardized Data Collection for Cardiovascular Trials Initiative.  Standardized Definitions 
for End Point Events in Cardiovascular Trials, May 31, 2011. 
 
23.1. 
Definition of Cardiovascular Death 
Cardiovascular death includes death resulting from an acute myocardial infarction, sudden 
cardiac death, death due to congestive heart failure (CHF), death due to stroke, death due to 
cardiovascular (CV) procedures, death due to CV hemorrhage, and death due to other 
cardiovascular causes. 
 
Classifying CV mortality more specifically (MI, sudden death etc.) is usually not needed for 
outcome trials.  In general, such classification is difficult because the classifications refer 
both to underlying cause (e.g., acute MI) and to mode of death (sudden/arrhythmic, 
progression of CHF).  The following definitions can, however, be used if desired. 
 
1. Death due to Acute Myocardial Infarction refers to a death by any mechanism 
(arrhythmia, CHF) within 30 days after a MI related to the immediate consequences of 
the MI, such as progressive CHF or recalcitrant arrhythmia.   
 
Mortal events that occur after a “break” (e.g., a CHF and arrhythmia-free period of at 
least a week) should be classified as CV or non-CV death, and if classified as a CV death, 
should be attributed to the immediate cause, even though the MI may have increased the 
risk of that event (e.g., the risk of arrhythmic death is increased for many months after an 
acute MI).   
 


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Acute MI should be verified to the extent possible by the diagnostic criteria outlined for 
acute MI (see Chapter 4, Universal Definition of MI) 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 a death due to a CV procedure. 
 
2. Sudden Cardiac Death refers to a death that occurs unexpectedly, not following an 
acute acute MI, and includes the following deaths: 
a. Death witnessed and instantaneous without new or worsening symptoms 
b. Death witnessed within 60 minutes of the onset of new or worsening cardiac 
symptoms, unless the symptoms suggest an 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 non-cardiac etiology 
f. Unwitnessed death without other cause of death (information regarding the 
patient’s clinical status preceding death should be provided, if available) 
 
General Considerations 
A subject seen alive and clinically stable 12-24 hours prior to being found dead 
 without any evidence or information of a specific cause of death should be 
 classified as “sudden cardiac death.” 
 


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Deaths for which there is no information beyond “Patient found dead at home” may 
be classified as “death due to other cardiovascular causes” or in some trials, 
“undetermined cause of death.” Please see Definition of Undetermined Cause of 
Death, for full details. 
 
3. Death due to Congestive Heart Failure refers to a death in association with clinically 
worsening symptoms and/or signs of heart failure (see Definition of Heart Failure Event).  
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 (see Definition of Transient 
Ischemic Attack and 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 (see Definition of Transient Ischemic Attack and 
Stroke), 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 (e.g., pulmonary embolism or peripheral arterial disease). 
23.2. 
Definition of Non-Cardiovascular Death 
 
Non-cardiovascular death is defined as any death that is not thought to be due to a 
cardiovascular cause. Detailed recommendations on the classification of non-cardiovascular 
causes of death are beyond the scope of this document. The level of detail required and the 
optimal classification will depend on the nature of the study population and the anticipated 


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number and type of non-cardiovascular deaths. Any specific anticipated safety concern 
should be included as a separate cause of death. The following is a suggested list of non-
cardiovascular* causes of death: 
 
 Pulmonary 
 Renal 
 Gastrointestinal 
 Hepatobiliary 
 Pancreatic 
 Infection (includes sepsis) 
 Non-infectious (e.g., systemic inflammatory response syndrome (SIRS)) 
 Hemorrhage that is neither cardiovascular bleeding nor a stroke  
 Accidental (e.g., physical accidents or drug overdoses) or trauma  
 Suicide 
 Prescription Drug Error (e.g., prescribed drug overdose, use of inappropriate drug, or 
drug-drug interaction) 
 Neurological process that is not a stroke or hemorrhage 
 Other non-CV 
 Malignancy 
Malignancy should be coded as the cause of death if: 
o 
Death results directly from the cancer; or 
o 
Death results from a concurrent illness that could be a consequence of a cancer or 
o 
Death results from withdrawal of other therapies because of concerns relating to the poor 
prognosis associated with the cancer 
o 
Death results from an illness that is not a consequence of a cancer 
Cancer deaths may arise from cancers that were present prior to randomization or which 
developed subsequently. It may be helpful to distinguish these two scenarios (i.e. worsening of 
prior malignancy; new malignancy). 
 Suggested categorization includes common organ systems, hematologic, or unknown. 
 


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23.3. 
Definition of Undetermined Cause of Death 
 
Undetermined Cause of Death refers to a death not attributable to one of the above 
categories of cardiovascular death or to a non-cardiovascular 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 in well-run clinical trials. 
A common analytic approach for cause of death analyses is to assume that all undetermined 
cases are included in the cardiovascular category (e.g., presumed cardiovascular death, 
specifically “death due to other cardiovascular causes”). Nevertheless, the appropriate 
classification and analysis of undetermined causes of death depends on the population, the 
intervention under investigation, and the disease process. The approach should be 
prespecified and described in the protocol and other trial documentation such as the end point 
adjudication procedures and/or the statistical analysis plan. 
 
23.4. 
Definition of Myocardial Infarction 
1. General Considerations 
The term myocardial infarction (MI) should be used when there is evidence of 
myocardial necrosis in a clinical setting consistent with myocardial ischemia. 
In general, the diagnosis of MI requires the combination of: 
 Evidence of myocardial necrosis (either changes in cardiac 
biomarkers or postmortem pathological findings); and 
 Supporting information derived from the clinical presentation, 
electrocardiographic changes, or the results of myocardial or 
coronary artery imaging 
The totality of the clinical, electrocardiographic, and cardiac biomarker 
information should be considered to determine whether or not a MI has 
occurred. Specifically, timing and trends in cardiac biomarkers and 
electrocardiographic information require careful analysis. The adjudication of 
MI should also take into account the clinical setting in which the event occurs.  


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MI may be adjudicated for an event that has characteristics of a MI but which 
does not meet the strict definition because biomarker or electrocardiographic 
results are not available. 
2. Criteria for Myocardial Infarction 
a. Clinical Presentation 
The clinical presentation should be consistent with diagnosis of myocardial 
ischemia and infarction. Other findings that might support the diagnosis of MI 
should be take into account because a number of conditions are associated 
with elevations in cardiac biomarkers (e.g., trauma, surgery, pacing, ablation, 
congestive heart failure, hypertrophic cardiomyopathy, pulmonary embolism, 
severe pulmonary hypertension, stroke or subarachnoid hemorrhage, 
infiltrative and inflammatory disorders of cardiac muscle, drug toxicity, burns, 
critical illness, extreme exertion, and chronic kidney disease). Supporting 
information can also be considered from myocardial imaging and coronary 
imaging. The totality of the data may help differentiate acute MI from the 
background disease process. 
b. Biomarker Elevation 
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. CK-MB and troponin are preferred, 
but CK may be used in the absence of CK-MB and troponin. 
 
For MI subtypes, different biomarker elevations for CK, CK-MB, or troponin 
will be required. The specific criteria will be referenced to the URL. 


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In many studies, particularly those in which patients present acutely to 
hospitals which are not participating sites, it is not practical to stipulate the use 
of a single biomarker or assay, and the locally available results are to be used 
as the basis for adjudication. However, if possible, using the same cardiac 
biomarker assay and preferably, a core laboratory, for all measurements 
reduces inter-assay variability. 
 
Since the prognostic significance of different types of myocardial infarctions 
(e.g., periprocedural myocardial infarction versus spontaneous myocardial 
infarction) may be different, consider evaluating outcomes for these subsets of 
patients separately. 
 
c. Electrocardiogram (ECG) Changes 
Electrocardiographic changes can be used to support or confirm a MI. 
Supporting evidence may be ischemic changes and confirmatory information 
may be new Q waves. 
 
 Criteria for acute myocardial ischemia (in absence of left 
ventricular hypertrophy (LVH) and left bundle branch block 
(LBBB)): 
 
o ST elevation 
New ST elevation at the J point in two anatomically contiguous 
leads with the cut-off points: ≥ 0.2 mV in men (> 0.25 mV in 
men < 40 years) or ≥ 0.15 mV in women in leads V2-V3 and/or 
≥ 0.1 mV in other leads. 
o 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.  
The above ECG criteria illustrate patterns consistent with myocardial 
ischemia. In patients with abnormal biomarkers, it is recognized that lesser 


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ECG abnormalities may represent an ischemic response and may be accepted 
under the category of abnormal ECG findings. 
 
 Criteria for pathological Q-wave 
o Any Q-wave in leads V2-V3 ≥ 0.02 seconds or QS complex in 
leads V2 and V3 
o Q-wave ≥ 0.03 seconds and ≥ 0.1 mV deep or QS complex in 
leads I, II, aVL, aVF, or V4-V6 in any two leads of a 
contiguous lead grouping (I, aVL, V6; V4-V6; II, III, and aVF) 
o R-wave 0.04 s in V1–V2 and R/S ratio >1 with a concordant 
positive T-wave in the absence of a conduction defect 
 
The same criteria are used for supplemental leads V7-V9, and for the Cabrera 
frontal plane lead grouping. 
 
 Criteria for Prior Myocardial Infarction 
o Pathological Q-waves, as defined above 
o R-wave ≥ 0.04 seconds in V1-V2 and R/S ≥ 1 with a 
concordant positive Twave in the absence of a conduction 
defect 
 
3. Myocardial Infarction Subtypes 
Several MI subtypes are commonly reported in clinical investigations and each is 
defined below: 
a. Spontaneous MI 
i. Detection of rise and/or fall of cardiac biomarkers with at least one 
value above the URL with at least one of the following: 
 Clinical presentation consistent with ischemia 
 ECG evidence of acute myocardial ischemia 
 New pathological Q waves 


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 Imaging evidence of new loss of viable myocardium or new regional 
wall motion abnormality 
 Autopsy evidence of acute MI 
 
ii. If biomarkers are elevated from a prior infarction, then a spontaneous 
myocardial infarction is defined as: 
1. One of the following: 
 Clinical presentation consistent with ischemia 
 ECG evidence of acute myocardial ischemia 
 New pathological Q waves 
 Imaging evidence of new loss of viable myocardium or 
new regional wall motion abnormality 
 Autopsy evidence of acute MI 
AND 
2. Both of the following: 
 Evidence that cardiac biomarker values were decreasing 
(e.g., two samples 3-6 hours apart) prior to the 
suspected MI* 
 ≥ 20% increase (and > URL) in troponin or CK-MB 
between a measurement made at the time of the initial 
presentation and a further sample taken 3-6 hours later 
*If biomarkers are increasing or peak is not reached, 
then a definite diagnosis of recurrent MI is generally 
not possible. 
 
b. Percutaneous Coronary Intervention-Related Myocardial Infarction 
Peri-PCI MI is defined by any of the following criteria. Symptoms of cardiac 
ischemia are not required. 
 
i. Biomarker elevations within 48 hours of PCI: 


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 Troponin or CK-MB (preferred) > 3 x URL and 
 No evidence that cardiac biomarkers were elevated prior to the 
procedure; 
OR 
 Both of the following must be true: 
o ≥ 50%1 increase in the cardiac biomarker result 
o Evidence that cardiac biomarker values were decreasing 
(e.g., two samples 3-6 hours apart) prior to the 
suspected MI 
ii. New pathological Q waves 
iii. Autopsy evidence of acute MI 
 
c. Coronary Artery Bypass Grafting-Related Myocardial Infarction 
 
Peri-coronary artery bypass graft surgery (CABG) MI is defined by the 
following criteria. Symptoms of cardiac ischemia are not required. 
 
i. Biomarker elevations within 72 hours of CABG: 
 Troponin or CK-MB (preferred) > 5 x URL and 
 No evidence that cardiac biomarkers were elevated prior to the 
procedure; 
OR 
 Both of the following must be true: 
o ≥ 50%2 increase in the cardiac biomarker result 
o Evidence that cardiac biomarker values were decreasing 
(e.g., two samples 3-6 hours apart) prior to the 
suspected MI. 
AND 
ii. One of the following: 
 New pathological Q-waves persistent through 30 days 
 New persistent non-rate-related LBBB 


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 Angiographically documented new graft or native coronary 
artery occlusion Other complication in the operating room 
resulting in loss of myocardium 
 Imaging evidence of new loss of viable myocardium 
 
Data should be collected in such a way that analyses using ≥ 
20% or ≥ 50% could both be performed. 
OR 
iii. Autopsy evidence of acute MI 
 
d. Silent Myocardial Infarction 
Silent MI is defined by the following: 
i. No evidence of acute myocardial infarction 
AND 
ii. Any one of the following criteria: 
 New pathological Q-waves. A confirmatory ECG is 
recommended if there have been no clinical symptoms or 
history of myocardial infarction. 
 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 
 Autopsy evidence of a healed or healing MI 
(NOTE: In the case of evanescent Q waves, the last ECG will determine whether a 
silent infarction has occurred.) 
 
23.5. 
Common Classification Schemes for Myocardial Infarction Categories 
For some trials, categorization of MI end points may be helpful or necessary using one or 
more of the classification schemes below: 
1. By the Universal MI Definition: 
a. Clinical Classification of Different Types of Myocardial Infarction 
 Type 1 


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Spontaneous myocardial infarction related to ischemia due to a 
primary coronary event such as plaque erosion and/or rupture, 
fissuring, or dissection 
 
 Type 2 
Myocardial infarction secondary to ischemia due to either increased 
oxygen demand or decreased supply, e.g., coronary artery spasm, 
coronary embolism, anemia, arrhythmias, hypertension, or 
hypotension 
 
 Type 3 
Sudden unexpected cardiac death, including cardiac arrest, often with 
symptoms suggestive of myocardial ischemia, accompanied by 
presumably new ST elevation, or new LBBB, or evidence of fresh 
thrombus in a coronary artery by angiography and/or at autopsy, but 
death occurring before blood samples could be obtained, or at a time 
before the appearance of cardiac biomarkers in the blood 
 
 Type 4a 
Myocardial infarction associated with PCI 
 
 Type 4b 
Myocardial infarction associated with stent thrombosis as documented 
by angiography or at autopsy 
 
 Type 5 
Myocardial infarction associated with CABG 
 
b. Sample Clinical Trial Tabulation of Randomized Patients by Types of 
Myocardial Infarction 


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2. By Electrocardiographic Features: 
 ST-Elevation MI (STEMI) 
o Additional subcategories may include: 
 Q-wave 
 Non-Q-wave 
 Unknown (no ECG or ECG not interpretable) 
 Non-ST-Elevation MI (NSTEMI) 
o Additional subcategories may include: 
 Q-wave 
 Non-Q-wave 
 Unknown (no ECG or ECG not interpretable) 
 Unknown (no ECG or ECG not interpretable) 
*All events adjudicated as MI will be classified as STEMI, NSTEMI, 
or Unknown; however, it is acknowledged that a significant proportion 
of peri-procedural (PCI or CABG) events may have missing, 
inadequate or uninterpretable ECG documentation. 
3. By Biomarker Elevation (per Universal MI Definition): 
The magnitude of cardiac biomarker elevation can be calculated as a ratio of the peak 
biomarker value divided by the 99th percentile URL.   
 
The biomarker elevation can be provided for various MI subtypes, as shown in the 
example below. 
 


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*Biomarkers are not available for this type of myocardial infarction since the patients 
expired before biomarker determination could be performed. 
** For the sake of completeness, the total distribution of biomarker values should be 
reported. The hatched areas represent biomarker elevations below the decision limit 
used for these types of myocardial infarction. 
23.6. 
Definition of Hospitalization for Unstable Angina 
 
Unstable angina requiring hospitalization is defined as 
 
1. Ischemic discomfort (angina, or symptoms thought to be equivalent) ≥ 10 minutes in 
duration occurring 
 at rest, or 
 in an accelerating 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 date change if the time of 
admission/discharge is not available). 
 
AND 
3. At least one of the following: 
a. New or worsening ST or T wave changes on resting ECG (in the absence of 
confounders, such as LBBB or LVH) 
 Transient ST elevation (duration < 20 minutes) 
New ST elevation at the J point in two anatomically contiguous leads 
with the cut-off points:  ≥ 0.2 mV in men (> 0.25 mV in men < 40 


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years) or ≥ 0.15 mV in women in leads V2-V3 and/or ≥ 0.1 mV in 
other leads 
 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. 
 
b. Definite evidence of inducible myocardial ischemia as demonstrated by:  
 an early positive exercise stress test, defined as ST elevation or ≥ 2 mm ST 
depression prior to 5 mets  
OR  
 stress echocardiography (reversible wall motion abnormality) OR 
 myocardial scintigraphy (reversible perfusion defect), OR 
 MRI (myocardial perfusion deficit under pharmacologic stress). 
  
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 intravenous nitrates or 
increasing dosages of β-blockers, should be considered supportive 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 


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category 3, would be insufficient alone to support classification as hospitalization for 
unstable angina. 
2. If subjects are admitted with suspected unstable angina, and subsequent testing 
reveals a noncardiac 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. 
 
 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. 
 
23.7. 
Definition of Transient Ischemic Attack and Stroke 
 
Transient Ischemic Attack 
Transient ischemic attack (TIA) is defined as a transient episode (< 24 hours) of neurological 
dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. 
 
Stroke 
Stroke is defined as an acute episode of neurological dysfunction caused by focal or global 
brain, spinal cord, or retinal vascular injury.  
Classification: 
1. Ischemic Stroke 


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Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal 
dysfunction caused by an 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. 
2. Hemorrhagic Stroke 
Hemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal 
dysfunction caused by a nontraumatic intraparenchymal, intraventricular, or 
subarachnoid hemorrhage.   
NOTE: Microhemorrhages seen on T2-weighted MRI imaging, subdural and epidural 
hemorrhages are not considered hemorrhagic strokes. 
3. Undetermined Stroke 
Undetermined stroke is defined as an acute episode of focal or global neurological 
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 ischemic or hemorrhagic. 
 
 
Stroke Disability 
Stroke disability should be measured by a reliable and valid scale in all cases, typically at 
each visit and 90 days after the event. For example, the modified Rankin Scale may be used 
to address this requirement: 
 
 
Additional Considerations 
In trials involving patients with stroke, evidence of vascular central nervous system injury 
without recognized neurological dysfunction may be observed. Examples include 


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micro-hemorrhage, silent infarction, and silent hemorrhage. When encountered, the clinical 
relevance of these findings may be unclear. If appropriate for a given clinical trial, however, 
they should be precisely defined and categorized. 
 
Subdural hematomas are intracranial hemorrhagic events and not strokes. 
 
The distinction between a Transient Ischemic Attack and an Ischemic Stroke is the presence 
of Infarction.  Persistence of symptoms is an acceptable indicator of acute infarction.  Thus, 
duration of symptom persistence that will be used to distinguish between transient ischemia 
and acute infarction should be defined for any clinical trial in which it is used. 
 
23.8. 
Definition of Heart Failure Event 
 
A Heart Failure Event may consist of a hospitalization (a required component of this end 
point and defined below), as well as urgent outpatient visits (optional component). 
Depending on the trial, there may be interest in capturing all heart failure (HF) events; 
however, HF hospitalizations should remain delineated from urgent visits. If urgent visits are 
included in the HF event endpoint, the number of urgent visits needs to be explicitly 
presented separately from the hospitalizations.  
 
A Heart Failure Hospitalization is defined as an event that meets ALL 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) 


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b. Decreased exercise tolerance 
c. Fatigue 
d.  Other symptoms of worsened end-organ perfusion or volume overload (must 
be specified and described by the protocol) 
 
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 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 


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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 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. Significant 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) 
 
New Heart Failure/Heart Failure Not Requiring Hospitalization: 
 
An Urgent Heart Failure Visit is defined as an event that meets all of the following:  
 
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 must be met as defined in A Heart 
Failure Hospitalization above. 
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.  
 


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23.9. 
Interventional Cardiology Definitions 
A.  Clinical Definitions 
1. Clinically-Driven Target Lesion Revascularization:  Revascularization is 
clinically-driven if the target lesion diameter stenosis is > 50% by quantitative 
coronary angiography (QCA) and the subject has clinical or functional ischemia 
which cannot be explained by another native coronary or bypass graft lesion.  Clinical 
or functional ischemia includes any of the following: 
a. A history of angina pectoris, presumably related to the target vessel 
b. Objective signs of ischemia at rest (electrocardiographic changes) or during 
exercise test (or equivalent), presumably related to the target vessel 
c. Abnormal results of any invasive functional diagnostic test [e.g., coronary flow 
reserve (CFR) or fractional flow reserve (FFR)] 
Comment:  Target lesion revascularization of a > 70% diameter stenosis by QCA in 
the absence of the above signs or symptoms may be considered clinically-driven. 
Comment:  In the absence of QCA data or if a < 50% stenosis is present, TLR may be 
considered clinically-driven by the Clinical Events Committee (CEC) if severe 
ischemic signs and symptoms attributed to the target lesion are present. 
 
2. Non-Target Lesion and Non-Target Lesion Revascularization:  A lesion for which 
revascularization is not attempted or one in which revascularization is performed 
using a non-study device, respectively. 
 
3. Non-Target Vessel and Non-Target Vessel Revascularization:  A vessel for which 
revascularization is not attempted or one in which revascularization is performed 
using a non-study device, respectively. 
 
4. Percutaneous Coronary Intervention (PCI) Status: 
 
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.  


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b. Urgent:  The procedure should be performed on an inpatient basis and prior to 
discharge because of significant concerns that there is risk of myocardial 
ischemia, MI, and/or death. Patients who are outpatients or in the emergency 
department at the time that the cardiac catheterization is requested would warrant 
hospital admission based on their clinical presentation.     
                                                          
c. Emergency:  The procedure should be performed as soon as possible because of 
substantial concerns that ongoing myocardial ischemia and/or MI could lead to 
death.  "As soon as possible" refers to a patient who is of sufficient acuity that one 
would cancel a scheduled case to perform this procedure immediately in the next 
available room during business hours, or one would activate the on-call team were 
this to occur during off-hours. 
 
d. Salvage:  The procedure is a last resort. The patient is in cardiogenic shock when 
the PCI begins (i.e., the time at which the first guide wire or intracoronary device 
is introduced into a coronary artery or bypass graft for the purpose of mechanical 
revascularization) OR within the last ten minutes prior to the start of the case or 
during the diagnostic portion of the case, the patient has also received chest 
compressions or has been on unanticipated circulatory support (e.g., intra-aortic 
balloon pump, extracorporeal mechanical oxygenation, or cardiopulmonary 
support). 
 
5. Percutaneous Coronary Intervention (PCI):  Placement of an angioplasty guide 
wire, 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. 
 
6. Procedural Success:  Achievement of < 30 % residual diameter stenosis of the target 
lesion assessed by visual inspection or QCA and no in-hospital major adverse cardiac 
events (MACE, a composite of death, MI, or repeat coronary revascularization of the 


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target lesion).  Ideally, the assessment of the residual stenosis at the end of the 
procedure should be performed by an angiographic core laboratory. 
 
Comment:  For some device interventions (e.g., balloon angioplasty), achievement of  
< 50% diameter stenosis by visual inspection or QCA is an acceptable definition for 
procedural success. 
 
7. Target Lesion:  Any lesion treated or attempted to be treated during the PCI with the 
study device.  The target lesion includes the arterial segment treated with the study 
device (stent, in most cases) plus 5 mm proximal and 5 mm distal to the treatment 
site. 
 
8. Target Lesion Failure (TLF):  The composite of ischemia-driven revascularization 
of the target lesion, MI related to the target vessel, or cardiac death related to the 
target vessel.  If it cannot be determined with certainty whether the MI or death was 
related to the target vessel, it is considered a TLF. 
 
9. Target Lesion Revascularization (TLR):  Any repeat percutaneous intervention of 
the target lesion (including 5 mm proximal and 5 mm distal to the target lesion) or 
surgical bypass of the target vessel performed for restenosis or other complication 
involving the target lesion.  In the assessment of TLR, angiograms should be assessed 
by an angiographic core laboratory (if designated) and made available to the CEC for 
review upon request. 
 
10. Target Vessel:  A major native coronary artery (e.g., left main coronary artery, left 
anterior descending coronary artery, left circumflex coronary artery, or right coronary 
artery) or bypass graft containing the target lesion.  A native coronary artery target 
vessel includes the arterial segments upstream and downstream to the target lesion 
plus major side branches. 
 
11. Target Vessel Failure (TVF):  The composite of ischemia-driven revascularization 
of the target vessel, MI related to the target vessel, or cardiac death related to the 


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target vessel.  If it cannot be determined with certainty whether the MI or death was 
related to the target vessel, it is considered a TVF. 
 
12. Target Vessel, Non-Target Lesion, and Target Vessel, Non-Target Lesion 
Revascularization:  Any lesion or revascularization of a lesion in the target vessel 
other than the target lesion, respectively. 
 
13. Target Vessel Revascularization (TVR):  Any repeat percutaneous intervention or 
surgical bypass of any segment of the target vessel.  In the assessment of TVR, 
angiograms should be assessed by an angiographic core laboratory (if designated) and 
made available to the CEC for review upon request. 
 
14. Vascular Complications:  
 Access site hematoma 
 Arteriovenous fistula 
 Peripheral ischemia 
 Peripheral nerve injury 
 Pseudoaneurysm 
 Retroperitoneal hemorrhage 
 
23.10. 
Definition of Peripheral Vascular Intervention 
 
1. Peripheral Vascular Intervention (PVI):  Peripheral vascular intervention is a catheter-
based or open surgical procedure designed to improve peripheral arterial or venous blood 
flow or otherwise modify or revise vascular conduits.  Procedures may include, but are 
not limited to, balloon angioplasty, stent placement, thrombectomy, embolectomy, 
atherectomy, dissection repair, aneurysm exclusion, treatment of dialysis conduits, 
placement of various devices, intravascular thrombolysis or other pharmacotherapies, and 
open surgical bypass or revision.   
 
In general, the intention to perform percutaneous peripheral vascular intervention is 
denoted by the insertion of a guide wire into a peripheral artery or vein. 


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The target vessel(s) and the type of revascularization procedure (e.g., surgical bypass, 
thrombectomy, endarterectomy, percutaneous angioplasty, stent placement, 
thromboembolectomy, and thrombolysis) should be specified and recorded.  For the sake 
of simplicity, this definition applies to the extracranial carotid artery and other non-
cardiac arteries and veins and excludes the intracranial vessels and lymphatics. 
 
2. Procedural Success:  In the case of percutaneous intervention for obstructive lesions, 
procedural success is defined as the achievement of a satisfactory final residual diameter 
stenosis by angiography at the end of the procedure (and without flow limiting dissection 
or hemodynamically significant translesional pressure gradient).  The specific parameter 
for final percent residual stenosis is typically between < 30% and < 50%; selection of the 
appropriate percentage may vary depending upon the specific intervention applied, the 
vascular territory, and anticipated or desired therapeutic response.  Procedural success 
also implies absence of in-hospital major adverse events (e.g., death, stroke, myocardial 
infarction, acute onset of limb ischemia, need for urgent/emergent vascular surgery, and 
other procedure-specific major adverse events). The balloon inflation, stent placement, or 
other therapeutic intervention may be preceded by use of adjunctive devices (e.g., 
percutaneous mechanical thrombectomy, directional or rotational atherectomy, laser, and 
chronic total occlusion crossing device), as predefined in the protocol. 
 
3. Procedural Status:  Non-Elective and Elective:  
 
a. Non-Elective:  Non-elective procedures include emergent and urgent procedures. A 
non-elective procedure is a procedure that is performed without delay, because there 
is clinical consensus that the procedure should occur imminently.  Non-elective 
procedures imply a degree of instability of the patient, urgency of the medical 
condition, or instability of the threatening lesion.  
 
 Emergent:  A procedure that is performed immediately because of the acute 
nature of the medical condition (e.g., acute limb ischemia, acute aortic dissection), 
and the increased morbidity or mortality associated with a temporal delay in 
treatment. 


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 Urgent:  An urgent procedure is one that is not emergent but required to be 
performed on a timely basis (≤ 24 hrs) (e.g., a patient who has been stabilized 
following initial treatment of acute limb ischemia, and there is clinical consensus 
that a definitive procedure should occur within the next 24 hours). 
 
b. Elective: An elective procedure is one that is scheduled and is performed on a patient 
with stable disease, or in whom there is no urgency and/or increased morbidity or 
mortality associated with a planned procedure. 
 
1. Target Lesion: A target lesion is any lesion treated or attempted to be treated during 
the trial procedure with the index device. The target lesion is the treated segment 
starting 5 mm proximal and ending 5 mm distal to the index device (stent, in most 
cases). 
2. Target Vessel: A target vessel is any vessel (e.g., non-cardiac or non-cerebrovascular 
vessel) that contains the target lesion treated with the study device. The target vessel 
includes the target lesion as well as the entire vessel upstream and downstream to the 
target lesion, including side branches (native vessel). 
3. Non-Target Lesion: A non-target lesion is one for which revascularization is not 
attempted or one in which revascularization is performed using a non-study device. 
4. Non-Target Vessel: A non-target vessel is one for which revascularization is not 
attempted or one in which revascularization is performed using a non-study device. 
5. Target Vessel, Non-Target Lesion: Any lesion or revascularization of a lesion in the 
target vessel other than the target lesion. 
6. Target Lesion Revascularization (TLR): Target lesion revascularization is any 
repeat percutaneous intervention of the target lesions (including 5 mm proximal and 
distal to the index device) or surgical bypass of the target vessel performed for 
restenosis or other complication involving the target lesion. In the assessment of TLR, 
angiograms should be assessed by an angiographic core laboratory (if designated) and 
made available to the Clinical End Points Committee (CEC) for review. 


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7. Target Vessel Revascularization (TVR): Target vessel revascularization is any 
repeat percutaneous intervention or surgical bypass of any segment of the target 
vessel. In the assessment of TVR, angiograms should be assessed by an angiographic 
core laboratory (if designated) and made available to the CEC for review. 
8.  Clinically-Driven Target Lesion Revascularization: Clinically-driven target lesion 
revascularization is a target lesion revascularization prompted by recurrent ipsilateral 
limb symptoms (intermittent claudication, critical limb ischemia) or objective 
imaging evidence of target lesion restenosis (i.e., most commonly with duplex 
ultrasonography). In the assessment of clinically driven TLR based on duplex 
ultrasonography, ultrasonographic images should be assessed by a duplex ultrasound 
core laboratory (if designated) and made available to the CEC for review. 
23.11. 
Definition of Any Revascularization Procedure  
Any revascularization includes any arterial vascular intervention done to treat ischemia or 
prevent major ischemic events, including percutaneous or surgical intervention of the 
coronary, peripheral, or carotid arteries. Aneurysm repairs, dissection repairs, arterial-venous 
fistula or graft placement or repairs, or renal arterial intervention for hypertension or renal 
dysfunction are not included.  
23.12. 
Definition of Cardiac Arrhythmia Requiring Hospitalization  
 
An arrhythmia that either results in hospitalization during or within 24 hours of the 
termination of the last episode for treatment or requires continued hospitalization for 
treatment, including any one of the following: 
1. Atrial arrhythmia – atrial fibrillation, atrial flutter, supraventricular tachycardia that 
requires cardio-version, drug therapy, or is sustained for greater than 1 minute) 
2. Ventricular arrhythmia - 
Ventricular tachycardia or ventricular fibrillation requiring 
cardio-version and/or intravenous anti-arrhythmics 
3. Bradyarrhythmia - High-level AV block (defined as third-degree AV block or second-
degree AV block), junctional or ventricular escape rhythm, or severe sinus bradycardia 


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(typically with HR < 30 bpm).  The bradycardia must require temporary or permanent 
pacing,  
23.13. 
Definition of Cardiac Arrest (Sudden Cardiac Death)  
A sudden, unexpected death due to the cessation of cardiac mechanical activity, confirmed 
by the absence of a detectable pulse, unresponsiveness, and apnea (or agonal, gasping 
respirations) of presumed cardiac etiology.  An arrest is presumed to be cardiac (i.e., related 
to heart disease) if this is likely, based on the available information, including hospital 
records and autopsy data. The cardiac arrest will be further sub-classified into either: 
a) witnessed, occurring within 60 min from the onset of new symptoms, in the absence of a 
clear cause other than cardiovascular; or  
b) unwitnessed, within 24 hours of being observed alive, in the absence of pre-existing other 
non-cardiovascular causes of death;  
Note: Non-cardiac causes of cardiac arrest, such as drug overdose, suicide, drowning, 
hypoxia, exsanguination, cerebrovascular accident, subarachnoid hemorrhage, or trauma 
must not be present. 
23.14. 
Definition of Resuscitated Cardiac Arrest 1 
Resuscitated Cardiac Arrest is present when there is restoration of both: 
1.       Organized electrical activity, and 
2.       Organized mechanical activity resulting in restoration of spontaneous circulation 
(defined as the documented presence of a measurable pulse and blood pressure at any time 
after initiation of resuscitative efforts).  
                                                 
 
 
1 Becker LB, Aufderheide TP, Geocadin RG, Callaway CW, Lazar RM, Donnino MW, 
Nadkarni VM, Abella BS, Adrie C, Berg RA, Merchant RM, O’Connor RE, Meltzer DO, 
Holm MB, Longstreth WT, Halperin HR.  AHA Consensus Statement: Primary Outcomes 
for Resuscitation Science Sturdies: A Consensus Statement From the American Heart 
Association. Circulation 2011; CIR.0b013e3182340239published online before print 
October 3 2011, doi:10.1161/CIR.0b013e3182340239 


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APPENDIX C: CRITERIA FOR THE DIAGNOSIS OF DIABETES 
 
Reference: 
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 
2010; 33 Suppl 1:S62. 
 
1. HbA1c ≥6.5%. The test should be performed in a laboratory using a method that is National 
Glycohemoglobin Standardization Program (NGSP) certified and standardized to the 
Diabetes Control and Complications Trial (DCCT) assay.* 
OR 
2. Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric 
intake for at least 8 hr.* 
OR  
3. 2-hr plasma glucose ≥200 mg/dL (11.1 mmol/L) during an Oral Glucose Tolerance Test 
(OGTT). The test should be performed as described by the World Health Organization, 
using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in 
water.* 
OR  
4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random 
plasma glucose ≥200 mg/dL (11.1 mmol/L). 
 
* In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat 
testing. 
 


™
 
 
 
CLINICAL STUDY PROTOCOL 
A Multi-Center, Prospective, Randomized, Double-Blind, 
Placebo-Controlled, Parallel-Group Study to Evaluate the Effect of AMR101 
on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients 
with Cardiovascular Disease or at High Risk for Cardiovascular Disease: 
REDUCE-IT (Reduction of Cardiovascular Events with EPA – Intervention Trial) 
 
Investigational Product: AMR101 (icosapent ethyl [ethyl-EPA]) 
Protocol Number: AMR-01-01-0019 
 
 
Sponsor: 
Amarin Pharma Inc. 
1430 Route 206 
Bedminster, New Jersey 07921, USA 
Telephone: +1-908-719-1315 
Facsimile: +1-908-719-3012 
 
 
Amendment #2: Final 8 July 2016 
Amendment #2 Protocol Version Number: Final v 3.0 
Amendment #1: Final 16 May 2013 
Amendment #1 Protocol Version Number: Final v 2.0 
Original Protocol: 2 August 2011 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the 
written consent of Amarin Pharma Inc., except to the extent that disclosure would be required 
by law and for the purpose of evaluating and/or conducting a clinical trial for Amarin Pharma 
Inc. You are allowed to disclose the contents of this document only to your Institutional 
Review Board or Independent Ethics Committee and study personnel directly involved with 
conducting this study. Persons to whom the information is disclosed must be informed that 
the information is confidential and proprietary to Amarin Pharma Inc. and that it may not be 
further disclosed to third parties. 


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SIGNATURE PAGE 
TRIAL TITLE: A Multi-Center, Prospective, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group Study to Evaluate the Effect of AMR101 on Cardiovascular 
Health and Mortality in Hypertriglyceridemic Patients with Cardiovascular Disease or at 
High Risk for Cardiovascular Disease: REDUCE-IT (Reduction of Cardiovascular Events 
with EPA – Intervention Trial) 
 
We, the undersigned, have reviewed and approved this protocol. 
 
Signature 
Date 
 
 
[Name / signature redacted]                    
[Signed (11 July 2016)] 
Executive Director, Clinical Development 
Amarin Pharma Inc.  
 
 
[Name / signature redacted]                    
[Signed (11 July 2016)] 
Executive Director, Clinical Development  
Amarin Pharma Inc. 
 
 
[Name / signature redacted]                    
[Signed (11 July 2016)] 
Chief Medical Officer, SVP 
Amarin Pharma Inc.  
 
 
[Name / signature redacted]                    
[Signed (15 July 2016)] 
President of R&D and Chief Scientific Officer, SVP 
Amarin Pharma Inc. 
 
 
[Name / signature redacted]                    
[Signed (19 July 2016)] 
Principal Investigator 


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SYNOPSIS 
TITLE: 
A Multi-Center, Prospective, Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group Study to Evaluate the Effect of AMR101 on Cardiovascular Health and Mortality in 
Hypertriglyceridemic Patients with Cardiovascular Disease or at High Risk for 
Cardiovascular Disease: REDUCE-IT (Reduction of Cardiovascular Events with EPA – 
Intervention Trial) 
PROTOCOL NUMBER: AMR-01-01-0019 
INVESTIGATIONAL PRODUCT: AMR101 (icosapent ethyl [ethyl-eicosapentaenoic acid 
(EPA)]) 1 g soft gel capsules for oral administration 
PHASE: 3b 
INDICATION: 
The intended expanded indication is treatment with AMR101 as an add-on to statin therapy 
to reduce the risk of cardiovascular events in patients with clinical cardiovascular disease or 
with multiple risk factors for cardiovascular disease. 
OBJECTIVES: 
The primary objective is, in patients at low-density lipoprotein cholesterol (LDL-C) goal 
while on statin therapy, with established cardiovascular disease (CVD) or at high risk for 
CVD, and hypertriglyceridemia (fasting triglycerides [TG] 200 mg/dL and <500 mg/dL 
[2.26 mmol/L and <5.64 mmol/L]), to evaluate the effect of 4 g/day AMR101 on the time 
from randomization to first occurrence of any component of the composite of the following 
major cardiovascular (CV) events: 
 CV death; 
 Nonfatal myocardial infarction (MI), (including silent MI; electrocardiograms 
[ECGs] will be performed annually for the detection of silent MIs); 
 Nonfatal stroke; 
 Coronary revascularization; or 
 Unstable angina determined to be caused by myocardial ischemia by 
invasive/non-invasive testing and requiring emergent hospitalization. 
The secondary objectives of this study are the following: 
The key secondary objective is to evaluate the effect of therapy on the time from 
randomization to the first occurrence of the composite of CV death, nonfatal MI (including 
silent MI), or nonfatal stroke. 


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Other secondary objectives for this study are to evaluate the effect of therapy on time from 
randomization to the first occurrence of: 
 Composite of CV death or nonfatal MI (including silent MI); 
 Fatal or nonfatal MI (including silent MI); 
 Non-elective coronary revascularization represented as the composite of emergent or 
urgent classifications; 
 CV death; 
 Unstable angina determined to be caused by myocardial ischemia by 
invasive/non-invasive testing and requiring emergent hospitalization; 
 Fatal or nonfatal stroke; 
 Composite of total mortality, nonfatal MI (including silent MI), or nonfatal stroke; 
 Total mortality. 
The tertiary objectives for this study are to evaluate the effect of therapy on the following. 
Where applicable and unless specified otherwise, endpoints represent time from 
randomization to the first occurrence of the individual or composite endpoints. 
 Total CV events analysis defined as the time from randomization to occurrence of the 
first and all recurrent major CV events defined as CV death, nonfatal MI (including 
silent MI), nonfatal stroke, coronary revascularization, or unstable angina determined 
to be caused by myocardial ischemia by invasive/non-invasive testing and requiring 
emergent hospitalization; 
 Primary composite endpoint in the subset of patients with diabetes mellitus at 
baseline; 
 Primary composite endpoint in the subset of patients with metabolic syndrome at 
baseline as defined in A Joint Interim Statement of the International Diabetes 
Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and 
Blood Institute; American Heart Association; World Heart Federation; International 
Atherosclerosis Society; and I nternational Association for the Study of Obesity 
(Alberti 2009); with cut points of parameters as defined in Table 1 of Alberti et al. 
and waist circumference cut points further guided by Table 2 of Alberti et al. and 
specifically set at ≥35 inches (88 cm) for all women and Asian, Hispanic, or Latino 
men, and ≥40 inches (102 cm) for all other men (see Appendix D); 
 Primary composite endpoint in the subset of patients with impaired glucose 
metabolism at baseline (Visit 2 FBG of 100-125 mg/dL); 
 Key secondary composite endpoint in the subset of patients with impaired glucose 
metabolism at baseline (Visit 2 FBG 100-125 mg/dL); 
 Composite of CV death, nonfatal MI (including silent MI), nonfatal stroke, cardiac 
arrhythmia requiring hospitalization of ≥24 hours, or cardiac arrest; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), or unstable angina 


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determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization, nonfatal stroke, or PVD requiring intervention, 
such as angioplasty, bypass surgery, or aneurism repair; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization, PVD requiring intervention, or cardiac arrhythmia 
requiring hospitalization of ≥24 hours; 
 New CHF; 
 New CHF as the primary cause of hospitalization; 
 Transient ischemic attack (TIA);  
 Amputation for PVD; 
 Carotid revascularization; 
 All coronary revascularizations defined as the composite of emergent, urgent, 
elective, or salvage; 
 Emergent coronary revascularizations; 
 Urgent coronary revascularizations; 
 Elective coronary revascularizations; 
 Salvage coronary revascularizations; 
 Cardiac arrhythmias requiring hospitalization of ≥24 hours; 
 Cardiac arrest; 
 Ischemic stroke; 
 Hemorrhagic stroke; 
 Fatal or nonfatal stroke in the subset of patients with a history of stroke prior to 
baseline; 
 New onset diabetes, defined as Type 2 diabetes newly diagnosed during the 
treatment/follow-up period;  
 New onset hypertension, defined as blood pressure ≥140 mmHg systolic OR 
≥90 mmHg diastolic newly diagnosed during the treatment/follow-up period; 
 Fasting TG, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apo B, hs-CRP (hsCRP and 
log[hsCRP]), hsTnT, and RLP-C (to be estimated from standard lipid panel, RLP-C = 
TC – HDL-C – LDL-C [Varbo 2014]), (based on ITT estimands):  


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o Assessment of the relationship between baseline biomarker values and 
treatment effects within the primary and key secondary endpoints, 
o Assessment of the effect of AMR101 on each marker, 
o Assessment of the relationship between post-baseline biomarker values and 
treatment effects within the primary and key secondary composite endpoints 
by including post-baseline biomarker values (for example, at 4 months, or at 1 
year) as a covariate; 
 Change in body weight; 
 Change in waist circumference. 
ENDPOINTS: 
Primary Endpoint: 
The primary efficacy endpoint is the time from randomization to the first occurrence of any 
component of the composite of the following clinical events: 
 CV death; 
 Nonfatal MI (including silent MI; ECGs will be performed annually for the detection 
of silent MIs); 
 Nonfatal stroke; 
 Coronary revascularization;  
 Unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization.  
The first occurrence of any of these major adverse cardiovascular events during the follow-
up period of the study will be included in the incidence. 
Secondary Endpoints: 
The key secondary efficacy endpoint is the time from randomization to the first occurrence of 
the composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke.  
Other secondary efficacy endpoints are time from randomization to the first occurrence of the 
individual or composite endpoints as follows (to be tested in the order listed): 
 Composite of CV death or nonfatal MI (including silent MI); 
 Fatal or nonfatal MI (including silent MI); 
 Non-elective coronary revascularization represented as the composite of emergent or 
urgent classifications; 
 CV death; 
 Unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization; 
 Fatal or nonfatal stroke; 
 Composite of total mortality, nonfatal MI (including silent MI), or nonfatal stroke; 
 Total mortality. 


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For the secondary efficacy endpoints that count a single event, the time from randomization 
to the first occurrence of this type of event will be counted for each patient. For secondary 
efficacy endpoints that are composites of two or more types of events, the time from 
randomization to the first occurrence of any of the event types included in the composite will 
be counted for each patient. 
Tertiary Endpoints: 
The following tertiary endpoints will be evaluated as supporting efficacy and safety analyses. 
Where applicable and unless specified otherwise, endpoint analyses will be conducted as 
time from randomization to the first occurrence of the individual or composite endpoints. 
 Total CV events analysis defined as the time from randomization to occurrence of the 
first and all recurrent major CV events defined as CV death, nonfatal MI (including 
silent MI), nonfatal stroke, coronary revascularization, or unstable angina determined 
to be caused by myocardial ischemia by invasive/non-invasive testing and requiring 
emergent hospitalization; 
 Primary composite endpoint in subset of patients with diabetes mellitus at baseline; 
 Primary composite endpoint in the subset of patients with metabolic syndrome at 
baseline as defined in A Joint Interim Statement of the International Diabetes 
Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and 
Blood Institute; American Heart Association; World Heart Federation; International 
Atherosclerosis Society; and I nternational Association for the Study of Obesity 
(Alberti 2009); with cut points of parameters as defined in Table 1 of Alberti et al. 
and waist circumference cut points further guided by Table 2 Alberti et al. and 
specifically set at ≥35 inches (88 cm) for all women and Asian, Hispanic, or Latino 
men, and ≥40 inches (102 cm) for all other men (see Appendix D); 
 Primary composite endpoint in the subset of patients with impaired glucose 
metabolism at baseline (Visit 2 FBG of 100-125 mg/dL); 
 Key secondary composite endpoint in the subset of patients with impaired glucose 
metabolism at baseline (Visit 2 FBG 100-125 mg/dL); 
 Composite of CV death, nonfatal MI (including silent MI), nonfatal stroke, cardiac 
arrhythmia requiring hospitalization of ≥24 hours, or cardiac arrest; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), or unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization, nonfatal stroke, or PVD requiring intervention, 
such as angioplasty, bypass surgery, or aneurism repair; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 


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requiring emergent hospitalization, PVD requiring intervention, or cardiac arrhythmia 
requiring hospitalization of ≥24 hours; 
 New CHF; 
 New CHF as the primary cause of hospitalization; 
 Transient ischemic attack (TIA); 
 Amputation for PVD; 
 Carotid revascularization; 
 All coronary revascularizations defined as the composite of emergent, urgent, 
elective, or salvage; 
 Emergent coronary revascularizations; 
 Urgent coronary revascularizations; 
 Elective coronary revascularizations; 
 Salvage coronary revascularizations; 
 Cardiac arrhythmias requiring hospitalization of ≥24 hours; 
 Cardiac arrest; 
 Ischemic stroke; 
 Hemorrhagic stroke; 
 Fatal or nonfatal stroke in the subset of patients with a history of stroke prior to 
baseline; 
 New onset diabetes, defined as Type 2 diabetes newly diagnosed during the 
treatment/follow-up period;  
 New onset hypertension, defined as blood pressure ≥140 mmHg systolic OR 
≥90 mmHg diastolic newly diagnosed during the treatment/follow-up period; 
 Fasting TG, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apo B, hs-CRP (hsCRP and 
log[hsCRP]), hsTnT, and RLP-C (to be estimated from standard lipid panel, RLP-C = 
TC – HDL-C – LDL-C [Varbo 2014]), (based on ITT estimands):  
o Assessment of the relationship between baseline biomarker values and 
treatment effects within the primary and key secondary composite endpoints, 
o Assessment of the effect of AMR101 on each marker, 
o Assessment of the relationship between post-baseline biomarker values and 
treatment effects within the primary and key secondary composite endpoints 
by including post-baseline biomarker values (for example, at 4 months, or at 1 
year) as a covariate; 
 Change in body weight; 
 Change in waist circumference. 
Where applicable and unless specified otherwise, for the tertiary endpoints that count a single 
event, the time from randomization to the first occurrence of this type of event will be 
counted in each patient. Similarly, where applicable and unless specified otherwise, for 
tertiary endpoints that are composites of two or more types of events, the time from 


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randomization to the first occurrence of any of the event types included in the composite will 
be counted in each patient. 
POPULATION: 
Inclusion Criteria: 
1. Fasting TG levels of 200 mg/dL (2.26 mmol/L) and <500 mg/dL (5.64 mmol/L).  
2. LDL-C >40 mg/dL (1.04 mmol/L) and ≤100 mg/dL (2.60 mmol/L) and on stable 
therapy with a statin (with or without ezetimibe) for at least 4 weeks prior to the LDL-
C/TG baseline qualifying measurements for randomization  
 Stable therapy is defined as the same daily dose of the same statin for at least 28 days 
before the lipid qualification measurements (TG and LDL-C) and, if applicable, the 
same daily dose of ezetimibe for at least 28 days before the lipid qualification 
measurements (TG and LDL-C). Patients who have their statin therapy or use of 
ezetimibe initiated at Visit 1, or have their statin, statin dose and/or ezetimibe dose 
changed at Visit 1, will need to go through a stabilization period of at least 28 days 
since initiation/change and have their qualifying lipid measurements measured (TG 
and LDL-C) after the washout period (at Visit 1.1).  
 Statins may be administered with or without ezetimibe.  
NOTE: If patients qualify at the first qualification visit (Visit 1) for TG and LDL-C, and 
meet all other inclusion/exclusion criteria, they may be randomized at Visit 2. If patients 
do not qualify at the first qualifying visit (Visit 1), a second re-qualifying visit (Visit 1.1) 
is allowed. For some patients, because they need to stabilize medications and/or need to 
washout medications, the second re-qualifying visit (Visit 1.1) will be needed after the 
stabilization/washout period. 
3. Either having established CVD (in CV Risk Category 1) or at high risk for CVD (in CV 
Risk Category 2). The CV risk categories are defined as follows: 
CV Risk Category 1: defined as men and women ≥45 years of age with one or more of 
the following: 
 Documented coronary artery disease (CAD; one or more of the following primary 
criteria must be satisfied): 
o Documented multi vessel CAD (≥50% stenosis in at least two major epicardial 
coronary arteries – with or without antecedent revascularization); 
o Documented prior MI; 
o Hospitalization for high-risk non-ST-segment elevation acute coronary 
syndrome (NSTE-ACS) (with objective evidence of ischemia: ST-segment 
deviation or biomarker positivity). 
 Documented cerebrovascular or carotid disease (one of the following primary 
criteria must be satisfied): 
o Documented prior ischemic stroke; 
o Symptomatic carotid artery disease with ≥50% carotid arterial stenosis; 
o Asymptomatic carotid artery disease with ≥70% carotid arterial stenosis per 
angiography or duplex ultrasound; 


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o History of carotid revascularization (catheter-based or surgical). 
 Documented peripheral arterial disease (PAD; one or more of the following 
primary criteria must be satisfied): 
o Ankle-brachial index (ABI) <0.9 with symptoms of intermittent claudication; 
o History of aorto-iliac or peripheral arterial intervention (catheter-based or 
surgical). 
OR 
CV Risk Category 2: defined as patients with: 
1. Diabetes mellitus (Type 1 or Type 2) requiring treatment with medication AND 
2. Men and women ≥50 years of age AND  
3. One of the following at Visit 1 (additional risk factor for CVD): 
 Men ≥55 years of age and Women ≥65 years of age; 
 Cigarette smoker or stopped smoking within 3 months before Visit 1; 
 Hypertension (blood pressure ≥140 mmHg systolic OR ≥90 mmHg diastolic) 
or on antihypertensive medication; 
 HDL-C ≤40 mg/dL for men or ≤50 mg/dL for women; 
 Hs-CRP >3.00 mg/L (0.3 mg/dL); 
 Renal dysfunction: Creatinine clearance (CrCL) >30 and <60 mL/min (>0.50 
and <1.00 mL/sec); 
 Retinopathy, defined as any of the following: non-proliferative retinopathy, 
pre-proliferative retinopathy, proliferative retinopathy, maculopathy, advanced 
diabetic eye disease or a history of photocoagulation; 
 Micro- or macroalbuminuria. Microalbuminuria is defined as either a positive 
micral or other strip test (may be obtained from medical records), an 
albumin/creatinine ratio ≥2.5 mg/mmol or an albumin excretion rate on timed 
collection 
≥20 mg/min 
all 
on 
at 
least 
two 
successive 
occasions; 
macroalbuminuria, defined as Albustix or other dipstick evidence of gross 
proteinuria, an albumin/creatinine ratio ≥25 mg/mmol or an albumin excretion 
rate on timed collection ≥200 mg/min all on at least two successive occasions; 
 ABI <0.9 without symptoms of intermittent claudication (patients with ABI 
<0.9 with symptoms of intermittent claudication are counted under CV Risk 
Category 1). 
Note: Patients with diabetes and CVD as defined above are eligible based on t he 
CVD requirements and will be counted under CV Risk Category 1. Only patients with 
diabetes and no documented CVD as defined above need at least one additional risk 
factor as listed, and will be counted under CV Risk Category 2. 
4. Women may be enrolled if all 3 of the following criteria are met: 
 They are not pregnant; 
 They are not breastfeeding; 


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 They do not plan on becoming pregnant during the study. 
5. Women of child-bearing potential must have a negative urine pregnancy test before 
randomization. 
Note: Women are not considered to be of childbearing potential if they meet one of the 
following criteria as documented by the investigator: 
 They have had a hysterectomy, tubal ligation or bilateral oophorectomy prior to 
signing the informed consent form; 
 They are post-menopausal, defined as ≥1 year since their last menstrual period or 
have a follicle-stimulating hormone (FSH) level in a menopausal range. 
6. Women of childbearing potential must agree to use an acceptable method of avoiding 
pregnancy from screening to the end of the study, unless their sexual partner(s) is/are 
surgically sterile or the woman is abstinent. 
7. Understanding of the study procedures, willing to adhere to the study schedules, and 
agreement to participate in the study by giving informed consent prior to screening. 
8. Agree to follow a physician recommended diet, and to maintain it through the duration 
of the study. 
Exclusion Criteria: 
1. Severe (New York Heart Association [NYHA] class IV) heart failure. 
2. Any life-threatening disease expected to result in death within the next 2 years (other 
than CVD). 
3. Active severe liver disease (evaluated at Visit 1): cirrhosis, active hepatitis, alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × the upper limit o f 
normal (ULN), or biliary obstruction with hyperbilirubinemia (total bilirubin >2 × ULN). 
4. Hemoglobin A1c (HbA1c ) >10.0% (or >86 mmol/mol International Federation of Clinical 
Chemistry [IFCC] units) at screening (Visit 1). If patients fail this criterion 
(HbA1c >10.0% or >86 mmol/mol IFCC units) at Visit 1, they may have their antidiabetic 
therapy optimized and be retested at Visit 1.1. 
5. Poorly controlled hypertension: blood pressure ≥200 systolic mmHg OR ≥100 mmHg 
diastolic (despite antihypertensive therapy). 
6. Planned coronary intervention (such as stent placement or heart bypass) or any non-
cardiac major surgical procedure. Patients can be (re)evaluated for participation in the 
trial (starting with Visit 1.1) after their recovery from the intervention/surgery. 
7. Known familial lipoprotein lipase deficiency (Fredrickson Type I), apolipoprotein C-II 
deficiency, or familial dysbetalipoproteinemia (Fredrickson Type III). 
8. Participation in another clinical trial involving an investigational agent within 90 days 
prior to screening (Visit 1). Patients cannot participate in any other investigational 
medication or medical device trial while participating in this study (participation in a 
registry or observational study without additional therapeutic intervention is allowed). 
9. Intolerance or hypersensitivity to statin therapy. 


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10. Known hypersensitivity to any ingredients of the study product or placebo (refer to Table 
5); known hypersensitivity to fish and or shellfish. 
11. History of acute or chronic pancreatitis. 
12. Malabsorption syndrome and/or chronic diarrhea. (Note: patients who have undergone 
gastric/intestinal bypass surgery are considered to have malabsorption, hence are 
excluded; patients who have undergone gastric banding are allowed to enter the trial). 
13. Non-study drug related, non-statin, lipid-altering medications, supplements or foods: 
 Patients are excluded if they used niacin >200 mg/day or fibrates during the screening 
period (after Visit 1) and/or plan to use during the study; patients who are taking 
niacin >200 mg/day or fibrates during the last 28 days before Visit 1 ne ed to go 
through washout of at least 28 days after their last use and have their qualifying lipids 
measured (TG and LDL-C) after the washout period (Visit 1.1); 
 Patients are excluded if they take any omega-3 fatty acid medications (prescription 
medicines containing EPA and/or docosahexaenoic acid [DHA]) during the screening 
period (after Visit 1) and/or plan to use during the treatment/follow-up period of the 
study. To be eligible for participation in the study, patients who are taking omega-3 
fatty acid medications during the last 28 days before Visit 1 (except patients in the 
Netherlands), need to go through a washout period of at least 28 days after their last 
use and have their qualifying lipid measurements measured (TG and LDL-C) after the 
washout period (at Visit 1.1); 
o For patients in the Netherlands only: patients being treated with omega-3 fatty 
acid medications containing EPA and /or DHA are excluded; no washout is 
allowed.  
 Patients are excluded if they use dietary supplements containing omega-3 fatty acids 
(e.g., flaxseed, fish, krill, or algal oils) during the screening period (after Visit 1) 
and/or plan to use during the treatment/follow-up period of the study. To be eligible 
for participation in the study, patients who are taking >300 mg/day omega-3 fatty 
acids (combined amount of EPA and DHA) within 28 days before Visit 1 (except 
patients in the Netherlands), need to go through a washout period of at least 28 days 
since their last use and have their qualifying lipid measurements measured (TG and 
LDL-C) after the washout period (at Visit 1.1); 
o For patients in the Netherlands only: patients being treated with dietary 
supplements containing omega-3 fatty acids of >300 mg/day EPA and/or 
DHA are excluded; no washout is allowed. 
 Patients are excluded if they use bile acid sequestrants during the screening period 
(after Visit 1) and/or plan to use during the treatment/follow-up period of the study. 
To be eligible for participation in the study, patients who are taking bile acid 
sequestrants within 7 days before Visit 1, need to go through a washout period of at 
least 7 days since their last use and have their qualifying lipid measurements 
measured (TG and LDL-C) after the washout period (at Visit 1.1); 
 Patients are excluded if they use proprotein convertase subtilisin kexin 9 (PCSK9) 
inhibitors during the screening period (after Visit 1) and/or plan to use during the 
treatment/follow-up period of the study. To be eligible for participation in the study, 


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patients cannot have taken a PCSK9 inhibitor within 90 days prior to their screening 
visit. 
14. Other medications (not indicated for lipid alteration): 
 Treatment with tamoxifen, estrogens, progestins, thyroid hormone therapy, systemic 
corticosteroids (local, topical, inhalation, or nasal corticosteroids are allowed), HIV-
protease inhibitors that have not been stable for ≥28 days prior to the qualifying lipid 
measurements (TG and LDL-C) during screening. To be eligible for participation in 
the study, patients who are not taking a stable dose of these medications within 
28 days before Visit 1, need to go through a stabilization period of at least 28 days 
since their last dose change and have their qualifying lipid measurements measured 
(TG and LDL-C) after the washout period (at Visit 1.1); 
 Patients are excluded if they use cyclophosphamide or systemic retinoids during the 
screening period (after Visit 1) and/or plan to use during the treatment/follow-up 
period of the study. To be eligible for participation in the study, patients who are 
taking these medications within 28 days before Visit 1, need to go through a washout 
period of at least 28 days since their last use and have their qualifying lipid 
measurements measured (TG and LDL-C) after the washout period (at Visit 1.1). 
15. Known to have acquired immune deficiency syndrome (AIDS) (patients who are human 
immunodeficiency virus (HIV) positive without AIDS are allowed). 
16. Requirement for peritoneal dialysis or hemodialysis for renal insufficiency or creatinine 
clearance (CrCL) <30 mL/min (0.50 mL/sec). 
17. Unexplained creatine kinase concentration >5 × ULN or creatine kinase elevation due to 
known muscle disease (e.g., polymyositis, mitochondrial dysfunction) at Visit 1. 
18. Any condition or therapy which, in the opinion of the investigator, might pose a risk to 
the patient or make participation in the study not in the patient’s best interest. 
19. Drug or alcohol abuse within the past 6 months, and unable/unwilling to abstain from 
drug abuse and excessive alcohol consumption during the study or drinking 5 units or 
more for men or 4 units or more for women in any one hour (episodic excessive drinking 
or binge drinking). Excessive alcohol consumption is on average >2 units of alcohol per 
day. A unit of alcohol is defined as a 12-ounce (350 mL) beer, 5-ounce (150 mL) wine, 
or 1.5-ounce (45 mL) of 80-proof alcohol for drinks. 
20. Mental/psychological impairment or any other reason to expect patient difficulty in 
complying with the requirements of the study or understanding the goal and potential 
risks of participating in the study (evaluated at Visit 1). 
STUDY DESIGN AND DURATION: 
This is a multi-center, multi-national, prospective, randomized, double-blind, placebo-
controlled, parallel-group study. 
This is an event-driven trial: It is expected that a minimum of approximately 1612 primary 
endpoint events will be required during the study. Approximately 7990 patients will be 
randomized at multiple Research Sites worldwide over an estimated period of approximately 
4.2 years. After randomization, patients will be treated and followed up to an estimated 


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maximum of 6.5 years. The study end date is determined to be when approximately 
1612 primary efficacy events have been adjudicated. 
Screening Period: 
During the screening period, patients will be evaluated for inclusion/exclusion criteria. 
Patients will be eligible for randomization if they meet all the inclusion/exclusion criteria. 
Prospectively, eligible patients with documented CVD or diabetes (with at least one 
additional risk factor for CVD) will undergo screening to establish suitability for inclusion in 
the trial. The qualifying lipid determination at Visit 1 requires that eligible patients must have 
a fasting TG level 200 mg/dL (2.26 mmol/L) and <500 mg/dL (5.64 mmol/L) in order to 
enter the treatment/follow-up period of the trial (and they need to meet all other 
inclusion/exclusion criteria). These patients will be randomized at Visit 2, which will occur 
soon after Visit 1 (there will be no Visit 1.1 for these patients). 
Patients who do not qualify at Visit 1, may return to the Research Site for a second qualifying 
visit (Visit 1.1) at which time procedures that caused failure of eligibility at Visit 1 will be 
repeated. In this case, patients will be eligible for randomization after Visit 1.1 if they meet 
all inclusion criteria and if they no longer fail the exclusion criteria. 
For some patients, Visit 1.1 will be mandatory at least 28 days after Visit 1 in order to check 
eligibility. These are patients who at Visit 1 started treatment with a statin, changed their 
statin, changed the daily dose of their statin, started to washout prohibited medications or 
started a stabilization period with certain medications. Any of these changes at Visit 1 may 
affect the qualifying lipid levels and therefore, patients will need to have Visit 1.1 to 
determine whether they qualify based on l ipid level requirements (TG and LDL-C) 
determined at Visit 1. Other procedures that caused failure of eligibility at Visit 1 will also be 
repeated at Visit 1.1. Details are listed in the main section of the protocol. 
Treatment/Follow-Up Period: 
At Visit 2 (Day 0), eligible patients will be randomly assigned 1:1 to one of the following 
treatment groups: 
 AMR101 4 g daily, or 
 Placebo. 
Stratification will be by CV risk category (established CVD or the presence of diabetes with 
≥1 risk factor for CVD), use of ezetimibe and by geographical region (Westernized, Eastern 
European, and Asia Pacific countries). 
During the treatment/follow-up period, patients will return to the Research Site at regular 
intervals for efficacy and safety evaluations, and drug supply and compliance checks. The 
visits after the randomization visit (Visit 2; Day 0) are scheduled for 4 months after Visit 2 
(for Visit 3); 8 months after Visit 3 (for Visit 4); and then every year thereafter. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
Eligible patients will be randomly assigned at Visit 2 to receive orally AMR101 4 g daily or 
matching placebo. AMR101 is provided in 1 g liquid-filled, oblong, gelatin capsules. The 
matching placebo capsule is filled with light liquid paraffin and contains 0 mg of AMR101. 


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AMR101 or matching placebo capsules are to be taken with food (i.e. with or at the end of a 
meal). 
During the treatment period, the daily dose of study drug is 4 capsules per day taken as two 
capsules taken on two occasions per day (2 capsules given twice daily). 
STATISTICAL ANALYSES: 
 Intent-to-treat (ITT), Modified ITT (mITT), Per Protocol (PP), and Safety analyses 
 Parameters will be summarized using mean, standard deviation, median, minimum, 
maximum, and interquartile range for continuous data and percentage for categorical 
data. 
 Survival analysis using the log-rank test for the primary efficacy outcome comparing 
the 2 treatment groups (AMR101 and Placebo) and including the stratification factors 
CV risk category, use of ezetimibe and geographical region (Westernized, Eastern 
European, and Asia Pacific countries). 
 Exploratory subgroup analyses will be performed for the primary and key secondary 
endpoints for the ITT, mITT and PP populations, based on demographics, disease 
parameters, treatment parameters, and baseline characteristics including lipid and 
lipoprotein parameters. 
Two interim analyses are planned, to occur when approximately 60% and 80% of the 
planned total number of events have been adjudicated. 
The analyses are planned to: 
 Describe at baseline: Patient characteristics, including lipids and lipoproteins, stroke 
history, CV risk factors, diabetes mellitus, or metabolic syndrome, among others. 
 Compare the primary, secondary, and tertiary endpoints between treatment groups at 
the corresponding follow-up time points. 
SAMPLE SIZE DETERMINATION: 
Sample size calculation was based on assumptions of constant hazard, asymmetric 
recruitment rate over time and without factoring for dropouts. A risk reduction corresponding 
to a hazard ratio of 0.85 (AMR101 vs. control) was assumed. A total of 1612 events would 
be required to detect this hazard ratio with approximately 90% power with one-sided alpha-
level at 2.5% and with two interim analyses. The operating characteristics of this design are 
identical to those of a corresponding group sequential design with a two-sided alpha level of 
0.05. 
The recruitment period was assumed to be approximately 4.2 years with 20% recruitment in 
the first year, 40% in the second year, 20% in the third year, 19% in the fourth year and the 
remaining 1% in the last 0.2 years. The expected maximum study duration is estimated at 
6.5 years unless the trial is terminated early for efficacy or safety issues. A one-year event 
rate of 5.2% (hazard = 0.053) in the control arm is also assumed. Under these assumptions 
the number of patients to be enrolled is N = 7990. 
Since this is an events-driven trial, the ‘sample size’ is the number of events rather than the 
number of patients. The number of events that occur depends primarily on three factors: how 


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many patients are enrolled, the combined group event rate, and how long the patients are 
followed. Because of the difficulty in predicting the combined event rate, the sponsor will 
monitor that event rate as the trial progresses. If the combined event rate is less than 
anticipated, either increasing the number of patients, extending the length of follow-up, or a 
balance of adjusting both factors may be necessary to achieve the sample size of 1612 events. 
Before completing the enrollment phase of the trial, i.e. approximately 3 to 6 months prior to 
the projected enrollment of the 7990th patient, the actual event rate based on pooled, blinded 
accumulation of primary efficacy endpoint events would be calculated and plotted.  If those 
analyses suggested the number of patients with at least 1 adjudicated, primary event (and 
appropriately accounting for patients with potential primary events for which the 
adjudication process is then incomplete) was consistent with projections, then the study could 
continue toward the protocol-specified target enrollment of 7990 patients.  However, if the 
number of such events appeared less than, and inconsistent with projections, the Sponsor 
would consider (under blinded conditions) re-calculating the number of patients needed to 
achieve the target number of events within the desired timeline or extending the follow-up 
period.  If the projected increase in number of patients was ≤25% of the original 7990 target 
population, the Sponsor could, with documented approval of both the REDUCE-IT Steering 
Committee and the Data Monitoring Committee, extend enrollment to the revised target 
number without need for an additional protocol amendment. Under those conditions, all 
principal investigators, ethics committees, and regulatory authorities associated with the 
protocol will be promptly notified of the action. If the projected increase in number of 
patients was more than 25% above the original 7990 target (i.e. more than 1998 additional 
patients) a formal protocol amendment would be initiated. 
Consistent with the plan stated above, an analysis and modeling of pooled, blinded primary 
efficacy endpoint events across the remainder of the trial was performed prior to the 
projected enrollment of the 7990th patient.  Based on this analysis, the sample size of 7990 
randomized patients is with 95% confidence likely to result in the target 1,612 adjudicated 
primary efficacy events within 2018.  T he results of this analysis were shared with and 
approved by the REDUCE-IT Steering Committee and Data Monitoring Committee. 
As of the completion of study enrollment, the actual number of patients randomized will vary 
from the target number as a result of the inherent lag between the date the last patient started 
screening and the date the last patient was randomized. 
SPONSOR: 
Amarin Pharma Inc. 
1430 Route 206 
Bedminster, New Jersey 07921, USA 
Telephone: +1-908-719-1315 
Facsimile: +1-908-719-3012 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................... 22 
1. 
INTRODUCTION AND BACKGROUND INFORMATION ...................................... 25 
1.1. 
Background ............................................................................................................. 25 
1.2. 
Summary of Completed Amarin-Sponsored Clinical Studies of AMR101 in 
Patients with Hypertriglyceridemia .................................................................................... 26 
1.2.1. 
Study AMR-01-01-0016 (MARINE) .............................................................. 26 
1.2.2. 
Study AMR-01-01-0017 (ANCHOR)............................................................. 27 
1.3. 
Clinical Safety ......................................................................................................... 29 
1.4. 
Rationale ................................................................................................................. 29 
1.5. 
Risk/Benefit ............................................................................................................ 44 
2. 
STUDY OBJECTIVES ................................................................................................... 45 
3. 
STUDY DESIGN............................................................................................................ 48 
3.1. 
Type of Study .......................................................................................................... 48 
3.2. 
Study Population ..................................................................................................... 48 
3.3. 
Study Periods .......................................................................................................... 48 
3.4. 
Study Duration ........................................................................................................ 49 
3.5. 
Study Groups .......................................................................................................... 49 
3.6. 
Number of Patients ................................................................................................. 50 
3.7. 
Number of Study Sites ............................................................................................ 50 
3.8. 
Randomization ........................................................................................................ 50 
3.9. 
Blinding................................................................................................................... 50 
3.10. Stratification ............................................................................................................ 50 
4. 
STUDY POPULATION ................................................................................................. 52 
4.1. 
Inclusion Criteria .................................................................................................... 52 
4.2. 
Exclusion Criteria ................................................................................................... 54 
5. 
STUDY COMMITTEES ................................................................................................ 57 
5.1. 
Steering Committee ................................................................................................ 57 
5.2. 
Study Operations Committee .................................................................................. 57 
5.3. 
Clinical Endpoint Committee (CEC) ...................................................................... 57 


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5.4. 
Data Monitoring Committee (DMC) ...................................................................... 57 
6. 
STUDY PROCEDURES ................................................................................................ 58 
6.1. 
Assessment Schedule .............................................................................................. 58 
6.1.1. 
Screening Period ............................................................................................. 58 
6.1.2. 
Treatment/Follow-Up Period .......................................................................... 59 
6.2. 
Telephone Follow-up Contact ................................................................................. 63 
6.3. 
Laboratory Procedures ............................................................................................ 64 
6.3.1. 
Clinical Laboratory Procedures ...................................................................... 64 
6.3.2. 
Medical Procedures ......................................................................................... 67 
7. 
TREATMENT AND RESTRICTIONS ......................................................................... 68 
7.1. 
Treatment ................................................................................................................ 68 
7.1.1. 
Treatment Regimen, Dosage, and Duration .................................................... 68 
7.1.2. 
Treatment Assignment .................................................................................... 68 
7.1.3. 
Compliance Control ........................................................................................ 69 
7.2. 
Study Restrictions ................................................................................................... 69 
7.2.1. 
Concomitant Medications during Treatment/Follow-Up Period .................... 69 
7.2.2. 
Patient Restrictions ......................................................................................... 71 
8. 
INVESTIGATIONAL PRODUCT ................................................................................. 72 
8.1. 
Clinical Trial Material............................................................................................. 72 
8.2. 
Pharmaceutical Formulations.................................................................................. 72 
8.3. 
Labeling and Packaging .......................................................................................... 72 
8.4. 
Dispensing Procedures and Storage Conditions ..................................................... 73 
8.4.1. 
Dispensing Procedures .................................................................................... 73 
8.4.2. 
Storage Conditions .......................................................................................... 73 
9. 
EFFICACY ASSESSMENTS ........................................................................................ 74 
9.1. 
Specification of Variables and Procedures ............................................................. 74 
9.2. 
Efficacy Endpoints .................................................................................................. 74 
9.2.1. 
Primary Endpoint ............................................................................................ 74 
9.2.2. 
Secondary Endpoints ...................................................................................... 74 
9.2.3. 
Tertiary Endpoints .......................................................................................... 75 
10. 
SAFETY ASSESSMENTS ......................................................................................... 78 
10.1. Specification of Variables and Procedures ............................................................. 78 
10.2. AEs .......................................................................................................................... 78 
10.2.1. 
Serious Adverse Events .................................................................................. 80 
10.3. Serious Adverse Event Reporting – Procedure for Investigators ........................... 80 
10.3.1. 
Initial Reports.................................................................................................. 80 


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10.3.2. 
Follow-Up Reports.......................................................................................... 81 
10.3.3. 
Reporting by the Sponsor................................................................................ 81 
10.4. Exposure in Utero During Clinical Trials ............................................................... 81 
11. 
TREATMENT DISCONTINUATION/PATIENT WITHDRAWAL ........................ 82 
11.1. Reasons for Early Study Drug Discontinuation ...................................................... 82 
11.2. Follow-Up after Early Study Drug Discontinuation/Lost to Follow-Up ................ 83 
12. 
STATISTICS .............................................................................................................. 84 
12.1. Analysis Populations ............................................................................................... 84 
12.1.1. 
Intent-to-Treat Population ............................................................................... 84 
12.1.2. 
Modified Intent-to-Treat Population ............................................................... 84 
12.1.3. 
Per-Protocol Population .................................................................................. 84 
12.1.4. 
Safety Population ............................................................................................ 84 
12.2. Statistical Methods .................................................................................................. 84 
12.2.1. 
Patient Disposition and Demographic/Baseline Characteristics ..................... 84 
12.2.2. 
Study Medication Exposure and Compliance ................................................. 85 
12.2.3. 
Concomitant Therapies ................................................................................... 85 
12.2.4. 
Analysis of Efficacy ........................................................................................ 85 
12.2.5. 
Analysis of Safety ........................................................................................... 90 
12.3. Sample Size Determination..................................................................................... 91 
13. 
MONITORING, DATA MANAGEMENT, AND RECORD KEEPING .................. 93 
13.1. Data Management ................................................................................................... 93 
13.1.1. 
Data Handling ................................................................................................. 93 
13.2. Record Keeping ...................................................................................................... 93 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ......................................... 94 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 95 
16. 
ETHICS AND GOOD CLINICAL PRACTICE COMPLIANCE ............................. 96 
17. 
INFORMED CONSENT ............................................................................................ 97 
18. 
PUBLICATION POLICY .......................................................................................... 97 
19. 
Financing and Insurance ............................................................................................. 98 
19.1. Finances .................................................................................................................. 98 
19.2. Insurance Compensation ......................................................................................... 98 
20. 
Completion of Study ................................................................................................... 99 
21. 
STUDY ADMINISTRATIVE INFORMATION ..................................................... 100 


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21.1. Protocol Amendments ........................................................................................... 100 
22. 
REFERENCES ......................................................................................................... 101 
23. 
INVESTIGATOR’S AGREEMENT ........................................................................ 109 
APPENDIX A: 
SCHEDULE OF PROCEDURES......................................................... 110 
APPENDIX B: 
STANDARDIZED 
DEFINITIONS 
FOR 
REDUCE-IT 
CARDIOVASCULAR TRIAL ENDPOINT EVENTS........................................................ 112 
23.1. Definition of Cardiovascular Death ...................................................................... 112 
23.2. Definition of Non-Cardiovascular Death .............................................................. 113 
23.2.1. 
Non-malignant, Non-cardiovascular Death .................................................. 113 
23.2.2. 
Malignancy ................................................................................................... 114 
23.3. Definition of Undetermined Cause of Death ........................................................ 114 
23.4. Definition of Myocardial Infarction ...................................................................... 115 
23.5. Sub-classification of Myocardial Infarction ......................................................... 119 
23.6. Definition of Hospitalization for Unstable Angina ............................................... 121 
23.7. Definition of Transient Ischemic Attack and Stroke ............................................ 122 
23.8. Definition of Heart Failure Event ......................................................................... 124 
23.11. 
Definition of Any Revascularization Procedure ............................................... 127 
23.12. 
Definition of Cardiac Arrhythmia Requiring Hospitalization .......................... 128 
23.13. 
Definition of Cardiac Arrest (Sudden Cardiac Death) ...................................... 128 
23.14. 
Definition of Resuscitated Cardiac Arrest2 ....................................................... 128 
APPENDIX C: 
CRITERIA FOR THE DIAGNOSIS OF DIABETES.......................... 130 
APPENDIX D: 
CRITERIA FOR THE DIAGNOSIS OF Metabolic Syndrome ........... 131 
 
LIST OF FIGURES AND TABLES 
Figure 1.  Placebo-Adjusted Median Percent Change from Baseline to Week 12 in Key 
Lipid and Inflammatory Endpoints – Intent-to-Treat Population (MARINE) ... 27 
Figure 2.  Placebo-Adjusted Median Percent Change from Baseline to Week 12 in Key 
Lipid Endpoints and Inflammatory Endpoints – Intent-to-Treat Population 
(ANCHOR) ........................................................................................................ 28 
Table 1: Adverse Reactions Occurring at Incidence >2% and Greater than Placebo in 
Double-Blind, Placebo-Controlled Trials* ........................................................ 29 


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Table 2.  Published Clinical Studies of the Effects of Lipid-modulating Agents Plus Statin 
Therapy versus Statin Monotherapy on Cardiovascular Events ........................ 33 
Table 3.  Omega Acid Mixture or EPA-only Outcomes Trials .......................................... 41 
Table 4.  Dosing Schedule during the Treatment Period .................................................... 68 
Table 5.  Components of AMR101 1 g Capsules and Placebo Capsules ........................... 72 
Table 6.  Current Recommended Waist Circumference Thresholds for Abdominal Obesity 
by Organization and Population (Alberti et. al. Table 2) ................................. 132 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ABI 
Ankle-brachial index 
ACC 
American College of Cardiology 
ACCORD 
Action to Control Cardiovascular Risk in Diabetes 
ACS 
Acute coronary syndrome 
AE 
Adverse event 
AHA 
American Heart Association 
AIDS 
Acquired immune deficiency syndrome 
AIM-HIGH 
Atherothrombosis Intervention in Metabolic Syndrome with Low 
HDL/High Triglycerides: Impact on Global Health Outcomes 
ALT 
Alanine aminotransferase 
AMR101 
Ethyl-EPA; ethyl eicosapentaenoic acid; icosapent ethyl 
ANCHOR 
Effect of AMR101 (Ethyl Icosapentate) on Triglyceride (Tg) Levels in 
Patients on Statins with High TG Levels (≥ 200 and < 500 mg/dL) 
AP 
Angina pectoris 
apo B 
Apolipoprotein B 
APOC3 
Apolipoprotein C3 
AST 
Aspartate aminotransferase 
ATP 
Adult Treatment Panel 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CABG 
Coronary artery bypass graft 
CAD 
Coronary artery disease 
CBC 
Complete blood count 
CEC 
Clinical Endpoint Committee 
CHD 
Coronary heart disease 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CK-MB 
Creatine kinase-MB fraction 
CrCL 
Creatinine clearance 
CRF 
Case report form 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
DART 
Diet and Reinfarction Trial 
DCCT 
Diabetes Control and Complications Trial 
DHA 
Docosahexaenoic acid 
DMC 
Data Monitoring Committee 
DYSIS 
The DYSlipidemia International Study 
EC 
Independent Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
eGRF 
Estimated glomerular filtration rate 


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EPA 
Eicosapentaenoic acid 
Ethyl-EPA 
AMR101; ethyl eicosapentaenoic acid; icosapent ethyl 
EU 
European Union 
FBG 
Fasting blood glucose 
FDA 
United States Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GISSI 
Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto 
Miocardico 
GMP 
Good Manufacturing Practice 
GWAS 
Genome-wide association study 
HbA1c 
Hemoglobin A1c 
Hct 
Hematocrit 
HDL-C 
High-density lipoprotein cholesterol 
HF 
Heart failure 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HPS2-THRIVE 
Heart Protection Study 2–Treatment of HDL to Reduce the Incidence 
of Vascular Events 
HR 
Hazard ratio 
hs-CRP 
High-sensitivity C-reactive protein 
hsTnT 
High-sensitivity troponin T 
HTG 
Hypertriglyceridemia 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IFCC 
International Federation of Clinical Chemistry 
IMP 
Investigational medicinal product 
IMPROVE-IT 
Examining Outcomes in Subjects with Acute Coronary Syndrome: 
Vytorin (Ezetimibe/Simvastatin) vs Simvastatin 
IQR 
Interquartile range 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response  System 
JAS 
Japanese Atherosclerosis Society 
JELIS 
Japan Eicosapentaenoic Acid Lipid Intervention Study 
LBBB 
Left bundle branch block 
LDL-C 
Low-density lipoprotein cholesterol 
LOE 
Lack of efficacy 
LpPLA2 
Lipoprotein-associated phospholipase A2 
LVH 
Left ventricle hypertrophy 
MACE 
Major adverse coronary event 
MARINE 
Efficacy and Safety of AMR101 (Ethyl Icosapentate) in Patients With 
Fasting Triglyceride (TG) Levels ≥ 500 and ≤ 2000 mg/dL 
MI 
Myocardial infarction 


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mITT 
Modified Intent-to-Treat 
NCEP 
National Cholesterol Education Program 
NGSP 
National Glycohemoglobin Standardization Program 
NMR 
Nuclear magnetic resonance 
NSTE-ACS 
Non-ST-segment elevation acute coronary syndrome 
O3FA 
Omega-3 fatty acid 
ODIS 
Off drug in study 
OGTT 
Oral glucose tolerance test 
OR 
Odds ratio 
PAD 
Peripheral arterial disease 
PCI 
Percutaneous coronary intervention 
PCSK9 
Proprotein convertase subtilisin kexin 9 
PH 
Proportional hazard 
PI 
Principal Investigator 
PP 
Per protocol 
PROVE-IT 
Pravastatin or Atorvastatin Evaluation and Infection Therapy 
PVD 
Peripheral vascular disease 
RBC 
Red blood cells 
REDUCE-IT 
Reduction of Cardiovascular Events with EPA – Intervention Trial 
RLP-C 
Remnant lipoprotein cholesterol 
RR 
Relative risk 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Steering Committee 
SPC 
Summary of Product Characteristics 
SUSAR 
Suspected unexpected serious adverse reaction 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TG 
Triglycerides 
TIA 
Transient Ischemic Attack 
TIMI 
Thrombolysis In Myocardial Infarction 
ULN 
Upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
VLDL-C 
Very low density lipoprotein cholesterol 
WBC 
White cell blood count 


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1. 
INTRODUCTION AND BACKGROUND INFORMATION 
AMR101 (marketed as Vascepa® in the United States [US]) is an ethyl ester of 
eicosapentaenoic acid (EPA) indicated as an adjunct to diet to reduce triglyceride (TG) levels 
in adult patients with severe (≥500 mg/dL) hypertriglyceridemia (HTG), which received 
initial US regulatory approval in 2012. AMR101, derived from fish oil, is being developed 
by Amarin Pharma Inc. (hereafter referred to as Amarin or the Sponsor) for the treatment of 
HTG. The purpose of this study is to evaluate whether AMR101, combined with a statin 
therapy, will be superior to the statin therapy alone, when used as a prevention in reducing 
long-term clinical events in patients with mixed dyslipidemia at high risk for cardiovascular 
(CV) events. 
1.1. 
Background 
Since the initial observation of a link between fish oil consumption and the reduced incidence 
of coronary heart disease in the Eskimos of Greenland (Bang 1972), a large body of evidence 
has accumulated suggesting that regular intake of omega-3 fatty acids (O3FAs) exerts 
cardioprotective effects in both primary and secondary coronary heart disease prevention 
(Harris 2008, Lee 2008). Several mechanisms have been proposed to account for these 
beneficial effects, including the reduction of TG, suppression of cardiac arrhythmias, 
decreased platelet aggregation, improved plaque composition and stabilization, and 
hemodynamic changes. This mounting body of evidence has led the American Heart 
Association (AHA) to recommend the consumption of O3FAs in dietary fish or in capsule 
form at a dose of 1 g/day for secondary prevention of cardiovascular disease (CVD) (Kris-
Etherton 2002). This recommendation has now been included in American College of 
Cardiology/American Heart Association (ACC/AHA) guidelines for the long-term 
management of patients with stable angina and acute coronary syndromes (Antman 2004, 
Fraker 2007, Anderson 2007). 
A large number of studies have also demonstrated the TG-lowering effects of O3FAs (Harris 
1997, Ginsberg 2001). Multiple products have been approved in the US and European Union 
(EU) consisting of approximately 85-90% of the O3FAs EPA and docosahexaenoic acid 
(DHA). These products have generally been approved as prescription products (up to 
4 g/day) to lower TG in patients with TG ≥500 mg/dL when diet alone is insufficient 
(Omacor Summary of Product Characteristics [SPC], 03/2015; Lovaza® United States 
Prescribing Information [USPI], 05/2014). Omacor® at a dose of 1 g/day is also approved in 
certain European and Asian markets for the secondary prevention of myocardial infarction 
(MI), post-MI. 
Epadel capsules, which contain highly purified (>95%) ethyl-EPA, have been marketed by 
Mochida in Japan since 1990 for the treatment of arteriosclerosis obliterans and since 1994 
for the treatment of hyperlipidemia (Epadel SPC 10/2013). The recommended dose is 
1.8 g/day for arteriosclerosis obliterans and 1.8 to 2.7 g/day for hyperlipidemia.  
Hypertriglyceridemia is a feature of many dyslipidemias and often occurs in persons who are 
obese and/or have Type 2 diabetes mellitus in isolation or as a component of the metabolic 
syndrome (Jacobson 2007, Bays 2008). 


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Elevation in TG confers dual risks of acute pancreatitis (most marked in patients with severe 
HTG [TG >1500 mg/dL]) (Yadav 2003) and accelerated atherosclerosis leading to CV 
events, the latter even after correction for other lipid and non-lipid risk factors (Jacobson 
2007). With this in mind, Amarin is assessing the potential of AMR101 capsules, which 
contain highly purified ethyl-EPA, as an adjunct to diet, for the treatment of patients with 
very high TG levels (≥500 mg/dL) and those at high risk for CVD with high TG levels 
(≥200 and <500 mg/dL) despite optimal statin therapy. Amarin-sponsored studies with 
AMR101 in patients with very high TGs (Study AMR-01-01-0016, the MARINE study) and 
in patients at high risk for CVD with high TGs despite statin therapy (Study AMR-01-01-
0017, the ANCHOR study) have been completed (Bays 2011, Ballantyne 2012). 
In July 2012, Vascepa (AMR101; ethyl-EPA; icosapent ethyl) received initial US regulatory 
approval as an adjunct to diet to reduce TG levels in adult patients with severe (≥500 mg/dL) 
HTG. 
1.2. 
Summary of Completed Amarin-Sponsored Clinical Studies of AMR101 in 
Patients with Hypertriglyceridemia 
As of Amendment 2 to this protocol, two Phase 3 studies in patients with HTG have been 
completed. These trials have investigated the efficacy of AMR101 in lowering TG: 
 Study AMR-01-01-0016 (the MARINE study) in 229 patients with very high TG 
(≥500 and ≤2000 mg/dL). 
 Study AMR-01-01-0017 (the ANCHOR study) in 702 patients at high risk for 
CVD with mixed dyslipidemia (high TG: ≥200 to <500 mg/dL) on statin therapy. 
1.2.1. 
Study AMR-01-01-0016 (MARINE) 
The primary objective of the MARINE Study was to determine the efficacy of AMR101 
compared to placebo in lowering fasting TG levels in patients with very high fasting TG 
levels (≥500 and ≤2000 mg/dL). 
A total of 229 patients were randomized (1:1:1) to 12-weeks of double-blind treatment with 
AMR101 2 g/day, AMR101 4 g/day, or pl acebo. Prior to randomization, there was a 4 - to 
6-week diet and lifestyle stabilization period and a 2-week TG qualifying period. Baseline 
characteristics were well balanced between treatment arms. Overall, the mean age was 
52.9 years, mean body mass index (BMI) was 30.8 kg/m2 and approximately 25% of patients 
were using a statin at baseline. In the evaluation of the primary endpoint, the MARINE results 
demonstrated significant placebo-adjusted reductions in median fasting TG levels with 
AMR101 2 g/day (-19.7%; p=0.0051) and 4 g/day (-33.1%; p<0.0001) after 12 weeks of 
treatment. Placebo-adjusted changes in key lipid and inflammatory endpoints are shown in 
Figure 1. The magnitudes of reductions in TG levels observed in MARINE are expectedly 
higher than those seen in ANCHOR, as the patients had very high baseline TG levels. Safety 
and tolerability results for the AMR101 groups were consistent with those seen in previous 
clinical studies in other populations and not notably different from the results in the placebo 
group.  
See Section 1.3 for safety. 


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Figure 1.  Placebo-Adjusted Median Percent Change from Baseline to Week 12 in Key 
Lipid and Inflammatory Endpoints – Intent-to-Treat Population (MARINE) 
 
 
**** p<0.0001; *** p<0.001; ** p<0.01; * p<0.05; NS = Not Significant (p≥0.05) 
Median 
Baseline 
TG: 
703 
(placebo, 
N=75), 
680 
(4 
g/day, 
N=76), 
657 
(2 
g/day, 
N=73) 
mg/dL 
Median Baseline LDL-C: 86 (placebo, N=75), 91 (4 g/day, N=76), 84 (2 g/day, N=73) mg/dL 
Medians are Hodges-Lehmann medians; p-values are from the Wilcoxon rank-sum test. 
Apo B = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol; hsCRP = high sensitivity C-reactive protein; 
LDL-C = low-density lipoprotein cholesterol; Lp-PLA2 = lipoprotein-associated phospholipase A2; non-HDL-C = non-high-
density lipoprotein cholesterol; TC = total cholesterol; TG = triglyceride; VLDL-C = very low density lipoprotein 
cholesterol; VLDL-TG = very low-density lipoprotein triglycerides. 
 
1.2.2. 
Study AMR-01-01-0017 (ANCHOR) 
The primary objective in the ANCHOR study was to determine the efficacy of AMR101 2 g 
daily and 4 g daily, compared to placebo, in lowering fasting TG levels in patients with high 
risk for CVD and fasting TG levels ≥200 mg/dL and <500 mg/dL, despite statin treatment to 
low density lipoprotein cholesterol (LDL-C) goal (>40 mg/dL and <100 mg/dL). 
After a 6 - to 8-week screening period which included diet and lifestyle stabilization, a 
washout period for excluded non-statin lipid-altering medications (if needed), and a TG 
qualifying period, patients were randomized to one of 3 treatment groups and received study 
medication during a 12-week, double-blind treatment period. Patients had to be treated with 
one of 3 s tatins (simvastatin, atorvastatin or rosuvastatin) to reach their LDL-C goal of 
<100 mg/dL (+15% allowed for variability) and had to be on a stable dose for a minimum 
period of 4 weeks before the TG qualifying measurements. The TG target for enrollment was 
for patients to have qualifying fasting TG levels of ≥200 mg/dL and <500 mg/dL based on 
the mean of 2 m easurements. During the 12-week double-blind treatment period, patients 
received orally AMR101 2 g/day, AMR101 4 g/day, or placebo. 
Patients were randomized to either 2 or 4 g/day of AMR101 or placebo for 12 weeks. The 
primary endpoint was the reduction in TG levels compared to placebo. Secondary endpoints 
were percent change in LDL-C compared to placebo, non-high density lipoprotein 


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cholesterol (non-HDL-C), apoB, LpPLA2, and very low density lipoprotein cholesterol 
(VLDL-C). 
The median placebo-adjusted changes in the major lipid parameters for the groups receiving 
statin plus AMR101 are shown in Figure 2.  
Figure 2.  Placebo-Adjusted Median Percent Change from Baseline to Week 12 in Key 
Lipid Endpoints and Inflammatory Endpoints – Intent-to-Treat Population 
(ANCHOR) 
 
**** p<0.0001; *** p<0.001; ** p<0.01; * p<0.05; NS = Not Significant (p≥0.05) 
Median Baseline TG: 259 (placebo, N=227), 265 (4 g/day, N=226), 254 (2 g/day, N=234) mg/dL 
Median Baseline LDL-C: 84 (placebo, N=226), 82 (4 g/day, N=225), 82 (2 g/day, N=233) mg/dL 
Median Baseline non-HDL-C: 128 mg/dL for all treatment groups. 
Median Baseline apoB: 91 (placebo, n=219), 93 (4 g/day, n=217), 91 (2 g/day, n=227) mg/dL 
Medians are Hodges-Lehmann medians; p-values are from the Wilcoxon rank-sum test. 
Apo B = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol; hsCRP = high sensitivity C-reactive protein; ITT=intent to treat; 
LDL-C = low-density lipoprotein cholesterol; Lp-PLA2 = lipoprotein-associated phospholipase A2; non-HDL-C = non-high-density 
lipoprotein cholesterol; TC = total cholesterol; TG = triglyceride; VLDL-C = very low density lipoprotein cholesterol; VLDL-TG = very 
low-density lipoprotein triglycerides. 
 
AMR101 4g/day reduced median placebo-adjusted TG levels nonsignificantly by 13.1% 
(n=45, p=0.5467) in the lowest statin potency regimen (simvastatin 5-10 mg/day); 
significantly by 20.1% (n=429; p<0.0001) in the medium potency statin regimen 
(rosuvastatin 5-10 mg, atorvastatin 10-20 mg, simvastatin 20-40 mg, simvastatin 10-20 mg + 
ezetimibe 5-10 mg); and significantly by 26% (n=213, p<0.0001) in the highest statin 
potency regimen (rosuvastatin 20-40 mg, atorvastatin 40-80 mg, simvastatin 80 mg or 
simvastatin with ezetimibe 5-10 mg). The statin potency regimens were predefined. 
Of the 702 patients with HTG enrolled in this study, 514 h ad diabetes mellitus. Efficacy 
results in patients with diabetes were similar to those of patients without diabetes, and no 
significant changes in fasting plasma glucose or HbA1c with AMR101 vs placebo were 
observed. 
The reduction in TG observed with AMR101 was also associated with a placebo-adjusted 
decrease in median LDL-C levels at both doses. Median baseline LDL-C levels were 
82.0 mg/dL (4 g/day), 82.0 mg/dL (2 g/day), and 84.0 m g/dL (placebo). AMR1014 g/day 


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decreased median placebo-adjusted LDL-C by 6.2% (p=0.0067) which was superior to 
placebo, based on a prespecified +6% margin.  
1.3. 
Clinical Safety 
In the MARINE and ANCHOR trials, a total of 622 patients have been exposed to ethyl-EPA 
from AMR101 capsules. AMR101 has been well tolerated (with incidence of adverse events 
[AEs] similar to placebo) and there have been no major safety concerns. See the 
Investigator’s Brochure for more information. 
The types (by preferred term) of common treatment-emergent adverse events (TEAEs) and 
their incidence in the MARINE and ANCHOR trials are listed in Table 1. 
Table 1: Adverse Reactions Occurring at Incidence >2% and Greater than Placebo in 
Double-Blind, Placebo-Controlled Trials* 
Adverse 
Reaction 
Placebo 
(N=309) 
AMR101 
(N=622) 
N 
% 
N 
% 
Arthralgia 
3 
1.0 
14 
2.3 
*Studies included patients with triglycerides values of 200 to 2000 mg/dL.An additional adverse reaction from clinical 
studies was oropharyngeal pain. 
Source: Vascepa PI, Table 1 
In a large study with Japanese patients (Japan EPA Lipid Intervention Study [JELIS]), long-
term administration of 1.8 g/day ethyl-EPA (Epadel®) was associated with an excellent safety 
and tolerability profile (Yokoyama 2007). Most AEs attributable to ethyl-EPA were regarded 
as mild. The most common adverse events were gastro-intestinal (nausea, diarrhea, epigastric 
discomfort) or dermatologic (eruption, itching, exanthema, eczema) in nature. 
1.4. 
Rationale 
Hypothesis 
The hypothesis is that combination anti-dyslipidemic therapy of an LDL-C lowering drug 
(statin therapy) with the TG-lowering drug AMR101 will be superior to the LDL-C lowering 
therapy alone when used as prevention in reducing long-term clinical events in patients with 
mixed dyslipidemia at high risk for CV events. 
Medical Need 
CVD resulting from progressive atherosclerosis remains the most common cause of 
morbidity and mortality all over the world. Based on 2009-2012 US statistics (AHA 2016), 
an estimated 85.6 million American adults (more than one in three) have one or more types 
of CVD. Of these, 43.7 million are estimated to be age 60 or older. Total CVD includes 80 
million with high blood pressure (HBP), 15.5 million with coronary heart disease (CHD), 
which includes 7.6 million with myocardial infarction and 8.2 million with angina pectoris, 
5.7 million with heart failure (HF) and 6.6 million with stroke (all types). Mortality data 
show that CVD as the underlying cause of death accounted for 30.8% of all deaths (about 
800,937 of all 2.6 million deaths in 2013). CVD is the leading global cause of death, 
accounting for >17.3 million deaths per year in 2013, a number that is expected to grow to 
>23 million by 2030. In 2013, CVD deaths represented 31% of all global deaths. In addition 


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to death, CVD also causes many serious non-fatal events and is the major cause of disability. 
Therefore, additional therapies for prevention of CVD would have a considerable public 
health benefit. 
Hypertriglyceridemia is a common lipid abnormality and often occurs in persons who are 
obese and have insulin resistance, Type 2 di abetes mellitus, or the metabolic syndrome 
(Jacobson 2007; Bays 2008). Elevation in TG is positively associated with accelerated 
atherosclerosis leading to CV events, the latter even after correction for other lipid and non-
lipid risk factors (Jacobson 2007). In the US (AHA 2016), the mean TG level for American 
adults age 20 and older is 108.8 mg/dL (men, 117.2 mg/dL; women, 101.4 mg/dL). 
Approximately 25.1% of adults had high triglyceride (TG) levels (>150 mg/dL) during 
2009-2012. 
Lifestyle modification is important for the management of patients with HTG; however, for 
patients who do not adequately respond to dietary and lifestyle restrictions, relatively few 
classes of drugs are available to treat HTG, and each is associated with risks that may limit 
their use alone or in combination. In addition to Vascepa, currently available 
pharmacological treatments for high and/or very TG include fibric acid derivatives (such as 
gemfibrozil and fenofibrate), niacin in various formulations, prescription omega-3-acid ethyl 
esters (Lovaza/Omacor) and statins (3-hydroxy-3-methylglutaryl coenzyme A reductase 
inhibitors).  
Although the above agents have robust TG-lowering effects in patients with HTG, the degree 
of TG-lowering is highly variable; generally greater TG-lowering effects are observed for 
each TG-lowering agent compared with statins, particularly compared to the efficacy of 
statin doubling in patients with dyslipidemia. Many patients will be satisfactorily treated with 
one or more of the above range of drugs (combined with appropriate diet and attention to 
other CV risk factors and lifestyle). 
A large number of studies have demonstrated the TG-lowering effects of O3FAs (Ballantyne 
2012; Ginsberg 2001; Harris 1997). Lovaza, comprised predominantly of ethyl-EPA and the 
ethyl ester of DHA (ethyl-DHA) and approved at 4 g/day (equivalent to 4 capsules/day), is 
indicated only in patients with very high TG levels (≥500 mg/dL), and raises LDL-C even 
when combined with statins in patients with high (200-499 mg/dL) and very high 
(≥500 mg/dL) TGs.  Of the seven CVOTs utilizing mixtures of EPA and DHA (see Table 3), 
two demonstrated significant primary endpoint risk reduction, one demonstrated CV risk 
reduction only in the post hoc analysis of diabetic patients, and four did not demonstrate 
benefit. 
Fibrates and niacin are clearly effective at raising HDL-C and lowering TG concentrations; 
fibrates also raise LDL-C in patients with very high TGs (≥500 mg/dL). However, their 
effects on vascular events remain uncertain. Several large-scale trials of fibrate therapy have 
been completed in the past few years. Although some of these trials have suggested benefit, 
others have shown no effect, leading to uncertainty about the presence and magnitude of any 
CV protective effects and difficulties for clinicians in interpretation of the results (Jun 2010). 
The ACCORD-Lipid study (Ginsberg 2010) reported no overall benefit for fenofibrate plus 
statin therapy over statin monotherapy, although a suggestion of benefit was observed in 
subjects with dyslipidemia defined by high TG and low HDL-C. Similarly, studies of niacin 
as add-on therapy to statin have not demonstrated a benefit with regard to CV outcomes in 


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their full study populations (see AIM-HIGH and HPS2-THRIVE ), although benefit was 
observed in a subset of AIM-HIGH patients with high TG and low HDL-C. While such 
subgroup analyses are suggestive of benefit in certain patients with dyslipidemia, the lack of 
benefit in the primary study populations nonetheless raises further questions about the 
usefulness of these agents. 
There are also safety issues with the above agents that limit th eir clinical use. Statins, 
particularly at high doses, may cause increases in hepatic transaminases and are also known 
to cause myopathy and occasionally rhabdomyolysis, which may lead to death from acute 
renal failure. This risk may be increased when fibrates and statins are co-administered and 
many clinicians will avoid co-prescribing these 2 medications. Fibrates are also associated 
with interactions with warfarin and hepatic transaminase elevations. The utility of niacin is 
limited by the occurrence of severe flushing and associated symptoms which can be difficult 
to manage even with careful dose titration and pre administration of aspirin or other non-
steroidal anti-inflammatory drugs. Niacin is also associated with impairment of glucose 
tolerance and precipitation of attacks of gout in susceptible patients. 
The DYSlipidemia International Study (DYSIS) assessed the prevalence of dyslipidemia 
among patients taking statins. This epidemiological observational study included more than 
22,000 patients in Europe and Canada aged 45 and older who received statin therapy for at 
least three months, and had a clinical diagnosis of coronary or other atherosclerotic disease, 
or were at high risk of developing CVD. The study found 48% of patients had LDL-C not at 
goal; 26% had low HDL-C levels; and 38% had elevated TG. This study demonstrates that 
persistent dyslipidemia is highly prevalent in statin-treated patients. 
Patients with dyslipidemia, particularly those with established CVD or diabetes, have 
therapeutic needs that cannot be met by statin monotherapy. It is hypothesized that achieving 
target values for LDL-C/non-HDL-C in these patients using a therapeutic approach of the 
combination of AMR101 and a statin will benefit these patients. Such a combination therapy 
might increase the likelihood of therapeutic success in these patients with regards to future 
risk of CVD, based on meeting of both LDL-C/non-HDL-C goals and TG goals according to 
the ACC/AHA guidelines (Anderson 2007). Approximately 40 million Americans have high 
TG levels (≥200 mg/dL), however only a minority (3.6%) are currently treated with 
prescription medication (Ford 2009). Patients with elevated TGs are currently under-served 
and would benefit from a new, safe and effective product that can provide the following 
attributes: 
 Robust efficacy to lower TGs 
 Safe to use with other lipid-lowering agents, including statins 
 Does not increase LDL-C when used in patients on s tatin therapy 
(TG=200-499 mg/dL) 
 Has convenient dosing regimen 
 Has class-specific positive outcomes data 
TG-Lowering as a Therapeutic CV Target 
Epidemiological, clinical, and recent genetic studies contribute to evidence that increased TG 
levels causatively increase the risk for CVD and that treating elevated TG levels results in 
CV benefit. Multiple studies of mutations within genes encoding various proteins associated 


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with TG and the metabolism of TG-rich lipoproteins have independently suggested a link 
between TG levels and CV risk.  For example, in one genetic study mutations of gene loci 
that lower TG levels were associated with decreased risk of CVD and other studies have 
further implicated loci associated with TG levels as contributing independently to coronary 
artery disease (CAD) risk (Pollin 2008, Schunkert 2011, Jørgensen 2014, Do 2013, Do 2015, 
Dewey 2016, S titziel 2016). In addition, loss-of-function mutations of the gene encoding 
apolipoprotein C3 (APOC3), associated with low non-fasting levels of TG, resulted in risk 
reduction of 41% for ischemic vascular disease for heterozygotes compared with non-carriers 
(hazard ratio [HR] 0.59, 95% confidence interval [CI]: 0.41-0.86; p=0.007) and a risk 
reduction of 36% for ischemic heart disease (HR 0.64, 95 % CI: 0.41-0.99; p=0.04) 
(Jørgensen 2014). Similarly, in another study, deleterious mutations to APOC3 resulted in 
reductions of risk of 40% (OR 0.60; 95% CI: 0.47-0.75; P=4×10-6) (The TG and HDL 
Working Group 2014) compared with non-carriers. In yet another study of genes strongly 
associated with TG levels (but not HDL-C), the direction of the association and its magnitude 
were both consistent with a contribution of risk for CAD (Do 2013). Moreover, studies 
centering on the metabolism of TG-rich lipoproteins have also put these TG-rich lipoproteins 
within the causative pathway of CVD, similar to LDL-C (Wittrup 1999, Do 2015). Of note, 
the same genetic correlation between HDL-C and CVD was not found.  
Epidemiological and clinical studies have shown that elevated levels of total cholesterol (TC) 
and LDL-C are associated with increased risk of CHD (LaRosa 2003), and therapeutic 
strategies that lead to a statistically significant reduction in LDL-C lower CHD event rates 
(Baigent 2005). One potential impediment to optimal reduction in CHD events despite low 
on-treatment LDL-C is residual elevation in serum TG levels (Miller 2000). Indeed, even 
after adjustment for HDL-C, detailed evaluation of population-based prospective studies has 
disclosed an independent effect of TG on C HD events (Sarwar 2007). Coupled with the 
knowledge that combined hyperlipidemia (i.e., elevated LDL-C and TG) promotes CHD to a 
significantly greater extent than either high LDL-C or TG alone (Manninen 1992), the 
hypothesis is strong that low on-treatment levels of TG when added to low LDL-C would be 
superior to low LDL-C alone in reducing subsequent CHD events. Supporting evidence for 
this hypothesis was obtained in a post-hoc analysis of the Pravastatin or Atorvastatin 
Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Trial (PROVE 
IT-TIMI 22) (Miller 2008) wherein among patients receiving statin therapy after acute 
coronary syndrome (ACS), on treatment TG <150 mg/dL was associated with a lower risk of 
recurrent CHD events independent of the level of LDL-C. For each 10% lowering of TG 
attained during the first 30 days of treatment after an ACS event, the risk for death, MI, or 
recurrent ACS was reduced by 2.3% (p =0.035) after adjustment for high LDL-C 
(>70 mg/dL) and low HDL-C (<40 and 50 mg/dL in men and women, respectively). 
Several large clinical studies have examined the effects of non-statin lipid-modifying agents 
(with TG-lowering effects) in combination with statin therapy versus statin monotherapy on 
CV events (see Table 2). 


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Table 2.  Published Clinical Studies of the Effects of Lipid-modulating Agents Plus Statin Therapy versus Statin Monotherapy 
on Cardiovascular Events  
Trial 
 
Pub. Year 
CV Risk 
Profile 
 
(therapy) 
 
N 
Stated Goal 
(as statin add-on) 
Statin-treated TG 
Lower Limit 
 
(Upper Limit) 
 
(mg/dL) 
Median 
Baseline TG 
(mg/dL) 
 
(IQR) 
Primary 
Endpoint 
 
(p-value) 
TG + HDL-C 
Subgroup 
Baseline Criterion 
(mg/dL) 
 
N (% full cohort) 
TG + HDL-C 
Subgroup 
Endpoint 
 
(p-value) 
ACCORD- 
Lipid 
 
Ginsberg 
2010 
Type II DM 
1o & 2o Prevention 
 
(fenofibrate) 
 
N = 5,518 
CV benefit of 
raising HDL-C & 
lowering TG 
None 
 
(<400) 
162 
(113, 229) 
 
Note: At BL 
~40% of 
patients were 
statin-naive 
MACE 
 
HR 0.92 (0.32) 
TG ≥204 
HDL-C ≤34 
 
N = 941 (17%) 
-31% 
(0.057) 
AIM-HIGH 
 
AIM-HIGH 
Investigators 
2011 
CVD 
2o Prevention 
 
(ER Niacin) 
 
N = 3,414 
CV benefit of 
raising HDL-C 
≥100 
 
(≤400) 
163 
(127, 218) 
Expanded 
MACE 
 
HR 1.02 (0.79) 
TG ≥198 
HDL-C <33 
 
N = 522 (15%) 
---------------------- 
TG ≥200 
HDL-C <32 
 
N = 439 (13%) 
-26% 
(0.073) 
 
--------------- 
 
-36% 
(0.032) 
HPS2-
THRIVE 
 
HPS2-
THRIVE 
Collaborative 
Group 2014 
CVD 
2o Prevention 
 
(ER Niacin + 
Laropiprant) 
 
N = 25,673 
CV benefit of 
raising HDL-C 
None 
 
(None) 
108 
(Full IQR = 73) 
MVE 
 
RR 0.96 (0.29) 
TG ≥151 
HDL-C: 
<40 (men) 
<51 (women) 
 
N = 4,362 (17%) 
No significant 
difference between 
groups* 
 
 
 
 
 
 


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Table 2. Published Clinical Studies of the Effects of Lipid-modulating Agents Plus Statin Therapy versus Statin Monotherapy 
on Cardiovascular Events (Continued) 
 
Trial 
 
Pub. Year 
CV Risk 
Profile 
 
(therapy) 
 
N 
Stated Goal 
(as statin add-on) 
Statin-treated TG 
Lower Limit 
 
(Upper Limit) 
 
(mg/dL) 
Median 
Baseline TG 
(mg/dL) 
 
(IQR) 
Primary 
Endpoint 
 
(p-value) 
TG + HDL-C 
Subgroup 
Baseline Criterion 
(mg/dL) 
 
N (% full cohort) 
TG + HDL-C 
Subgroup 
Endpoint 
 
(p-value) 
JELIS 
 
Yokoyama 
2007 
High Cholesterol 
1o & 2o Prevention 
 
(EPA) 
 
N = 18,645 
CV benefit of EPA 
therapy in Japanese 
with high 
cholesterol 
None 
 
(None) 
153 
(109, 220) 
 
Note: Statin 
therapy 
initiated at BL 
in all patients 
Expanded 
MACE 
 
HR 0.81 
(0.011) 
TG ≥150 
HDL-C ≤40 
 
N = 957 (5%) 
 
Note: Only 
1o Prevention patients 
were analyzed 
-53% 
(0.043) 
1o: Primary, 2o: Secondary, ACCORD: Action to Control Cardiovascular Risk in Diabetes; AIM-HIGH: Atherothrombosis Intervention in Metabolic Syndrome with Low 
HDL/High Triglycerides: Impact on Global Health Outcomes; BL: baseline; CVD: cardiovascular disease; DM: diabetes mellitus; EPA: eicosapentaenoic acid; ER: extended-
release; HDL-C: high-density lipoprotein cholesterol; HPS2-THRIVE: Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events; HR: hazard ratio; 
IQR: interquartile range; JELIS: Japan Eicosapentaenoic Acid Lipid Intervention Study; MACE: major adverse coronary events ; MVE: major vascular events; RR: relative risk; 
TG: triglycerides. 


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The ACCORD-Lipid Study 
The ACCORD-Lipid study, a substudy of ACCORD, was a randomized, double-blind study 
of fenofibrate+statin therapy vs placebo+statin therapy in 5518 patients with Type 2 diabetes 
mellitus with clinical CVD, anatomical evidence of CVD, or 2 additional risk factors (in 
addition to diabetes) for CVD (Ginsberg 2010). The study evaluated whether the use of 
fenofibrate and simvastatin to increase plasma HDL-C and reduce TG would provide an 
additional CV benefit compared to simvastatin alone, as determined by the rate of first 
occurrence of any of a composite of nonfatal MI, nonfatal stroke, or CV death. Baseline 
characteristics were similar between treatment groups. After a mean follow-up of 4.7 years, 
the annual rates of CV events were not significantly different between treatment groups 
(2.2% for fenofibrate and 2.4% for placebo; HR: 0.92, 95%  CI: 0.79-1.08; p=0.32). In 
examined subgroups, there was a suggestion of heterogeneity according to baseline lipid 
levels. Although ACCORD-Lipid did not prospectively enroll patients specifically with high 
TG (baseline median 162 mg/dL; interquartile range [IQR] of 113-229 mg/dL), and 40% of 
patients were not on statin therapy at baseline, a non-significant numerical reduction in CV 
event rate with fenofibrate was observed in patients in the highest baseline TG tertile (11.1% 
for fenofibrate vs 12.8% for placebo). A more compelling trend toward benefit approached 
significance in a smaller subgroup of patients within both the highest baseline TG tertile 
(≥204 mg/dL) and lowest baseline HDL-C tertile (≤34 mg/dL), with fenofibrate vs placebo 
(12.4% vs 17.3%; p=0.057 for interaction). Although the results of ACCORD-Lipid suggest 
an association of TG reduction with reduction in CV events in patients with dyslipidemia, the 
facts that approximately 65% of patients had had baseline TG <200 mg/dL, and that 40% of 
patients were not on statin therapy at baseline, diminish the ability of the study to examine 
the effects of TG-lowering in patients with high TG levels despite stable statin therapy.  
The AIM-HIGH Study 
The AIM-HIGH Study was a randomized, blinded, placebo-controlled study of the effects of 
extended-release niacin 1500–2000 mg/day in 3414 CVD patients receiving simvastatin on 
the primary endpoint of incidence of CV events (first event of death from coronary heart 
disease, nonfatal MI, ischemic stroke, hospitalization for >23 hours from ACS, or symptom-
driven coronary or cerebral revascularization) (AIM-HIGH Investigators 2011). The study 
was stopped early due to futility and safety concerns, which subsequently were determined 
not to be drug-related. In this trial, extended-release (ER) niacin plus simvastatin as 
compared with simvastatin alone was associated with significant increases in HDL–C levels 
and decreases in TG levels, but there was no significant reduction in the primary composite 
endpoint of CV events over a mean follow-up period of 36 m onths (HR=1.02, 95% 
CI=0.87-1.21, p=0.79). Although AIM-HIGH did not prospectively enroll patients with 
elevated TG levels (baseline median TG for the niacin arm was 164 mg/dL; IQR=127-218 
mg/dL), when the effect of treatment on CV events by baseline lipid/lipoprotein tertiles was 
studied, for the 522 (15.3%) subjects who simultaneously had baseline TG levels in the 
highest tertile (>198 mg/dL) and HDL-C levels in the lowest tertile (<33 mg/dL), a 
nonsignificant trend toward reduction of CV risk was evident in the ER niacin group (HR: 
0.74, p=0.073). In a smaller subgroup (n=439 [12.9%]) that met somewhat stricter criteria of 
TG levels >200 mg/dL and HDL-C levels <32 mg/dL, the reduction in events in the niacin 
group was significant (HR: 0.64, p=0.032). Although AIM-HIGH did not prospectively seek 


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to enroll statin-treated patients with persistently high TG, and therefore was not well suited to 
studying the benefit of TG-lowering in this patient population, the results of subgroup 
analyses are consistent with a CV benefit to TG-lowering therapy in patients with 
dyslipidemia despite statin-controlled LDL-C. 
The HPS2-THRIVE Study 
The HPS2-THRIVE Study was a randomized, double-blind, placebo-controlled study of 
niacin 2000 mg/day and laropiprant 40 mg/day in addition to statin therapy vs matching 
placebo added to statin therapy in 25,673 adult patients with occlusive arterial disease at high 
risk for CVD (HPS2-THRIVE Collaborative Group 2014). The primary endpoint was the 
first event of a composite of major vascular events (including nonfatal MI, coronary death, 
nonfatal or fatal stroke, coronary or non-coronary artery surgery or angioplasty [including 
amputation]). Mean follow-up was 3.9 years. The study did not demonstrate a benefit to 
niacin therapy added to statin vs statin alone in the full study population (HR=0.96; 95% 
CI = 0.90-1.03, p=0.29). An exploratory analysis of patients with high TG (≥151 mg/dL) and 
low HDL-C (<35 mg/dL) found no significant difference between the niacin/laropiprant 
group and the placebo group in the incidence of major vascular events (15.1% vs 15.5%, 
respectively, of patients with an event). Of note, an important consideration for this analysis 
is that there were no lipid inclusion criteria in HPS2-THRIVE and, as a result, the median 
baseline TG value was 108 mg/dL with a full interquartile range of 73 mg/dL (mean TG ± 
standard deviation was 125 ± 74 m g/dL), markedly lower than the median baseline TG 
values in ACCORD-Lipid and AIM-HIGH. In addition, the interquartile range is reflected in 
the fact that only 26% of patients in the HPS2-THRIVE trial had TG values at or above 151 
mg/dL, and suggests that very few subjects had TG levels >200 mg/dL. Accordingly, it is 
difficult to glean from HPS2-THRIVE any conclusive information regarding the potential 
CV benefit of niacin therapy in subjects with high TG despite statin therapy. 
The Japan EPA Lipid Intervention Study (JELIS) 
While no outcome study to date has specifically tested the benefit of lowering TG in a statin-
treated population with persistent HTG, JELIS has demonstrated the CV benefit of 1.8 g/day 
ethyl-EPA added to a statin in 18,645 patients with elevated cholesterol (Yokoyama 2007). 
JELIS was a prospective, randomized, open-label, blinded endpoint evaluation (PROBE 
design) study of ethyl-EPA 1.8 g/day added to statin therapy versus statin alone in Japanese 
patients with hypercholesterolemia. JELIS is the only completed cardiovascular outcomes 
trial (CVOT) that has looked specifically at the effects of ethyl-EPA therapy – without DHA 
or other omega-3 fatty acids – on CV risk reduction.  The mean follow-up was 4.6 years. The 
primary endpoint was the occurrence of major coronary events, including sudden cardiac 
death, fatal and non-fatal MI, unstable angina pectoris, angioplasty, stenting, and coronary 
artery bypass grafting. JELIS demonstrated a 19% relative reduction in the risk of major 
coronary events (primary endpoint) in the ethyl-EPA plus statin group vs statin alone group 
(HR = 0.81, 95% CI = 0.69 to 0.95). In addition to the significant primary outcome, and as 
performed in the ACCORD-Lipid, AIM-HIGH, and HPS2-THRIVE trials, the JELIS 
investigators conducted a sub-analysis of primary prevention patients with abnormal lipid 
levels, defined as baseline (statin-naïve) TG ≥150 mg/dL and HDL-C <40 mg/dL. Compared 
to patients with normal baseline serum TG and HDL-C levels, those with abnormal levels 


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had a significantly higher risk of CAD, and ethyl-EPA treatment suppressed the risk of 
primary events by 53% (HR: 0.47, 95% CI: 0.23-0.98; p=0.043). 
As the only major published CVOT administering ethyl-EPA-only co-therapy with statin, 
JELIS is most similar in design to the current REDUCE-IT study. Therefore, it is worthwhile 
to note some details of JELIS design and the resulting data that differ from REDUCE-IT. 
First, the baseline TG levels in JELIS were fairly low (153-154 mg/dL). Also of note, JELIS 
was conducted exclusively in Japanese patients, and the Japanese population is generally 
found to have lower CV risk rates and higher baseline EPA levels in comparison to Western 
populations; the latter, which is believed to be due to higher dietary intake. Baseline plasma 
EPA levels were high in JELIS, and yet despite the differences in EPA baseline levels, along 
with the dose and duration of treatment between JELIS (1.8 g/day in a Japanese population 
for a median follow-up of 4.6 years) and the ANCHOR study (4 g/day in a more diverse and 
Westernized population for 12 w eeks), the final plasma EPA levels were similar between 
these studies. In addition, there are other aspects of the JELIS study that might limit its  
applicability to broader patient populations. The majority (69%) of patients enrolled in JELIS 
were women. Furthermore, treatment in JELIS was open-label (although endpoint 
adjudication was blinded), which could influence patient and physician behavior and 
reporting of symptoms, decisions regarding hospitalization, and referral of events for 
adjudication. This may be particularly relevant since the number of hospitalizations for 
unstable angina was a primary contributor to the overall positive result, and is considered a 
softer endpoint than fatal CV events. Finally, at baseline, statin-naïve patients had a high 
LDL-C and a d ose of statins was administered that would be considered low in a more 
Westernized patient population, potentially limiting the generalizability of the JELIS study 
results to a broader, more aggressively-treated population. Therefore, overall it is unknown 
whether the positive treatment effects observed in JELIS would have persisted if patients had 
been more optimally treated with statins using contemporary LDL-C targets in the United 
States. Nonetheless, 80% of JELIS patients were primary prevention and the mean baseline 
LDL-C of 182 mg/dL was reduced by 25% with statin therapy, to approximately 136 mg/dL. 
For primary prevention Japanese patients at low risk for CAD death, an LDL-C <160 mg/dL 
would meet LDL-C treatment goals according to the Japanese Atherosclerosis Society (JAS) 
guidelines, and an LDL-C <140 mg/dL would meet treatment goals for primary prevention 
Japanese patients at moderate risk (Teramoto 2013). Therefore, while some higher risk JELIS 
subjects may not have been treated as aggressively as guidelines for a United States-based 
population would recommend, the mean LDL-C data and the patient distribution from JELIS 
would suggest that many of the low-to-moderate risk primary prevention subjects were 
treated to Japanese guidelines. 
Overall, in the JELIS study, ethyl-EPA therapy added to statin therapy resulted in a coronary 
benefit beyond statin monotherapy in both the full cohort of patients with relatively normal 
TG levels (-19%; p=0.011) and a more dramatic benefit within a subgroup of higher risk 
patients with dyslipidemia (-53%; p=0.043). In contrast, there was a suggestion of CV 
benefit from fenofibrate or niacin co-therapy with statin only in subjects with dyslipidemia 
within ACCORD-Lipid (-31%; p=0.057) and AIM-HIGH (-36%; p=0.032). Taken together, 
these studies suggest that there may be a CV benefit to TG-lowering therapies in subjects 
with dyslipidemia despite statin-controlled LDL-C (sub-group analyses), and that ethyl-EPA 
therapy may have additional unique CV benefits beyond treatment of dyslipidemia (JELIS 
full cohort). 


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IMPROVE-IT 
In addition to studies of TG-lowering agents as add-on to statins, the IMPROVE-IT study 
assessed the effect of ezetimibe on lipids via inhibition of cholesterol absorption in 18,144 
patients with ACS. The study found reductions in LDL-C, along with TG and other lipid 
changes, corresponding to reduced incidence of a composite primary endpoint of CV events 
(median follow-up of 6 years). The reduction in the composite of CV death, nonfatal MI, 
unstable angina requiring rehospitalization, coronary revascularization (≥30 days after 
randomization), or nonfatal stroke suggests that CV benefit can be derived from add-on 
therapy to statin. 
In contrast to the CV benefit of ezetimibe co-therapy with statin observed in IMPROVE-IT, 
many studies have co-administered therapies that reduce TG levels without CV benefit in the 
full study populations, despite reductions in TG levels and increases in HDL-C (Table 2). 
Importantly, these studies did not prospectively enroll subjects at risk due to high TG levels 
despite statin therapy, which resulted in mean/median baseline TG levels that were normal or 
only slightly elevated (108-163 mg/dL). Nonetheless, in subgroup analyses of patients with 
high TG and low HDL-C, three of the four studies in Table 2 suggest that patients with 
dyslipidemia may derive CV benefit from TG-lowering therapies. 
Omega-3 Fatty Acids in Fish Oils 
There is a growing body of evidence, encompassing molecular, cellular, animal and human 
studies defining the roles for O3FAs as bioactive agents for reducing the risks of and treating 
CVD (Torrejon 2007). Many epidemiological studies have demonstrated inverse associations 
between fish intake and CV death, and more specifically between the intake and blood levels 
of O3FAs and CV death. For example, when comparing blood levels of O3FAs among men 
who had died of sudden cardiac death with controls matched for age and smoking status, it 
was found that participants with the highest blood levels of EPA and DHA had a 90% risk 
reduction for sudden cardiac death compared with those with the lowest levels (Albert 2002). 
Clinical trials and experimental studies, suggest important antiatherogenic and antithrombotic 
effects of O3FAs. These result from wide-ranging biological effects, including benefits on 
lipoprotein metabolism, blood pressure, endothelial function and vascular reactivity, 
inflammation, platelet and fibrinolytic function, cytokine production, coagulation and 
oxidative stress (Mori and Woodman 2006). Evidence suggests that increased consumption 
of O3FAs from fish or fish-oil supplements reduces the rates of all-cause mortality, cardiac 
and sudden death, and possibly stroke (Wang 2006). The effect was evident in both primary-
prevention (general population without a history of CVD) and secondary-prevention (patients 
with a history of CVD) studies with a stronger effect in secondary prevention. 
The Diet and Reinfarction Trial (DART) was one of the first randomized, controlled studies 
to demonstrate the beneficial effects of O3FAs in secondary prevention of CHD and reported 
a 29% reduction in all-cause mortality over a 2-year period in 2033 male MI survivors 
advised to increase their intake of oily fish (200 to 400 g of fatty fish per week, which 
provided 500 to 800 mg/day of O3FAs) (Burr 1989). While not statistically significant, there 
was also a trend toward a reduction in recurrent ischemic heart disease events with increased 
fatty fish consumption. A post hoc analysis of patients receiving fish oil capsules 
(900 mg/day of EPA+DHA) in DART suggested that the protective effect was attributable to 


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O3FAs (Burr 1994). The greatest benefit was seen in fatal MIs, and this observation led to 
the hypothesis that O3FAs might protect the myocardium against the adverse sequela of 
acute ischemic stress. 
A cardioprotective effect for O3FAs derived from fish oil is also supported by other 
prospective studies demonstrating inverse associations between fish intake and coronary 
heart disease mortality, especially amongst high-risk individuals (Mori and Woodman 2006). 
Early separation of survival curves in the Gruppo Italiano per lo Studio della Sopravvivenza 
nell’Infarto Miocardico (GISSI)-Prevenzione study (GISSI-Prevenzione Investigators 1999; 
discussed below) and the DART trial support a reduction in ventricular fibrillation and a 
decreased incidence of myocardial infarction (Leaf 1996) as primary mechanisms through 
which O3FAs prevent CVD (Mori and Woodman 2006). 
Many international bodies including the AHA, ACC, and the European Society of 
Cardiology have found the overall evidence for benefit sufficiently strong to make public 
recommendations for increased O3FA intake for both primary and secondary prevention 
(Harris 2007). 
Omega-3 Fatty Acid Ethyl Esters 
Most CV primary and secondary prevention outcomes trials utilizing OM3FA focused on 
mixtures predominantly comprised of EPA+DHA, while one focused on EPA alone.  The 
largest prospective, randomized, controlled trial to test the efficacy of O3FAs for secondary 
prevention of CHD is the GISSI study (GISSI-Prevenzione Investigators 1999). In this study, 
11,324 patients with preexisting CHD (experienced an MI and were receiving conventional 
cardiac pharmacotherapy) were randomized to either 300 mg of vitamin E, 850 mg of O3FA 
ethyl esters (as EPA and DHA), both, or neither. After 3.5 years of follow-up, the group 
given the O3FAs alone experienced a 15% reduction in the primary endpoint of death, 
nonfatal MI, and nonfatal stroke (p <0.02). There was a 20% reduction in all-cause mortality 
(p =0.01) and a 45% reduction in sudden death (p <0.001) compared with the control group; 
vitamin E provided no additional benefit. TG decreased by 4% and LDL cholesterol levels 
increased by 2.5% after six months in the O3FA treatment groups compared with controls. 
This trial, although very large and carried out in a relatively "usual-care" setting, was not 
placebo controlled, dropout rates were high (>25%), and statin use was not required. A 
follow-up study (Marchioli 2002) assessed the time-course of the benefit of O3FAs on 
mortality in subjects in the GISSI-P Study and found that survival curves diverged early after 
randomization. Total mortality was significantly lowered by 28% after 3 months of treatment 
(RR =0.59), and by 4 months, the risk of sudden cardiac death was reduced by 45% 
(RR =0.47). 
Since the completion of GISSI, several primary and secondary prevention studies failed to 
find a CV benefit to OM3FA therapy, especially beyond statin monotherapy. High-level 
tabulated summaries of eight major CV outcomes trials testing omega acid mixtures or ethyl-
EPA alone are presented in Table 3. Of the seven trials utilizing mixtures of EPA and DHA, 
two demonstrated significant primary endpoint risk reduction, one demonstrated CV risk 
reduction only in the post hoc analysis of diabetic patients, and four did not demonstrate 
benefit. All seven of these trials had design limitations, but key consistent limitations were 
low OM3FA dosing (containing 376-850 mg/day EPA+DHA), possible underutilization of 


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statin therapy, and lack of statistical powering. It is also worth noting that of the six studies 
that reported baseline LDL-C, median levels were relatively low (95-137 mg/dL). Median 
baseline TG were also relatively low across the studies (106-185 mg/dL), with all seven 
studies being below 200 mg/dL. These patients therefore do not necessarily represent patients 
presenting with persistent HTG despite LDL-C being treated to goal, nor did they test the CV 
benefit of higher dose OM3FA therapy. 
Ethyl-EPA 
While no outcome study to date has specifically tested the benefit of lowering TG with 
ethyl-EPA in a statin-treated population with persistent HTG, JELIS has demonstrated the 
CV benefit of 1.8 g/day ethyl-EPA added to a statin in 18,645 pa tients with elevated 
cholesterol (Table 3).  As discussed above, JELIS exhibited a 19% relative reduction in the 
risk of major coronary events (primary endpoint) in the EPA plus statin group vs statin alone 
group (HR = 0.81, 95% CI=0.69 to 0.95) (see Section 1.4, The Japan EPA Lipid Intervention 
Study). There is evidence supporting a benefit in both primary and secondary prevention, as 
there was a nonsignificant 18% decrease in CV events in the 80% of patients in the JELIS 
trial without documented CAD (p =0.13); with this effect size being essentially the same as 
that observed in the secondary prevention cohort (19%, p <0.05) (Lee 2008). 
Unlike the other OM3FA studies presented in Table 3 that administered an EPA+DHA 
mixture, the JELIS trial established the safety and efficacy of combination therapy with 
ethyl-EPA and a statin versus statin therapy alone for improving CV prognosis. The JELIS 
trial was conducted with Epadel that contains the same active ingredient, ethyl-EPA, as 
AMR101. Ethyl-EPA was shown in the JELIS study to reduce CAD events even in a 
Japanese population with very high intakes of O3FAs due to the high fish consumption.  
 


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Table 3.  Omega Acid Mixture or EPA-only Outcomes Trials 
Study 
Population 
Baseline 
LDL-C 
[mg/dL] 
Baseline 
TG 
[mg/dL] 
Interventions 
Statin Use 
(% at BL) 
Duration  
(years) 
Primary Endpoint 
Outcomes (CI) 
Omega acid mixture studies 
GISSI-P 
(GISSI-
Prevenzione 
Investigators 
1999) 
11,324 pts 
recent MI 
(≤3 mon) 
137 
163 
850 mg 
EPA+DHA vs. Vit 
E vs.n-3+Vit E vs. 
placebo 
5% 
(EoS=46%) 
3.5 
Death+non-fatal 
MI/stroke 
RR = 0.85 
(0.74 to 0.98) 
[four-way analysis] 
GISSI-HF 
(GISSI-HF 
Investigators 
2008) 
6975 pts 
symptomatic HF 
Not 
provided 
126 
850 mg 
EPA+DHA vs. 
placebo 
22-23% 
3.9 
Co-primary of death, 
and death or CV 
hospitalization 
Death HR: 0.91 (0.833– 
0.998) 
Death or CV 
hospitalization HR: 0.92 
(0.849–0.999) 
OMEGA 
(Rauch 2010) 
3851 pts 
recent MI 
(≤2 wks) 
Not  
provided 
Not 
provided 
840 mg 
EPA+DHA vs. 
placebo 
94-95% 
1 
SCD 
OR = 0.95 
(0.56 to 1.60) 
Alpha-Omega 
(Hoogeveen 
2014) 
4837 pts 
history of MI 
(median 3.7 yrs) 
99-102 
144-150 
376 mg 
EPA+DHA vs. 
placebo and ALA  
(1.9 g combined) 
83% 
3.4 
MACE 
HR = 1.01 
(0.87–1.17) 
SU.FOL.OM3 
(Galan 2010) 
2501 pts recent 
coronary or 
cervical 
ischemic event 
(median 101 d) 
104 
106 
600 mg 
EPA+DHA vs. 
placebo and B 
vitamin 
83-87% 
(lipid-
lowering 
agents) 
4.2 
MACE 
HR = 1.08 
(0.79 to 1.47) 
ORIGIN 
(ORIGIN Trial 
Investigators 
2012) 
12,536 pts 
dysglycemia 
112 
140-142 
840 mg 
EPA+DHA vs. 
placebo 
53-54% 
6.2 
CV death 
HR = 0.98  
(0.87–1.10) 
 
 
 
 
 


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Table 3.  Omega Acid Mixture or EPA-only Outcomes Trials  (Continued) 
 
Study 
Population 
Baseline 
LDL-C 
[mg/dL] 
Baseline 
TG 
[mg/dL] 
Interventions 
Statin Use 
(% at BL) 
Duration  
(years) 
Primary Endpoint 
Outcomes (CI) 
Risk & 
Prevention 
(Risk & 
Prevention 
Study 
Collaborative 
Group 2013) 
12,505 pts 
high risk CVD 
132 
150 
840 mg 
EPA+DHA vs. 
placebo 
41% 
5 
CV death or CV 
hospital admission 
HR = 0.98 
(0.88–1.08) 
Ethyl-EPA Study 
JELIS 
(Yokoyama 
2007) 
18,645 pts 
hyper-
cholesterolemic 
182 
152-163 
1800 mg ethyl-
EPA + statin vs. 
statin 
100% 
4.6 
Any major coronary 
event 
HR = 0.81 
(0.69–0.95) 
BL: baseline; CI: confidence interval; CV: cardiovascular; CVD: cardiovascular disease; DHA: docosahexaenoic acid; EoS: end of study; EPA: eicosapentaenoic acid; GISSI-HF: 
Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico – Heart Failure; GISSI-P: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico – 
Prevenzione; HF: heart failure; HR: hazard ratio; JELIS: Japan Eicosapentaenoic Acid Lipid Intervention Study; LDL-C: low density lipoprotein cholesterol; MACE: major 
adverse cardiovascular event; MI: myocardial infarction; OMEGA: Effect of Omega 3-Fatty Acids on the Reduction of Sudden Cardiac Death After Myocardial Infarction; OR: 
odds ratio; ORIGIN: Outcome Reduction With Initial Glargine Intervention; RR: relative risk; SCD: sudden cardiac death ; TC: total cholesterol; TG: triglycerides. 


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Pleiotropic Effects 
In addition to lowering TG, OM3FA may lead to reduced CV risk through other potential 
non-cholesterol mechanisms, but the exact mechanisms by which OM3FA may exert such 
benefit are not completely understood. Some of the possible mechanisms have been reviewed 
by Mozaffarian et.al. (Mozaffarian 2011, Mozaffarian 2012) and Borow et. al (Borow 2015). 
These mechanisms include changes in lipid profiles (Harris 2008), lipid uptake into the 
arterial wall (Chang 2010), plaque stabilization (Thies 2003, Cawood 2010, Yamano 2015), 
endothelial function (Geleijnse 2002, M ozaffarian 2005, W ang 2012, Yamakawa 2012), 
vascular function (Sasaki 2012), arterial stiffness (Pase 2011), vasodilation (Tagawa 1999), 
carotid intima-media thickness (Mita 2007), platelet aggregation (Nomura 2009, Needleman 
1979), heart rate and blood pressure (Morris 1993, Mori 2010), HF (Djousse 2012, Gissi-HF 
Investigators 2008, Yamagishi 2008), oxidative stress (Mori 2003), and anti-inflammatory 
properties (systemic and endothelial) (Cawood 2010, Calder 2010, Aaresetoey 2012, Serhan 
2008 , Wall 2010, DeCaterina 1994, Caughey 1996, Jinno 2011). Of note, EPA+DHA have 
been proposed to benefit arrhythmic properties (Leaf 2005, Mozaffarian 2004, Gillet 2011, 
Anand 2008), which has been supported by at least one meta-analysis (Costanzo 2013), but 
not by others (Khoueiry 2013, Cao 2012, A rmaganijan 2011), and may depend on t he 
specific patient populations being studied.  
The vast majority of studies addressing the effects of omega acids on CV risk have studied 
mixtures of omega acids comprised primarily of EPA+DHA. The scientific literature also 
indicates that other omega fatty acids derived from fish oil have biological effects. For 
instance, the manufacturer of Lovaza, an FDA approved complex mixture of omega acids 
comprised primarily of EPA and DHA, noted that “experimental evidence suggests that the 
individual omega-3 fatty acids EPA, DHA, DPA, SDA, HPA, and ALA are each either 
biologically active or are metabolized in the body to form biologically active agents” (Citizen 
Petition 2009). How different omega acid components work together to produce clinical 
effects observed in patients is not completely understood. No studies have been conducted to 
elucidate the relative contribution of individual omega acid constituents within a mixture or 
any combination of various mixed constituents. Nonetheless, potential differential effects 
have been reviewed by Mozaffarian and Yu (Mozaffarian 2012) and distinctions in the 
effects of EPA and DHA on biologic pathways have been suggested. 
Dose Selection 
The dose regimen of AMR101 in this study is 4 g/day (4 capsules/day). 
The effects of combination treatment with ethyl-EPA plus statins on clinical CV events has 
been studied previously in JELIS (Yokoyama 2007), wherein ethyl-EPA combined with low-
dose pravastatin or simvastatin compared with statin therapy alone reduced major coronary 
events without altering rates of sudden cardiac death. These effects were achieved without 
any significant changes in total, LDL- or HDL-C and a statistically significant (p <0.0001), 
but relatively small (5%) decrease in TG, suggesting that EPA can lower CVD risk by 
mechanisms other than lipid lowering (Yokoyama 2007). In a sub-analysis of this study, the 
addition of ethyl-EPA to pravastatin or simvastatin also reduced the incidence of CHD events 
in high-risk patients with metabolic syndrome and atherogenic dyslipidemia characterized by 
high TG and low HDL-C (Saito 2008). The JELIS study was performed in a large patient 


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population wherein an ethyl-EPA dose of 1.8 g/day translated to significant benefits on CV 
events beyond statin monotherapy. 
In the ANCHOR study (Amarin-sponsored), both the 2 a nd 4 g/day dosing regimens of 
AMR101 resulted in statistically significant reductions of TGs (see Section1.2.2). However, 
the 4 g/day dose caused a larger reduction in TG and other lipid, lipoprotein and 
inflammatory markers. In addition, the JELIS study was conducted in an exclusively 
Japanese patient population with higher baseline plasma EPA levels than most patients that 
live in more Westernized countries, likely due to differences in diet and fish intake.  
Nonetheless, 12-week dosing of 4 g/day ethyl-EPA in the ANCHOR study in a Westernized 
patient population resulted in similar final plasma EPA levels as approximately 4.6-year 
dosing of 1.8 g/day ethyl-EPA in JELIS.  Based on these changes in lipid and inflammatory 
parameters, and the resulting final plasma levels, the AMR101 4 g/day dose was selected for 
the present study. 
1.5. 
Risk/Benefit 
Across all completed Amarin-sponsored studies, the proportion of patients (based on the 
safety population from the randomized, double-blind periods of the studies) experiencing any 
adverse events was similar for patients on pl acebo (light paraffin oil) and patients on 
AMR101 (57.1% and 57.4% for placebo and AMR101, respectively). The proportion of 
patients experiencing a serious adverse event (SAE) was also similar for both treatment 
groups (5.2% and 6.0% for placebo and AMR101, respectively). The safety profile in the 
open-label extensions was similar to that observed in the double-blind treatment periods. 
There were no SAEs attributed to AMR101 during the open-label extension periods of the 
studies. 
In summary, AMR101 is very well tolerated at daily doses up t o 4 g. The side effects 
reported by the patients taking AMR101 were generally similar to those reported by the 
patients taking placebo. Ethyl-EPA is a pro-drug, and is rapidly and completely hydrolyzed 
to EPA. EPA is a natural substance found universally as a component of all cell membranes. 
It is classified as an essential fatty acid. Therefore, EPA is an essential component of normal 
tissue and is handled in normal metabolism, and human studies have demonstrated that it is 
safe. See the Investigator’s Brochure for more information. 


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2. 
STUDY OBJECTIVES 
The primary objective is, in patients at low-density lipoprotein cholesterol (LDL-C) goal 
while on s tatin therapy, with established cardiovascular disease (CVD) or at high risk for 
CVD, and hypertriglyceridemia (fasting triglycerides [TG] 200 mg/dL and <500 mg/dL 
[2.26 mmol/L and <5.64 mmol/L]), to evaluate the effect of 4 g/day AMR101 on the time 
from randomization to first occurrence of any component of the composite of the following 
major cardiovascular (CV) events: 
 CV death; 
 Nonfatal myocardial infarction (MI), including silent MI; 
 Nonfatal stroke; 
 Coronary revascularization; or 
 Unstable angina determined to be caused by myocardial ischemia by 
invasive/non-invasive testing and requiring emergent hospitalization. 
The secondary objectives of this study are the following: 
The key secondary objective is to evaluate the effect of therapy on the time from 
randomization to the first occurrence of the composite of CV death, nonfatal MI (including 
silent MI), or nonfatal stroke. 
Other secondary objectives for this study are to evaluate the effect of therapy on time from 
randomization to the first occurence of: 
 Composite of CV death or nonfatal MI (including silent MI); 
 Fatal or nonfatal MI (including silent MI); 
 Non-elective coronary revascularization represented as the composite of emergent or 
urgent classifications; 
 CV death; 
 Unstable angina determined to be caused by myocardial ischemia by 
invasive/non-invasive testing and requiring emergent hospitalization;  
 Fatal or nonfatal stroke; 
 Composite of total mortality, nonfatal MI (including silent MI), or nonfatal stroke; 
 Total mortality. 
The tertiary objectives for this study are to evaluate the effect of therapy on the following.  
Where applicable and unless specified otherwise, endpoints represent time from 
randomization to the first occurrence of the individual or composite endpoints. 
 The total CV events analysis defined as the time from randomization to occurrence of 
the first and all recurrent major CV events defined as CV death, nonfatal MI 
(including silent MI), nonfatal stroke, coronary revascularization, or unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization; 


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 Primary composite endpoint in the subset of patients with diabetes mellitus at 
baseline; 
 Primary composite endpoint in the subset of patients with metabolic syndrome at 
baseline as defined in A Joint Interim Statement of the International Diabetes 
Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and 
Blood Institute; American Heart Association; World Heart Federation; International 
Atherosclerosis Society; and I nternational Association for the Study of Obesity 
(Alberti 2009); with cut points of parameters as defined in Table 1 of Alberti et al. 
and waist circumference cut points further guided by Table 2 of Alberti et al. and 
specifically set at ≥35 inches (88 cm) for all women and Asian, Hispanic, or Latino 
men, and ≥40 inches (102 cm) for all other men (see Appendix D); 
 Primary composite endpoint in the subset of patients with impaired glucose 
metabolism at baseline (Visit 2 FBG of 100-125 mg/dL); 
 Key secondary composite endpoint in the subset of patients with impaired glucose 
metabolism at baseline (Visit 2 FBG 100-125 mg/dL); 
 Composite of CV death, nonfatal MI (including silent MI), nonfatal stroke, cardiac 
arrhythmia requiring hospitalization of ≥24 hours, or cardiac arrest; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), or unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization, nonfatal stroke, or PVD requiring intervention, 
such as angioplasty, bypass surgery, or aneurism repair; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization, PVD requiring intervention, or cardiac arrhythmia 
requiring hospitalization of ≥24 hours; 
 New CHF; 
 New CHF as the primary cause of hospitalization; 
 Transient ischemic attack (TIA);  
 Amputation for PVD; 
 Carotid revascularization; 
 All coronary revascularizations defined as the composite of emergent, urgent, 
elective, or salvage; 
 Emergent coronary revascularizations; 


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 Urgent coronary revascularizations; 
 Elective coronary revascularizations; 
 Salvage coronary revascularizations; 
 Cardiac arrhythmias requiring hospitalization of ≥24 hours; 
 Cardiac arrest; 
 Ischemic stroke; 
 Hemorrhagic stroke; 
 Fatal or nonfatal stroke in the subset of patients with a history of stroke prior to 
baseline; 
 New onset diabetes, defined as Type 2 diabetes newly diagnosed during the 
treatment/follow-up period;  
 New onset hypertension, defined as blood pressure ≥140 mmHg systolic OR 
≥90 mmHg diastolic newly diagnosed during the treatment/follow-up period; 
 Fasting TG, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apo B, hs-CRP (hsCRP and 
log[hsCRP]), hsTnT, and RLP-C (to be estimated from standard lipid panel, RLP-C = 
TC – HDL-C – LDL-C [Varbo 2014]), (based on ITT estimands):  
o Assessment of the relationship between baseline biomarker values and 
treatment effects within the primary and key secondary composite endpoints, 
o Assessment of the effect of AMR101 on each marker, 
o Assessment of the relationship between post-baseline biomarker values and 
treatment effects within the primary and key secondary composite endpoints 
by including post-baseline biomarker values (for example, at 4 months, or at 1 
year) as a covariate; 
 Change in body weight; 
 Change in waist circumference. 


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3. 
STUDY DESIGN 
3.1. 
Type of Study 
Phase 3b, multi-center, multinational, prospective, randomized, double-blind, placebo-
controlled, parallel-group study 
3.2. 
Study Population 
The population for this study is men and women ≥45 years of age with established CVD, or 
men and women ≥50 years of age with diabetes in combination with one additional risk 
factor for CVD. In addition, all patients will have atherogenic dyslipidemia defined as on 
treatment for hypercholesterolemia (but at treatment goal for LDL-C, by treatment with a 
statin) and HTG. More details are listed in the inclusion criteria. 
The patients will need to provide consent to participate in the study and be willing and able 
to comply with the protocol and the study procedures. 
3.3. 
Study Periods 
This study consists of the following study periods: 
 Screening Period: During the screening period, patients will be evaluated for 
inclusion/exclusion criteria. 
At the first visit to the Research Unit (Visit 1), study procedures will be performed for 
evaluation of patient’s eligibility in the study. At this screening visit, patients will sign an 
informed consent form before any study procedure is performed; the informed consent 
form will cover the treatment/follow-up period. Based on the evaluation from Visit 1, the 
following situations may occur: 
o 
Patients who are eligible for participation based on the study procedures on Visit 1 
will return to the Research Unit for Visit 2 (randomization visit) to start the 
treatment/follow-up period. This case includes, for example, patients at Visit 1who 
are on a stable dose of a statin, are planning to stay on the same statin and the same 
dose of the statin, and who not need to wash out any non-statin lipid-altering 
medications. 
o 
Patients who are not eligible for participation based on the study procedures on 
Visit 1 and are unlikely to become eligible in the next 28 da ys (for example: 
unlikely to stabilize statin dose, unable to wash out non-statin lipid-altering 
medications, etc.): these patients will be screen failed after Visit 1. 
o 
Patients not eligible for participation in the study based on the study procedures on 
Visit 1 may possibly become eligible in the next 28 days: these patients may return 
at the discretion of the investigator for a second optional screening visit (Visit 1.1) 
at which time the procedures needed for re-evaluation of the previously failed 
inclusion/exclusion criteria will be repeated. This case includes, for example, 
patients who are started on a statin at Visit 1, whose statin dose is changed at Visit 1, 
and/or needed to wash out non-statin lipid-altering medications. The following 
applies for these patients: 


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 Patients with a change in the statin or statin dose on Visit 1 will need to be on a 
stable statin dose for at least 28 days before the lipid qualifying measurements at 
Visit 1.1. Other concomitant medications (antidiabetic therapy, for example) can 
be optimized or stabilized during this period. 
 Patients starting a washout at Visit 1 will have a washout period of at least 
28 days (only 7 days for bile acid sequestrants) before the lipid qualifying 
measurements at Visit 1.1. 
 Patients at Visit 1 who are on a stable dose of a statin, are planning to stay on the 
same statin at the same dose, and who do not need any medication washout, but 
were asked to return for Visit 1.1 to repeat one or more of the other study 
procedures not related to concomitant medications  
o 
Patients who become eligible for participation based on the additional study 
procedures at Visit 1.1 will return to the Research Unit for Visit 2 (randomization 
visit) to start the treatment/follow-up period. 
At the end of the screening period, patients will need to meet all inclusion/exclusion criteria 
before they can be randomized. Patients who are not eligible for participation after the 
screening period (based on study procedures at Visit 1 and/or Visit 1.1) may return at a later 
date for rescreening. These patients will need to re-start with all procedures starting with 
Visit 1. This includes patients who need more time to stabilize one or more conditions or 
therapies (for example: statin, antidiabetic, antihypertensive, thyroid hormone, HIV-protease 
inhibitor therapy). 
 Treatment/Follow-Up Period: Within 42 days after the first screening visit (Visit 1) or 
within 60 days after the first screening visit (Visit 1) for those patients that have a second 
screening visit (Visit 1.1), eligible patients will enter the treatment/follow-up period. 
During this period, the patients will receive study drug during the planned visits at the 
Research Site and take the study drug while away from the Research Site. 
During the visits, study procedures will be performed for evaluation of efficacy and safety. A 
detailed schedule of procedures is provided in Appendix A. 
3.4. 
Study Duration 
Patients will be randomized at different times during the enrollment period but will all end 
the study at approximately the same date (study end date) and, therefore, the duration of 
follow-up will differ based on da te of randomization. It is planned that all randomized 
patients will receive study medication and be followed-up until the study end date.  It is 
expected that a minimum of approximately 1612 primary endpoint events will be required 
during the study. Approximately 7990 patients will be randomized at multiple Research Sites 
worldwide over an estimated period of approximately 4.2 years. After randomization, 
patients will be treated and followed up to an estimated maximum of 6.5 years. The study 
end date is determined to be when approximately 1612 primary efficacy events have been 
adjudicated. 
3.5. 
Study Groups 
At Visit 2 (Day 0), eligible study patients will be randomly assigned to the following 
treatment groups: 


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 Group 1: AMR101 4 g daily (four 1 g capsules daily) 
 Group 2: placebo (four capsules daily) 
The four AMR101 or placebo capsules daily will be taken as two capsules in the morning 
and two capsules in the evening (twice-per-day dosing regimen). 
3.6. 
Number of Patients 
This is an event-driven trial: It is expected that a minimum of approximately 1612 primary 
endpoint events will be required during the study. A total of approximately 7990 patients will 
be entered into the study to either receive AMR101 or placebo (approximately 3995 patients 
per treatment group) in order to observe an estimated 1612 events that make up the primary 
composite endpoint for efficacy. Additional patients may be enrolled beyond the projected 
7990 if the number of events contributing to the primary endpoint appears less than, and 
inconsistent with, projections (see Section 12.3).  
3.7. 
Number of Study Sites 
Participants will be enrolled at multiple Research Sites in multiple countries. 
3.8. 
Randomization 
On Day 0, eligible patients will be randomized to one of 2 study groups using a computer-
generated randomization schema. Randomized treatment assignment to either AMR101 or 
placebo in a 1:1 ratio will be provided using the internet (via the Interactive Web Response 
System [IWRS]). 
3.9. 
Blinding 
This is a double-blind study. Patients, investigators, pharmacists and other supporting staff at 
the Research Sites, personnel and designees of the Sponsor, study administrators and 
personnel at the organization(s) and vendors supporting the study will be unaware of the 
randomization code (i.e., they will not know which study participants are receiving the 
experimental drug and which are receiving the placebo drug). The study medication 
AMR101 and placebo capsules will be similar in size and appearance to maintain blinding. 
During the double-blind treatment/follow-up period, everyone (patients, investigators, 
pharmacists and other supporting staff at the Research Sites, personnel and designees of the 
Sponsor, study administrators and personnel at the organization(s) and vendors 
managing/supporting the study), with the exception of the laboratory personnel performing 
the analysis, will be blinded to individual results of the efficacy laboratory measurements 
(including lipid values). Individual results from the lipid profile may be unblinded in the 
event of an emergency for a patient. 
3.10. 
Stratification 
Participants will be assigned to treatment groups stratified by CV risk category, use of 
ezetimibe and by geographical region (Westernized, Eastern European, and Asia Pacific 
countries). There are two CV risk categories: 
 
CV Risk Category 1: patients with established CVD defined in the inclusion criteria. 
Patients with diabetes and established CVD are included in this category. 


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 
CV Risk Category 2: patients with diabetes and at least one additional risk factor for 
CVD, but no established CVD. 
Stratification will be recorded in the IWRS at the time of enrollment. Approximately 70% of 
the planned 7990 randomized patients will be in the CV Risk Category 1 and approximately 
30% of randomized patients will be in the CV Risk Category 2. Enrollment with patients of a 
CV risk category will be stopped when the planned number of patients in that risk category is 
reached. If total study enrollment exceeds 7990 patients, inclusion of new patients will be 
limited to CV Risk Category 1. 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Patients meeting the following criteria will be eligible to participate in the study: 
1. Fasting TG levels of ≥200 mg/dL (2.26 mmol/L) and <500 mg/dL (5.64 mmol/L). 
2. LDL-C >40 mg/dL (1.04 mmol/L) and ≤100 mg/dL (2.60 mmol/L) and on stable 
therapy with a statin (with or without ezetimibe) for at least 4 weeks prior to the LDL-
C/TG baseline qualifying measurements for randomization  
 
Stable therapy is defined as the same daily dose of the same statin for at least 
28 days before the lipid qualification measurements (TG and LDL-C) and, if 
applicable, the same daily dose of ezetimibe for at least 28 days before the lipid 
qualification measurements (TG and LDL-C). Patients who have their statin therapy 
or use of ezetimibe initiated at Visit 1, or have their statin, statin dose and/or 
ezetimibe dose changed at Visit 1, will need to go through a stabilization period of at 
least 28 days since initiation/change and have their qualifying lipid measurements 
measured (TG and LDL-C) after the washout period (at Visit 1.1).  
 
Statins may be administered with or without ezetimibe.  
NOTE: If patients qualify at the first qualification visit (Visit 1) for TG and LDL-C, and 
meet all other inclusion/exclusion criteria, they may be randomized at Visit 2. If patients 
don’t qualify at the first qualifying visit (Visit 1), a second re-qualifying visit (Visit 1.1) 
is allowed. For some patients, because they need to stabilize medications and/or need to 
washout medications, the second re-qualifying visit (Visit 1.1) will be needed after the 
stabilization/washout period. 
3. Either having established CVD (in CV Risk Category 1) or at high risk for CVD (in CV 
Risk Category 2). The CV risk categories are defined as follows: 
CV Risk Category 1: defined as men and women ≥45 years of age with one or more of 
the following: 
o Documented coronary artery disease (CAD; one or more of the following primary 
criteria must be satisfied): 
 Documented multivessel CAD (≥50% stenosis in at least two major epicardial 
coronary arteries – with or without antecedent revascularization) 
 Documented prior MI 
 Hospitalization for high-risk NSTE-ACS (with objective evidence of 
ischemia: ST-segment deviation or biomarker positivity) 
o Documented cerebrovascular or carotid disease (one of the following primary 
criteria must be satisfied): 
 Documented prior ischemic stroke 
 Symptomatic carotid artery disease with ≥50% carotid arterial stenosis 
 Asymptomatic carotid artery disease with ≥70% carotid arterial stenosis per 
angiography or duplex ultrasound 


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 History of carotid revascularization (catheter-based or surgical) 
o Documented peripheral arterial disease (PAD; one or more of the following 
primary criteria must be satisfied):  
 ABI <0.9 with symptoms of intermittent claudication 
 History of aorto-iliac or peripheral arterial intervention (catheter-based or 
surgical) 
OR 
CV Risk Category 2: defined as patients with: 
o Diabetes mellitus (Type 1 or Type 2) requiring treatment with medication AND 
o Men and women ≥50 years of age AND  
o One of the following at Visit 1 (additional risk factor for CVD): 
 Men ≥55 years of age or women ≥65 years of age; 
 Cigarette smoker or stopped smoking within 3 months before Visit 1; 
 Hypertension (blood pressure ≥140 mmHg systolic OR ≥90 mmHg diastolic) 
or on antihypertensive medication; 
 HDL-C ≤40 mg/dL for men or ≤50 mg/dL for women; 
 Hs-CRP >3.00 mg/L (0.3 mg/dL); 
 Renal dysfunction: CrCL >30 and <60 mL/min (>0.50 and <1.00 mL/sec); 
 Retinopathy, defined as any of the following: non-proliferative retinopathy, 
pre-proliferative 
retinopathy, 
proliferative 
retinopathy, 
maculopathy, 
advanced diabetic eye disease or a history of photocoagulation; 
 Micro- or macroalbuminuria. Microalbuminuria is defined as either a positive 
micral or other strip test (may be obtained from medical records), an 
albumin/creatinine ratio ≥2.5 mg/mmol or an albumin excretion rate on timed 
collection ≥20 mg/min all on at least two successive occasions; 
macroalbuminuria, defined as Albustix or other dipstick evidence of gross 
proteinuria, an albumin/creatinine ratio ≥25 mg/mmol or an albumin excretion 
rate on timed collection ≥200 mg/min all on at least two successive occasions; 
 ABI <0.9 without symptoms of intermittent claudication (patients with ABI 
<0.9 with symptoms of intermittent claudication are counted under CV Risk 
Category 1). 
Note: Patients with diabetes and CVD as defined above are eligible based on the CVD 
requirements and will be counted under CV Risk Category 1. Only patients with 
diabetes and no doc umented CVD as defined above need at least one additional risk 
factor as listed, and will be counted under CV Risk Category 2. 
4. Women may be enrolled if all 3 of the following criteria are met: 
 They are not pregnant; 
 They are not breastfeeding; 
 They do not plan on becoming pregnant during the study. 


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5. Women of child-bearing potential must have a negative urine pregnancy test before 
randomization.  
Note: Women are not considered to be of childbearing potential if they meet one of the 
following criteria as documented by the investigator: 
 They have had a hysterectomy, tubal ligation or bilateral oophorectomy prior to 
signing the informed consent form; 
 They are post-menopausal, defined as 1 year since their last menstrual period or 
have a follicle-stimulating hormone (FSH) level in a menopausal range. 
6. Women of childbearing potential must agree to use an acceptable method of avoiding 
pregnancy from screening to the end of the study, unless their sexual partner(s) is/are 
surgically sterile or the woman is abstinent.  
7. Understanding of the study procedures, willing to adhere to the study schedules, and 
agreement to participate in the study by giving informed consent prior to screening. 
8. Agree to follow a physician recommended diet and to maintain it through the duration of 
the study. 
4.2. 
Exclusion Criteria 
Patients are excluded from participation in the study if any of the following criteria apply: 
1. Severe (New York Heart Association [NYHA] class IV) heart failure. 
2. Any life-threatening disease expected to result in death within the next 2 years (other 
than CVD). 
3. Active severe liver disease (evaluated at Visit 1): cirrhosis, active hepatitis, ALT or AST 
>3 × ULN, or biliary obstruction with hyperbilirubinemia (total bilirubin >2 × ULN). 
4. Hemoglobin A1c >10.0% (or >86 mmol/mol IFCC units) at screening (Visit 1). If 
patients fail this criterion (HbA1c >10.0% or >86 mmol/mol IFCC units) at Visit 1, they 
may have their antidiabetic therapy optimized and be retested at Visit 1.1. 
5. Poorly controlled hypertension: blood pressure ≥200 systolic mmHg OR ≥100 mmHg 
diastolic (despite antihypertensive therapy). 
6. Planned coronary intervention (such as stent placement or heart bypass) or any non-
cardiac major surgical procedure. Patients can be (re)evaluated for participation in the 
trial (starting with Visit 1.1) after their recovery from the intervention/surgery. 
7. Known familial lipoprotein lipase deficiency (Fredrickson Type I), apolipoprotein C-II 
deficiency, or familial dysbetalipoproteinemia (Fredrickson Type III)]. 
8. Participation in another clinical trial involving an investigational agent within 90 days 
prior to screening (Visit 1). Patients cannot participate in any other investigational 
medication or medical device trial while participating in this study (participation in a 
registry or observational study without an additional therapeutic intervention is 
allowed). 
9. Intolerance or hypersensitivity to statin therapy. 


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10. Known hypersensitivity to any ingredients of the study product or placebo (refer to 
Table 5); known hypersensitivity to fish and or shellfish. 
11. History of acute or chronic pancreatitis. 
12. Malabsorption syndrome and/or chronic diarrhea (Note: patients who have undergone 
gastric/intestinal bypass surgery are considered to have malabsorption, hence are 
excluded; patients who have undergone gastric banding are allowed to enter the trial). 
13. Non-study drug related, non-statin, lipid-altering medications, supplements or foods: 
 Patients are excluded if they used niacin >200 mg/day or fibrates during the during 
the screening period (after Visit 1) and/or plan to use during the study; patients who 
are taking niacin >200 mg/day or fibrates during the last 28 days before Visit 1 need 
to go through washout of at least 28 days after their last use and have their qualifying 
lipids measured (TG and LDL-C) after the washout period (Visit 1.1); 
 Patients are excluded if they take any omega-3 fatty acid medications (prescription 
medicines containing EPA and/or DHA) during the screening period (after Visit 1) 
and/or plan to use during the treatment/follow-up period of the study. To be eligible 
for participation in the study, patients who are taking omega-3 fatty acid medications 
during the last 28 days before Visit 1 (except patients in the Netherlands), need to go 
through a washout period of at least 28 days after their last use and have their 
qualifying lipids measured (TG and LDL-C) after the washout period (at Visit 1.1);  
 Note: For patients in the Netherlands only: patients being treated with omega-3 fatty 
acid medications containing EPA and/or DHA are excluded; no washout is allowed.  
 Patients are excluded if they use dietary supplements containing omega-3 fatty acids 
(e.g., flaxseed, fish, krill, or algal oils) during the screening period (after Visit 1) 
and/or plan to use during the treatment/follow-up period of the study. To be eligible 
for participation in the study, patients who are taking >300 mg/day omega-3 fatty 
acids (combined amount of EPA and DHA) within 28 days before Visit 1 (except 
patients in the Netherlands), need to go through a washout period of at least 28 days 
since their last use and have their qualifying lipid measurements measured (TG and 
LDL-C) after the washout period (at Visit 1.1); 
 Note: For patients in the Netherlands only: patients being treated with dietary 
supplements containing omega-3 fatty acids of >300 mg/day EPA and/or DHA are 
excluded; no washout is allowed. 
 Patients are excluded if they use bile acid sequestrants during the screening period 
(after Visit 1) and/or plan to use during the treatment/follow-up period of the study. 
To be eligible for participation in the study, patients who are taking bile acid 
sequestrants within 7 days before Visit 1, need to go through a washout period of at 
least 7 days since their last use and have their qualifying lipid measurements 
measured (TG and LDL-C) after the washout period (at Visit 1.1); 
 Patients are excluded if they use PCSK9 inhibitors during the screening period (after 
Visit 1) and/or plan to use during the treatment/follow-up period of the study. To be 
eligible for participation in the study, patients cannot have taken a PCSK9 inhibitor 
within 90 days prior to their screening visit. 


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14. Other medications (not indicated for lipid alteration): 
 Treatment with tamoxifen, estrogens, progestins, thyroid hormone therapy, systemic 
corticosteroids (local, topical, inhalation, or nasal corticosteroids are allowed), HIV-
protease inhibitors that have not been stable for ≥28 days prior to the qualifying lipid 
measurements (TG and LDL-C) during screening. To be eligible for participation in 
the study, patients who are not taking a stable dose of these medications within 
28 days before Visit 1, need to go through a stabilization period of at least 28 days 
since their last dose change and have their qualifying lipid measurements measured 
(TG and LDL-C) after the washout period (at Visit 1.1). 
 Patients are excluded if they use cyclophosphamide or systemic retinoids during the 
screening period (after Visit 1) and/or plan to use during the treatment/follow-up 
period of the study. To be eligible for participation in the study, patients who are 
taking these medications within 28 days before Visit 1, need to go through a washout 
period of at least 28 days since their last use and have their qualifying lipid 
measurements measured (TG and LDL-C) after the washout period (at Visit 1.1). 
15. Known to have AIDS (patients who are HIV positive without AIDS are allowed). 
16. Requirement for peritoneal dialysis or hemodialysis for renal insufficiency or creatinine 
clearance (CrCL) <30 mL/min (0.50 mL/sec). 
17. Unexplained creatine kinase concentration >5 × ULN or creatine kinase elevation due to 
known muscle disease (e.g., polymyositis, mitochondrial dysfunction) at Visit 1. 
18. Any condition or therapy which, in the opinion of the investigator, might pose a risk to 
the patient or make participation in the study not in the patient’s best interest. 
19. Drug or alcohol abuse within the past 6 months, and unable/unwilling to abstain from 
drug abuse and excessive alcohol consumption during the study or drinking 5 units or 
more for men or 4 units or more for women in any one hour (episodic excessive drinking 
or binge drinking). Excessive alcohol consumption is on average >2 units of alcohol per 
day. A unit of alcohol is defined as a 12-ounce (350 mL) beer, 5-ounce (150 mL) wine, 
or 1.5-ounce (45 mL) of 80-proof alcohol for drinks. 
20. Mental/psychological impairment or any other reason to expect patient difficulty in 
complying with the requirements of the study or understanding the goal and potential 
risks of participating in the study (evaluated at Visit 1). 


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5. 
STUDY COMMITTEES 
5.1. 
Steering Committee 
The Steering Committee (SC) will include the chairperson (the Principal Investigator [PI]) 
and medical/scientific specialists with expertise in clinical trials, cardiovascular outcomes 
and lipidology.  
The SC has overall responsibility for: 
 
Scientific and strategic direction for the trial. The SC must address and resolve all 
scientific issues regarding the conduct of the trial. All sub-studies must be approved 
by the SC. 
 
The execution of the study protocol, and the reporting and publication of the study 
results. 
 
Logistical coordination of the different study committees. 
The SC will meet at least twice per year, and the SC meetings will be conducted as defined 
within the SC Charter drafted and approved by the SC. 
5.2. 
Study Operations Committee 
The Study Operations Committee is responsible for ensuring that study execution and 
management is of the highest quality, and will monitor recruitment, compliance, and the 
adjudication process and address the day to day issues arising from the trial. This committee 
will be composed of representatives from the Sponsor and the organization(s) conducting the 
study (as delegated by the Sponsor). This committee will meet by telephone and/or in person 
on a periodic basis, and each meeting will be documented with minutes. 
5.3. 
Clinical Endpoint Committee (CEC) 
The CEC is composed of multidisciplinary medical experts. This committee will be 
responsible for blindly validating all primary, secondary, and tertiary efficacy outcome 
events reported by the investigators (event adjudication). The CEC will operate in 
accordance with a charter drafted and approved by the CEC that contains details of the 
adjudication process and methods based on the definitions of the events. 
5.4. 
Data Monitoring Committee (DMC) 
A DMC will be instituted for this study in order to ensure its ongoing safety and to oversee 
and review the interim and final analyses. Recommendation for trial continuation will be 
guided by monitoring boundaries at the interim analyses at which a formal efficacy analysis 
is performed as well as safety evaluations at all safety data reviews. Members of the DMC 
will not otherwise be participating in the trial. The committee will include at least one 
cardiologist and one independent statistician. The DMC meetings will be conducted as 
defined within the DMC Charter drafted and approved by the DMC and the SC. The Charter 
will provide details regarding the interim analysis and monitoring plan. 


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6. 
STUDY PROCEDURES 
6.1. 
Assessment Schedule  
A detailed schedule of procedures is provided in Appendix A. Study sites are to actively 
support patient progress and study protocol adherence (i.e., compliance with scheduled office 
and phone visit schedules). 
6.1.1. 
Screening Period 
6.1.1.1. 
Screening Visit (Visit 1) 
Patients will come to the Research Site for Visit 1. They will be instructed to fast for at least 
10 hours before their visit. 
If patients qualify for randomization based on the procedures at Visit 1, they need to be 
randomized within 42 days after Visit 1. The following procedures will be performed at the 
screening visit: 
 
Obtain signed informed consent 
 
Assign the patient a patient number 
 
Obtain medical, surgical and family history 
 
Record demographics 
 
Obtain height, weight, and body mass index 
 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and body temperature) 
 
Obtain a 12-lead ECG 
 
Evaluate inclusion/exclusion criteria 
 
This includes procedures and (fasting) blood samples (for example, hs-CRP, 
calculated creatinine clearance) as needed to determine the CV risk category (see 
inclusion criteria) 
 
Obtain fasting blood samples for chemistry and hematology testing 
 
Obtain a fasting blood sample for the lipid profile (TG, TC, HDL-C, LDL-C, non-
HDL-C, VLDL-C) 
 
Perform a urine pregnancy test on women of childbearing potential 
 
Record concomitant medication(s) 
 
Instruct patient to fast for 10 hours prior to the next visit 
6.1.1.2. 
Screening Visit (Visit 1.1) 
Some patients will skip Visit 1.1: Patients who qualify for study participation after Visit 1 
because they meet all inclusion criterion and none of the exclusion criteria, may return to the 
Research Site for Visit 2 to be randomized and to start the treatment/follow-up period of the 
study. For these patients, Visit 2 will occur soon after Visit 1. 


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Patients, who do not qualify at Visit 1, may return to the Research Site for a second 
qualifying visit (Visit 1.1) at the discretion of the investigator. At Visit 1.1, procedures that 
caused failure of eligibility at Visit 1 will be repeated. Patients will be eligible for 
randomization after Visit 1.1 if they meet all inclusion criteria and if they no longer fail the 
exclusion criteria. If patients are evaluated at Visit 1.1 and qualify for randomization based 
on the repeated procedures at Visit 1.1, they need to be randomized within 60 days after 
Visit 1. 
For some patients, Visit 1.1 will be mandatory at least 28 days after Visit 1 in order to check 
eligibility. These are patients who at Visit 1 started treatment with a statin, changed their 
statin, changed the daily dose of their statin, started to washout prohibited medications or 
started a stabilization period with certain medications (see inclusion/exclusion criteria for 
details). Any of these changes at Visit 1 may affect the qualifying lipid levels and therefore, 
patients will need to have Visit 1.1 to determine whether they qualify based on lipid level 
requirements (TG and LDL-C) determined at Visit 1. Other procedures that caused failure of 
eligibility at Visit 1 will also be repeated at Visit 1.1. 
The following procedures will be performed at the screening visit: 
 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and body temperature) 
 
Evaluate inclusion/exclusion criteria; only those evaluations will be repeated that 
deemed the patient not eligible on Visit 1. 
 
Obtain fasting blood samples for chemistry and hematology testing. Only those 
samples will be obtained that deemed the patient not eligible on Visit 1. 
 
Obtain a fasting blood sample for the lipid profile (TG, TC, HDL-C, LDL-C, non-
HDL-C, VLDL-C) if the patient was deemed not eligible on Visit 1. This includes 
patients who at Visit 1 started treatment with a statin, changed their statin, changed 
the daily dose of their statin, started to washout prohibited medications or started a 
stabilization period with certain medications (see inclusion/exclusion criteria for 
details). These patients will have a fasting blood sample collected at Visit 1.1 for the 
qualifying lipid values (TG and LDL-C), and the TG and LDL-C inclusion criteria 
will be evaluated. 
 
Record concomitant medication(s) 
6.1.2. 
Treatment/Follow-Up Period 
Every attempt should be made to complete the follow-up visits during the defined window 
periods. 
6.1.2.1. 
Randomization visit (Visit 2; Day 0) 
Qualified patients will return to the Research Site for Visit 2. 
The following procedures will be performed at Visit 2: 
 
Perform physical examination 
 
Obtain weight 


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 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and body temperature) 
 
Measure waist circumference (one of the 5 factors used to diagnose metabolic 
syndrome) 
 
Obtain a 12-lead ECG 
 
Evaluate inclusion/exclusion criteria 
 
Obtain fasting blood samples for: 
o 
Chemistry and hematology testing 
o 
Lipid profile (baseline) 
o 
Biomarker assays (baseline) 
o 
Genetic testing (optional blood sample) 
o 
Archiving (in countries and at sites approved by IRB/IEC and dependent on 
country regulations) 
 
Perform a urine pregnancy test on w omen of childbearing potential (must be 
negative for randomization) 
 
Dispense study drug and record randomization number 
 
Instruct patient on how to take study drug 
 
Administer study drug - Note: Study drug should be taken orally with food following 
the collection of all fasting blood samples 
 
Assess for and record adverse events 
 
Record concomitant medication(s) 
 
Instruct patient: 
o 
To bring all study supplies with them to the next visit 
o 
Not to take study drug on the morning of their next visit 
o 
To fast for 10 hours prior to the next visit 
6.1.2.2. 
Visit 3 (Day 120; ~4 Months) 
Patients will return to the Research Site for Visit 3 on Day 120 ±10 days. 
The following procedures will be performed: 
 
Perform physical examination 
 
Obtain weight 
 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and body temperature) 
 
Obtain fasting blood samples for: 
o 
Chemistry and hematology testing 
o 
Lipid profile 


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 
Review study drug compliance by unused capsule count; discuss with and counsel 
patients about compliance if needed 
 
Administer study drug - Note: Study drug should be taken orally with food following 
the collection of all fasting blood samples 
 
Assess and record efficacy events 
 
Assess for and record adverse events 
 
Record concomitant medication(s) 
 
Instruct patient: 
o 
To bring all study supplies with them to the next visit 
o 
Not to take study drug on the morning of their next visit 
o 
To fast for 10 hours prior to the next visit 
6.1.2.3. 
Visits 4, 5, 6, 7, 8 and 9 
At Visit 4: Day 360 ± 10; Visit 5: Day 720 ± 10; Visit 6: Day 1080 ± 10; Visit 7: Day 1440 ± 
10, Visit 8: Day 1800 ± 10, Visit 9: Day 2160 ± 10) the following procedures will be 
performed: 
 
Perform physical examination 
 
Obtain weight 
 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and body temperature) 
 
Measure waist circumference (collected at Visit 5 only) 
 
Obtain a 12-lead ECG 
 
Obtain fasting blood samples for: 
o 
Chemistry and hematology testing 
o 
Lipid profile 
o 
Biomarker assays (collected at Visit 5 only) 
o 
Archiving (in countries and at sites approved by IRB/IEC and dependent on 
country regulations) 
 
Review study drug compliance by unused capsule count; discuss with and counsel 
patients about compliance if needed 
 
Administer study drug - Note: Study drug should be taken orally with food following 
the collection of all fasting blood samples 
 
Assess and record efficacy events 
 
Assess for and record adverse events 
 
Record concomitant medication(s) 
 
Instruct patient: 


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o 
To bring all study supplies with them to the next visit 
o 
Not to take study drug on the morning of their next visit 
o 
To fast for 10 hours prior to the next visit 
6.1.2.4. 
Additional Visits 
The end date of the study is expected for Day 2160 but the actual end date will be dependent 
on the determination of the study end date by the DMC. The study end date is determined to 
be when approximately 1612 primary efficacy events have been adjudicated. If the actual 
study end date is later than the expected end date, additional visits will be planned between 
Visit 9 and the Last Visit with a maximum of 360 ±10 days between visits. If the actual study 
end date is sooner than the expected end date, fewer visits will occur, and the last visit (See 
Section 6.1.2.5) will occur sooner. 
On additional visits the same procedures will be performed as listed in Section 6.1.2.3. 
Irrespective of the number of additional visits, after the DMC has established the end of the 
study date, there will be a last visit with procedures as listed in Section 6.1.2.5. 
6.1.2.5. 
Last Visit – End of Study 
All patients will complete the study at the same time (within a target of 30 days after the 
study end date), irrespective of the date that they were randomized. The end date of the study 
is planned for Day 2160 but the actual end date will be dependent on the determination of the 
study end date by the DMC when approximately 1612 primary efficacy events have been 
adjudicated (event-driven trial). For each patient, the last visit may occur within a target of 
30 days after the actual study end date as determined by the DMC. However, for the efficacy 
endpoints based on C V events, only events occurring up t o and including the scheduled 
actual study end date will be included in the efficacy analyses. 
A final follow-up visit is required for all patients. In the rare cases that a final follow-up visit 
cannot occur within the targeted 30-day timeframe following the study end date, any attempt 
to contact the patient must be recorded on a special contact form, until/unless appropriate 
information is obtained. 
At the Last Visit, the following procedures will be performed: 
 
Perform physical examination 
 
Obtain weight 
 
Obtain vital signs (systolic and diastolic blood pressure, heart rate, respiratory rate, 
and body temperature) 
 
Measure waist circumference  
 
Obtain a 12-lead ECG 
 
Obtain fasting blood samples for: 
o 
Chemistry and hematology testing 
o 
Lipid profile 
o 
Biomarker assays 


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o 
Archiving (in countries and at sites approved by IRB/IEC and dependent on 
country regulations) 
 
Determine study drug compliance by unused capsule count 
 
Assess and record efficacy events 
 
Assess for and record adverse events 
 
Record concomitant medication(s) 
6.2. 
Telephone Follow-up Contact 
Site personnel will contact each patient by telephone on the following study days: 
 
Day 60 ±3 days 
 
Day 180 ±5 days 
 
Day 270 ±5 days 
 
Day 450 ±5 days 
 
Day 540±5 days 
 
Day 630 ±5 days 
 
Day 810 ±5 days 
 
Day 900 ±5 days 
 
Day 990 ±5 days 
 
Day 1170 ±5 days 
 
Day 1260 ±5 days 
 
Day 1350 ±5 days 
 
Day 1530 ±5 days 
 
Day 1620 ±5 days 
 
Day 1710 ±5 days 
 
Day 1890 ±5 days 
 
Day 1980 ±5 days 
 
Day 2070 ±5 days 
If the treatment/follow-up period of the study is extended beyond the expected end date 
(Day 2160), additional follow-up phone calls will be made every 90 days in-between 
additional visits ±5 days. See Section 6.1.2.4 for the timing of the additional visits. If the 
treatment/follow period of the study is shorter than the expected end date, less follow-up 
phone calls will be needed. 
Every attempt will be made to talk to each patient within this time frame. 
The following information will be collected from the patient: 


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 
Possible efficacy endpoints related to CV events. Patients will be asked to return to 
the Research Site to assess for any endpoints or events identified. 
 
Adverse events 
 
Concomitant medications 
 
Current address and contact information (update if changed or will be changing) 
Patients will be reminded about the following items: 
 
To take the study medication according to the dosing schedule assigned, with food 
 
When to return to the Research Center for the next visit 
 
To bring the unused study medication to the next visit 
 
To not take study drug on the morning of their next visit 
 
To fast for at least 10 hours prior to the next visit 
6.3. 
Laboratory Procedures 
6.3.1. 
Clinical Laboratory Procedures 
All clinical laboratory determinations for screening and safety will be performed by a 
certified clinical laboratory under the supervision of the Sponsor or its designee. 
Whenever possible and appropriate, samples for the clinical laboratory procedures will be 
collected after fasting for at least 10 hours. For the purposes of this study, fasting is defined 
as nothing by mouth except water (and any essential medications). 
The investigator must review and sign all laboratory test reports. At screening, patients who 
have laboratory values that are outside the exclusionary limits specified in the exclusion 
criteria may not be enrolled in the study. After randomization, the investigator will be 
notified if laboratory values are outside of their normal range. In this case, the investigator 
will be required to conduct clinically appropriate follow-up procedures. 
6.3.1.1. 
Safety Laboratory Tests 
The safety laboratory tests include: 
 
Hematology with complete blood count (CBC), including RBC, hemoglobin (Hgb), 
hematocrit (Hct), white cell blood count (WBC), white cell differential, and platelet 
count 
 
Biochemistry panel including total protein, albumin, alkaline phosphatase, alanine 
aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), total 
bilirubin, glucose, calcium, electrolytes (sodium, potassium, chloride), blood urea 
nitrogen (BUN), serum creatinine, uric acid, creatine kinase, and HbA1c. 
6.3.1.2. 
Fasting Lipid Profile 
The fasting lipid panel includes: TG, TC, LDL-C, HDL-C, non-HDL-C, and VLDL-C.  
At all visits, LDL-C will be calculated using the Friedewald equation if TG <400 mg/dL. At 
Visit 1 and Visit 1.1 Direct LDL-C will be used if at the same visit TG >400 mg/dL 
(4.52 mmol/L). These LDL-C values will be used for the evaluation of the LDL-C inclusion 


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criteria (LDL-C qualifying measurements for randomization) and for the assessment of 
changes in the statin therapy when LDL-C is not at goal. At all remaining visits LDL-C will 
be measured by Direct LDL-C or by Preparative Ultracentrifugation if at the same visit TG 
>400 mg/dL (4.52 mmol/L). In addition, irrespective of the TG levels, at Visit 2 (0 Months 
of Follow-up, baseline) and at Visit 4 (12 Months of Follow-up), LDL-C direct and LDL-C 
Preparative Ultracentrifugation will be taken. These Preparative Ultracentrifugation LDL-C 
measurements will be used in the statistical analysis including the calculation of the percent 
change from baseline (1 year versus baseline). Hopkins LDL-C (Martin 2013) will be 
calculated for each visit. 
6.3.1.3. 
Genetic testing 
A fasting blood sample will be stored for future genetic testing at the discretion of the 
sponsor. The specifics of this test will be determined at a later date. This sample is optional 
as local regulations may prohibit genetic samples to be collected or shipped outside the 
country, or patients may not consent. 
Research on genetic testing will look for links between genes and certain diseases, including 
their treatment(s) such as medicines and medical care. The blood samples will be collected in 
the study center with the regular protocol-required labs. Each patient tube with sample for 
genetic testing will be labeled with patient number only. The site will maintain a Subject 
Code Identification List for cross-reference. The patient number does not contain any 
identifiable information (i.e. Patient initials, date of birth, etc.). Un-analyzed samples will be 
stored frozen by the sponsor for a period of up to 2 years following the end of the study, at 
which time they will be destroyed. If samples are tested, results will not be reported to the 
patient, parents, relatives, or attending physician and will not be recorded in the patient’s 
medical records. There will be no follow-up contact with the sites or patients regarding this 
sample. The subject can withdraw their consent for genetic testing at any time up to analysis, 
even after the sample has been obtained. The subject can notify the site in writing that they 
withdraw their consent for the genetic testing portion of the study, and it will be documented 
by the site in the subject chart, as well as captured in the CRF. The lab will be notified to pull 
the sample and destroy it.  
Potential genetic bioassays may be performed and may be as broad as a genome-wide 
association study (GWAS) or as limited as a single gene-target approach; potential target 
genes include, but are not limited to the genes encoding: Apo C3, Apo A5, CETP, LPL, 
PCSK9, TNFα, TNFβ, ALOX5, COX2, FABP genes, haptoglobin 1 and haptoglobin 2. 
6.3.1.4. 
Biomarkers Assays 
The biomarker assays include: hs-CRP, Apo B and hsTnT. 
6.3.1.5. 
Additional laboratory tests 
Additional laboratory tests include: 
 
A urine pregnancy test will be administered to women of childbearing potential at 
certain visits as listed in schedule of procedures (Appendix A). The urine pregnancy 
tests will be performed at the Research Site utilizing marketed test kits, or at a 
certified clinical laboratory. 


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 
A fasting blood sample (10 mL) for serum archiving. This sample will be collected 
only at sites in countries where allowed by local regulations and at sites for which 
approved by the IRB or EC. The serum from the archiving sample will be stored 
frozen in 2 separate equal aliquots, and will be used at the Sponsor’s discretion to 
perform repeat analyses described in the protocol or to perform other tests related to 
CV health. 
o Potential non-genetic bioassays may be performed, including but not limited to: 
Apo A1, Apo C3, Apo E, NMR lipid profile (particle size and number), oxidized 
LDL, Lp(a), Lp-PLA2, serum fatty-acids concentrations, and gamma-
glutamyltransferase (GGT). 
6.3.1.6. 
Blinding of Laboratory Results 
All efficacy laboratory results during the double-blind period of the trial will be blinded 
(values not provided) to patients, investigators, pharmacists and other supporting staff at the 
Research Sites, personnel and designees of the Sponsor, study administrators and personnel 
at the organization(s) and vendors managing and/or supporting the study, with the exception 
of the laboratory personnel conducting the assays. To ensure patient safety, hsTnT values 
will be reported to the site. 
6.3.1.7. 
Flagging of Critical Lab Values 
Critical lab values are values that may warrant medical intervention to avoid possible harm to 
a patient. Critical lab values will be defined in the Laboratory Manual for the study, and the 
Research Site will be notified of the occurrence of a critical lab value (critical high or critical 
low) by a special annotation (flag) in the laboratory reports provided to the Research Sites. 
Although laboratory values that are part of the efficacy endpoints during the double-blind 
period of the study will not be provided to the Research Site (see Section 6.3.1.6), the sites 
will be notified when the TG value of a patient sample is >1000 mg/dL (11.29 mmol/L) 
(critical high TG value) or if the LDL-C values of a patient sample is >130 mg/dL 
(3.37 mmol/L) (critical high LDL-C value). These critical high values will need to be 
confirmed by a repeat measurement (new fasting blood sample) within 7 days. TG value of 
>2000 mg/dL (22.58 mmol/L) will also be flagged, so that appropriate medical action can be 
taken by the investigator as soon as possible. 
If TG values are confirmed critically high, patients may be discontinued from study drug 
with the option to remain on study (see Section 11.1). The investigator should use the best 
clinical judgment for each patient which could include the use of approved TG-lowering 
medications after patients have been discontinued from study drug. 
If LDL-C values are confirmed critically high, the investigator may need to take appropriate 
medical action which could include: reinforce/intensify therapeutic lifestyle changes 
(including diet and physical activity), increase the dose of the present statin therapy, add 
ezetimibe, or prescribe a more potent statin to lower LDL-C. The investigator should use the 
best clinical judgment for each patient. 


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6.3.2. 
Medical Procedures 
6.3.2.1. 
Medical, Surgical and Family History 
Medical history, including family history and details regarding all illnesses and allergies, 
date(s) of onset, status of current condition, and smoking and alcohol use will be collected on 
all patients. 
6.3.2.2. 
Demographics 
Demographic information including day, month, and year of birth, race, and gender will be 
collected for all patients. 
6.3.2.3. 
Vital Signs 
Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, and body 
temperature. Blood pressure will be measured using a standardized process: 
 
Patient should sit for 5 minutes with feet flat on the floor and measurement arm 
supported so that the midpoint of the manometer cuff is at heart level. 
 
Use a mercury sphygmomanometer or automatic blood pressure device with an 
appropriately sized cuff with the bladder centered over the brachial artery. 
Blood pressure should be recorded to the nearest 2 mmHg mark on the manometer or to the 
nearest whole number on an automatic device. A blood pressure reading should be repeated 1 
to 2 minutes later, and the second reading should also be recorded to the nearest 2 mmHg 
mark or to the nearest whole number on an automatic device.  
6.3.2.4. 
Physical Examination 
A physical examination must include source documentation of general appearance, skin, and 
specific head and neck, heart, lung, abdomen, extremities, and neuromuscular assessments.  
6.3.2.5. 
Height, Weight and Body Mass Index 
Height and weight will be measured. Measurement of weight should be performed with the 
patient dressed in indoor clothing, with shoes removed, and bladder empty.  
6.3.2.6. 
Waist Circumference 
Waist circumference will be measured with a tape measure, as follows: Start at the top of the 
hip bone then bring the tape measure all the way around – level with the navel. Make sure the 
tape measure is snug, but without compressing the skin, and that it is parallel with the floor.  
Patients should not hold their breath while measuring waist circumference. 
6.3.2.7. 
12-Lead ECG 
ECGs (standard 12-lead) will be obtained annually. Site personnel should make every 
attempt to perform a patient’s ECG using the same equipment at each visit. ECGs will be 
reviewed by the site for the detection of silent MI. Silent MIs will be sent for event 
adjudication. All post-randomization ECGs (protocol-specified and other) are to be sent to 
the CEC for evaluation of silent MI. 


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7. 
TREATMENT AND RESTRICTIONS 
7.1. 
Treatment 
7.1.1. 
Treatment Regimen, Dosage, and Duration 
Eligible study patients will be randomly assigned on Day 0 to one of the 2 treatment groups. 
Patients in each group will receive either 4 g/day AMR101 or placebo as in Table 4 for up to 
approximately 6.5 years, depending on individual date of randomization and overall study 
stop date (see Section 3.4). 
The daily dose of study drug is 4 capsules per day taken as two capsules taken on t wo 
occasions per day (2 capsules given twice daily). 
Table 4.  Dosing Schedule during the Treatment Period 
Treatment 
Group 
Daily 
Dose 
Number of Capsules per Day 
1 
4 g 
4 capsules of 1 g AMR101 
2 
Placebo 
4 capsules of matching placebo 
Patients will be instructed to take study drug with food (i.e., with or at the end of their 
morning and evening meals). On days that patients are scheduled for study visits, the daily 
dose of study drug will be administered by site personnel with food provided by the site 
following collection of all fasting blood samples. For the purposes of this study, fasting is 
defined as nothing by mouth except water (and any essential medications) for at least 
10 hours. 
7.1.2. 
Treatment Assignment 
7.1.2.1. 
Identification number 
A unique patient identification number (patient number) will be established for each patient 
at each site. The patient number will be used to identify the patient throughout the study and 
will be entered on all documentation. If a patient is not eligible to receive treatment, or if a 
patient discontinues from the study, the patient number cannot be reassigned to another 
patient. The patient number will be used to assign patients to one of the 2 treatment groups 
according to the randomization schedule. 
7.1.2.2. 
Drug Randomization 
Only qualified patients who meet all of the inclusion criteria and none of the exclusion 
criteria will be randomized and will receive study medication starting at Visit 2 (Day 0). 
Eligible patients will be randomly assigned to one of the 2 treatment groups. Randomization 
will be stratified by CV risk category, use of ezetimibe and by geographical region 
(Westernized, Eastern European, and Asia Pacific countries) (See Section 3.10). 
Approximately 70% of randomized patients will be in the CV Risk Category 1, including 
patients with established CVD, and approximately 30% of randomized patients will be in the 
CV Risk Category 2, including patients with diabetes and at least one additional risk factor 
but no e stablished CVD. Enrollment with patients of a CV risk category will be stopped 


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when the planned number of patients in that risk category is reached. If total study enrollment 
exceeds 7990 patients, enrollment of new patients will be limited to CV Risk Category 1. 
7.1.2.3. 
Emergency Unblinding 
In an emergency, when knowledge of the patient’s treatment assignment is essential for the 
clinical management or welfare of the patient, the investigator may request the patient’s 
treatment assignment for unblinding. Prior to unblinding the patient’s individual treatment 
assignment, the investigator should assess the relationship of an adverse event to the 
administration of the study drug (Yes or No). If the blind is broken for any reason, the 
investigator must record the date and reason for breaking the blind on the appropriate Case 
Report Form (CRF) and source documents. 
7.1.3. 
Compliance Control 
It is recommended that, unless clear contraindications arise, patients be strongly encouraged 
to adhere to their treatment regimen with the study drug for the duration of the trial. Any 
interruptions of therapy should, if possible, be brief (e.g., <4 weeks) and only for clinically 
indicated reasons, such as adverse events. While reduction in study drug dose to fewer than 
4 capsules per day is discouraged, patients may remain on study medication at a reduced dose 
with approval by the Medical Monitor. Under such conditions, resumption of the dose of 
4 capsules per day should be attempted when/if medically appropriate. Discontinuations will 
be discouraged as much as possible. Any discontinuations should be based on compelling 
clinical reasons. 
For every patient, an assessment of compliance to the study drug treatment regimen must be 
obtained at each scheduled visit. Study medication will be dispensed in amounts exceeding 
the amount required for the study. Patients will be instructed to return all unused study 
medication at the next visit. Compliance to the study drug regimen will be evaluated at each 
visit by counting unused capsules. Discrepancies will be evaluated and discussed with each 
patient to assess compliance. If compliance is unsatisfactory, the patient will be counseled 
about the importance of compliance to the dosing regimen. At the end of the study, the final 
study medication compliance will be determined by unused capsule count (see Section 
12.2.2). 
7.2. 
Study Restrictions 
7.2.1. 
Concomitant Medications during Treatment/Follow-Up Period 
Any medications administered during the study period must be documented on t he 
Concomitant Medication CRF. Patients must not have taken any investigational agent within 
90 days prior to screening. Patients cannot participate in any other investigational medication 
trial while participating in this study.  
The following non-study drug related, non-statin, lipid-altering medications and supplements, 
and foods are prohibited during the study (from Visit 1 until after the Last Visit-End of 
Study), except for compelling medical reasons in patients characterized as being Off Drug in 
Study (ODIS). A detailed description of ODIS is provided in Section 11.1: 
 
niacin >200 mg/day; 
 
fibrates; 


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 
prescription omega-3 fatty acid medications; 
 
dietary supplements containing omega-3 fatty acids (e.g., flaxseed, fish, krill, or 
algal oils); 
 
bile acid sequestrants; 
 
PCSK9 inhibitors; 
 
cyclophosphamide; 
 
systemic retinoids 
If any of these products would be used during the treatment/follow-up period of the study, it 
should be for compelling medical reasons in ODIS patients, and it should be documented in 
the Concomitant Medication CRF. If the ODIS patient agrees to restart study medication, the 
use of excluded medication must be discontinued. 
Foods enriched with omega-3 fatty acids are strongly discouraged after Visit 1 for the 
duration of the study (does not apply to the Netherlands or Canada only. Therefore, all 
centers in the Netherlands and Canada must ignore this request).  
The following products are allowed: statins, ezetimibe, and herbal products & dietary 
supplements not containing omega-3 fatty acids. 
Statins: 
 
The same statin at the same dose should be continued until the end of the study, 
unless deemed medically necessary to change because of an adverse event or lack of 
efficacy (LOE). It is preferred that if LOE is the determining factor that ezetimibe be 
added to the present dose. 
 
Switching between a brand name statin and the generic version of the same statin is 
allowed at any time during the study. 
 
Statins may be administered with or without ezetimibe. 
 
Based on the FDA recommendation, simvastatin 80 mg may be used only in patients 
who have been taking this dose for 12 months or more and have not experienced any 
muscle toxicity. (See reference: FDA Drug Safety Communication: Ongoing safety 
review of high-dose Zocor (simvastatin) and increased risk of muscle injury. 
(http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatient
sandProviders/ucm204882.htm)  
 
Changing of the type of statin or the statin dose during the treatment/follow-up 
period of the study should only be done for compelling medical reasons and must be 
documented in the CRF. Maintaining statin therapy throughout the study is 
important and, in the rare circumstance that it b ecomes medically compelling to 
discontinue statin use, the patient may remain in the study and on study medication 
with approval from the Medical Monitor. Under such conditions, resumption of 
statin therapy should be attempted when/if medically appropriate. 


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LDL-C Rescue: 
 If the level of LDL-C exceeds 130 mg/dL (3.37 mmol/L) during the study (initial 
measurement and confirmed by a second determination at least 1 week later), the 
investigator may either increase the dose of the present statin therapy or may add 
ezetimibe to lower LDL-C. The investigator should use the best clinical judgment for 
each patient.  
No data are available with regard to potential interactions between ethyl-EPA and oral 
contraceptives. There are no r eports suggesting that omega-3 fatty acids, including ethyl-
EPA, would decrease the efficacy of oral contraceptives. 
Medications that were excluded if not at a stable dose for ≥28 days prior to screening (see 
Section 4.2, Criterion 14), may be initiated post-randomization if medically warranted (i.e., 
tamoxifen, estrogens, progestins, thyroid hormone therapy, systemic corticosteroids and 
HIV-protease inhibitors). 
7.2.2. 
Patient Restrictions 
Beginning at the screening visit, all patients should be instructed to refrain from excessive 
alcohol consumption, to follow a physician recommended diet and to maintain it through the 
duration of the study. Excessive alcohol consumption is on average 2 units of alcohol per 
day or drinking 5 units or more for men or 4 units or more for women in any one hour 
(episodic excessive drinking or binge drinking). A unit of alcohol is defined as a 12-ounce 
(350 mL) beer, 5-ounce (150 mL) wine, or 1.5-ounce (45 mL) of 80-proof alcohol for drinks. 


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8. 
INVESTIGATIONAL PRODUCT 
8.1. 
Clinical Trial Material 
The following will be supplied by the Sponsor: 
 AMR101 1 g Capsules 
 Placebo Capsules (to match AMR101 1 g Capsules) 
The Sponsor will supply sufficient quantities of AMR101 1 g Capsules and Placebo Capsules 
to allow for completion of the study. The lot numbers of the drugs supplied will be recorded 
in the final study report. 
Records will be maintained indicating the receipt and dispensation of all drug supplies. At 
the conclusion of the study, any unused study drug will be destroyed. 
8.2. 
Pharmaceutical Formulations 
AMR101 1 g Capsules and Placebo Capsules are provided in liquid-filled, oblong, soft 
gelatin capsules. Each capsule is filled with a clear liquid (colorless to pale yellow in color). 
The capsules are approximately 25.5 mm in length with a diameter of approximately 9.5 mm.  
Table 5 summarizes the components of each capsule. 
Table 5.  Components of AMR101 1 g Capsules and Placebo Capsules 
Component 
AMR101 
1 g Capsules 
Quantity 
(mg/capsule) 
Placebo 
Capsules 
Quantity 
(mg/capsule) 
Function 
Capsule Fill 
 
 
 
 
Icosapent ethyl 
998 
- 
Active 
 
Paraffin, light liquid 
- 
932 
Inactive 
 
All-rac-α-tocopherol 
2 
1.86 
Antioxidant 
Capsule Shella 
 
 
 
 
Gelatin 
285 
285 
Capsule shell material 
 
Sorbitol 
80 
80 
Plasticizer 
 
Glycerol 
45 
45 
Plasticizer 
 
Purified Water 
38 
38 
Solvent 
 
Maltitol 
29 
29 
Plasticizer 
a The capsule shell quantities represent a nominal “dry shell” formula weight. 
8.3. 
Labeling and Packaging 
Study medication will be packaged in high-density polyethylene bottles. Labeling and 
packaging will be performed according to GMP guidelines and all applicable country-
specific requirements. The bottles will be numbered for each patient based on t he 
randomization schedule. The patient randomization number assigned by IWRS or a designee 
of the Sponsor for the study (if no IWRS is used), will correspond to the number on t he 


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bottles. The bottle number for each patient will be recorded in the Electronic Data Capture 
(EDC) system for the study. 
8.4. 
Dispensing Procedures and Storage Conditions 
8.4.1. 
Dispensing Procedures 
At Visit 2 (Day 0), patients will be assigned study drug according to their treatment group 
determined by the randomization schedule. Once assigned to a treatment group, patients will 
receive study drug supplies. At each visit, patients will bring unused drug supplies dispensed 
to them earlier. From the drug supplies assigned to each patient, site personnel will 
administer drug while the patients are at the Research Site. 
The investigator or designee must contact the IWRS or a designee of the Sponsor for the 
study (if no IWRS is used) when any unscheduled replacements of study medication are 
needed. 
During the last visit during the treatment period, patients will bring the unused drug supplies 
for site personnel to calculate the final study medication compliance by unused capsule count 
(see Section 12.2.2). 
8.4.2. 
Storage Conditions 
At the Research Sites, study drugs must be stored at room temperature, 68°F to 77°F (20°C 
to 25°C). Do not allow storage temperature to go below 59°F (15°C) or above 86°F (30°C). 
Store in the original package. 
Study drugs must be stored in a pharmacy or locked and secure storage facility, accessible 
only to those individuals authorized by the investigator to dispense the drug. The investigator 
or designee will keep accurate dispensing records. At the conclusion of the study, study site 
personnel will account for all used and unused study drug. Any unused study drug will be 
destroyed. The investigator agrees not to distribute study drug to any patient, except those 
patients participating in the study. 


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9. 
EFFICACY ASSESSMENTS 
9.1. 
Specification of Variables and Procedures 
The primary endpoint and the majority of the secondary and tertiary endpoints are based on 
clinical events related to CVD and mortality. All events occurring between randomization 
and the study end date (inclusive) must be recorded. Only adjudicated events will be included 
in the final analysis. Further details on the assessment of clinical events and their definitions 
will be found in the CEC charter. Important definitions are listed in Appendix B and 
Appendix C of this protocol. 
9.2. 
Efficacy Endpoints 
9.2.1. 
Primary Endpoint 
The primary efficacy endpoint is the time from randomization to the first occurrence of any 
component of the composite of the following clinical events: 
 CV death; 
 Nonfatal MI (including silent MI; ECGs will be performed annually for the detection 
of silent MIs); 
 Nonfatal stroke; 
 Coronary revascularization;  
 Unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization.  
The first occurrence of any of these major adverse cardiovascular events during the follow-
up period of the study will be included in the incidence. 
9.2.2. 
Secondary Endpoints 
The key secondary efficacy endpoint is the time from randomization to the first occurrence of 
the composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke.  
Other secondary efficacy endpoints are time from randomization to the first occurrence of the 
individual or composite endpoints as follows (to be tested in the order listed): 
 Composite of CV death or nonfatal MI (including silent MI); 
 Fatal or nonfatal MI (including silent MI); 
 Non-elective coronary revascularization represented as the composite of emergent or 
urgent classifications; 
 CV death; 
 Unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization; 
 Fatal or nonfatal stroke; 
 Composite of total mortality, nonfatal MI (including silent MI), or nonfatal stroke; 
 Total mortality. 


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For the secondary efficacy endpoints that count a single event, the time from randomization 
to the first occurrence of this type of event will be counted for each patient. For secondary 
efficacy endpoints that are composites of two or more types of events, the time from 
randomization to the first occurrence of any of the event types included in the composite will 
be counted for each patient. 
9.2.3. 
Tertiary Endpoints 
The following tertiary endpoints will be evaluated as supporting efficacy and safety analyses. 
Where applicable and unless specified otherwise, endpoint analyses will be conducted as 
time from randomization to the first occurrence of the individual or composite endpoints. 
 Total CV events analysis defined as the time from randomization to occurrence of the 
first and all recurrent major CV events defined as CV death, nonfatal MI (including 
silent MI), nonfatal stroke, coronary revascularization, or unstable angina determined 
to be caused by myocardial ischemia by invasive/non-invasive testing and requiring 
emergent hospitalization; 
 Primary composite endpoint in subset of patients with diabetes mellitus at baseline; 
 Primary composite endpoint in the subset of patients with metabolic syndrome at 
baseline as defined in A Joint Interim Statement of the International Diabetes 
Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and 
Blood Institute; American Heart Association; World Heart Federation; International 
Atherosclerosis Society; and I nternational Association for the Study of Obesity 
(Alberti 2009); with cut points of parameters as defined in Table 1 of Alberti et. al. 
and waist circumference cut points further guided by Table 2 and specifically set at 
≥35 inches (88 cm) for all women and Asian, Hispanic, or Latino men, and ≥40 
inches (102 cm) for all other men (see Appendix D); 
 Primary composite endpoint in the subset of patients with impaired glucose 
metabolism at baseline (Visit 2 FBG of 100-125 mg/dL); 
 Key secondary composite endpoint in the subset of patients with impaired glucose 
metabolism at baseline (Visit 2 FBG 100-125 mg/dL); 
 Composite of CV death, nonfatal MI (including silent MI), nonfatal stroke, cardiac 
arrhythmia requiring hospitalization of ≥24 hours, or cardiac arrest; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), or unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization, nonfatal stroke, or PVD requiring intervention, 
such as angioplasty, bypass surgery, or aneurism repair; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 


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requiring emergent hospitalization, PVD requiring intervention, or cardiac arrhythmia 
requiring hospitalization of ≥24 hours; 
 New CHF; 
 New CHF as the primary cause of hospitalization; 
 Transient ischemic attack (TIA); 
 Amputation for PVD; 
 Carotid revascularization; 
 All coronary revascularizations defined as the composite of emergent, urgent, 
elective, or salvage; 
 Emergent coronary revascularizations; 
 Urgent coronary revascularizations; 
 Elective coronary revascularizations; 
 Salvage coronary revascularizations; 
 Cardiac arrhythmias requiring hospitalization of ≥24 hours; 
 Cardiac arrest; 
 Ischemic stroke; 
 Hemorrhagic stroke; 
 Fatal or nonfatal stroke in the subset of patients with a history of stroke prior to 
baseline; 
 New onset diabetes, defined as Type 2 diabetes newly diagnosed during the 
treatment/follow-up period;  
 New onset hypertension, defined as blood pressure ≥140 mmHg systolic OR ≥90 mm 
Hg diastolic newly diagnosed during the treatment/follow-up period; 
 Fasting TG, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apo B, hs-CRP (hsCRP and 
log[hsCRP]), hsTnT, and RLP-C (to be estimated from standard lipid panel, RLP-C = 
TC – HDL-C – LDL-C [Varbo 2014]), (based on ITT estimands):  
o Assessment of the relationship between baseline biomarker values and 
treatment effects within the primary and key secondary composite endpoints, 
o Assessment of the effect of AMR101 on each marker, 
o Assessment of the relationship between post-baseline biomarker values and 
treatment effects within the primary and key secondary composite endpoints 
by including post-baseline biomarker values (for example, at 4 months, or at 1 
year) as a covariate;  
 Change in body weight;  
 Change in waist circumference. 
Where applicable and unless specified otherwise, for the tertiary endpoints that count a single 
event, the time from randomization to the first occurrence of this type of event will be 
counted in each patient. Similarly, where applicable and unless specified otherwise, for 
tertiary endpoints that are composites of two or more types of events, the time from 


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randomization to the first occurrence of any of the event types included in the composite will 
be counted in each patient. 


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10. 
SAFETY ASSESSMENTS 
10.1. 
Specification of Variables and Procedures 
Safety assessments will include adverse events (AEs), clinical laboratory measurements 
(chemistry, hematology), 12-lead electrocardiograms (ECGs), vital signs (seated systolic and 
diastolic blood pressures, heart rate, respiration rate, and body temperature), weight, waist 
circumference, and physical examinations as per Study Procedures/Appendix A.   
A complete medical, surgical and family history will be completed at Visit 1. 
A list of the analytes to be measured for the safety evaluation is found in Section 6.3.1.1. All 
laboratory test results must be evaluated by the investigator as to their clinical significance. 
Any observations at physical examinations or laboratory values considered by the 
investigator to be clinically significant should be considered an AE. 
10.2. 
AEs 
An AE is defined as any untoward medical occurrence, which does not necessarily have a 
causal relationship with the medication under investigation. An AE can therefore be any 
unfavorable and/or unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an investigational medication product, whether 
or not related to the investigational medication product. All AEs, including observed or 
volunteered problems, complaints, or symptoms, are to be recorded on the appropriate CRF. 
Each AE is to be evaluated for duration, intensity, and causal relationship with the study 
medication or other factors. 
AEs, which include clinical laboratory test variables, will be monitored from the time of 
informed consent until study participation is complete. Patients should be instructed to report 
any AE that they experience to the investigator. Beginning with Visit 2, investigators should 
assess for AEs at each visit and record the event on the appropriate AE CRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the investigator and recorded on the CRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the investigator, it should be recorded as a separate AE on the CRF. 
Any medical condition that is present when a patient is screened or present at baseline that 
does not deteriorate should not be reported as an AE. However, medical conditions or signs 
or symptoms present at baseline and that change in severity or seriousness at any time during 
the study should be reported as an AE. 
Clinically significant abnormal laboratory findings or other abnormal assessments that are 
detected during the study or are present at baseline and significantly worsen will be reported 
as AEs or SAEs. The investigator will exercise his or her medical and scientific judgment in 
deciding whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. 
The investigator will rate the severity (intensity) of each AE as mild, moderate, or severe, 
and will also categorize each AE as to its potential relationship to study drug using the 
categories of Yes or No. 


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Severity: 
 Mild – An event that is usually transient in nature and generally not interfering with 
normal activities. 
 Moderate – An event that is sufficiently discomforting to interfere with normal 
activities. 
 Severe – An event that is incapacitating with inability to work or do usual activity or 
inability to work or perform normal daily activity. 
Causality Assessment: 
The relationship of an AE to the administration of the study drug is to be assessed according 
to the following definitions: 
 No (unrelated, not related, no relation) – The time course between the administration 
of study drug and the occurrence or worsening of the AE rules out a cau sal 
relationship and another cause (concomitant drugs, therapies, complications, etc.) is 
suspected. 
 Yes (related, probably related, possibly related) – The time course between the 
administration of study drug and the occurrence or worsening of the AE is consistent 
with a causal relationship and no ot her cause (concomitant drugs, therapies, 
complications, etc.) can be identified. 
The following factors should also be considered: 
 The temporal sequence from study medication administration 
 The event should occur after the study medication is given. The length of time from 
study medication exposure to event should be evaluated in the clinical context of the 
event. 
 Underlying, concomitant, intercurrent diseases 
 Each report should be evaluated in the context of the natural history and course of the 
disease being treated and any other disease the patient may have. 
 Concomitant medication 
 The other medications the patient is taking or the treatment the patient receives 
should be examined to determine whether any of them might be recognized to cause 
the event in question. 
 Known response pattern for this class of study medication 
 Clinical and/or preclinical data may indicate whether a particular response is likely to 
be a class effect. 
 Exposure to physical and/or mental stresses 
 The exposure to stress might induce adverse changes in the patient and provide a 
logical and better explanation for the event. 
 The pharmacology and pharmacokinetics of the study medication 
 The known pharmacologic properties (absorption, distribution, metabolism, and 
excretion) of the study medication should be considered. 
Unexpected AEs – An unexpected AE is an AE either not previously reported or where the 
nature, seriousness, severity, or outcome is not consistent with the current Investigator’s 
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10.2.1. 
Serious Adverse Events 
A serious adverse event (SAE) is defined as an AE that meets any of the following criteria: 
 Results in death; 
 Is life-threatening- Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the patient was at risk of death at the time of the event. It 
does not refer to an event, which hypothetically might have caused death, if it were 
more severe. 
 Requires hospitalization or prolongation of existing hospitalization- Note: In general, 
hospitalization for treatment of a pre-existing condition(s) that did not worsen from 
baseline is not considered an AE(s) and should not be reported as a SAE(s). 
 Results in disability/incapacity; 
 Is a congenital anomaly/birth defect; 
 Is an important medical event- Note: Important medical events that may not result in 
death, be life threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalizations, or the development of drug dependency. 
By design of this study SAEs that are endpoint events will only be recorded for the endpoint 
determination and not captured as SAEs. The intention is that the endpoint events are not 
reported to IRBs as SAEs, unless the IRB requires that these are reported. Investigators 
should specifically inform their institution/IRB of this plan and confirm whether or not they 
want the endpoint events reported. By agreement with the US FDA, these endpoints will also 
not be reported to the US FDA as SAEs; rather they will be reported as endpoint events. 
Following adjudication if the event is determined to not meet the criteria for an event, the 
event will be evaluated as an SAE beginning with that day as Day 0. 
10.3. 
Serious Adverse Event Reporting – Procedure for Investigators 
10.3.1. 
Initial Reports 
All SAEs occurring from the time of informed consent until 28 days following the last 
administration of study medication (or until 28 days following study completion for ODIS 
patients) must be reported to the Sponsor or designee within 24 hours of the knowledge of 
the occurrence (this refers to any AE that meets any of the aforementioned serious criteria). 
SAEs that the investigator considers related to study medication occurring after the 28-day 
follow-up period will also be reported to the Sponsor or designee.  
The investigator is required to submit SAE reports to the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) in accordance with local requirements. All 
investigators involved in studies using the same investigational medicinal product (IMP) will 
receive any Suspected Unexpected Serious Adverse Reaction (SUSAR) reports for onward 
submission to their local IRB as required. All reports sent to investigators will be blinded. 
In addition, regulatory agencies will be notified of SAEs per the requirements of the specific 
regulatory jurisdiction regulations and laws. 


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10.3.2. 
Follow-Up Reports 
The investigator must continue to follow the patient until the SAE has subsided, or until the 
condition becomes chronic in nature, stabilizes (in the case of persistent impairment), or the 
patient dies. Within 24 hours of receipt of follow-up information, the investigator must 
update the SAE form electronically in the EDC system for the study and submit any 
supporting documentation (e.g., laboratory test reports, patient discharge summary, or 
autopsy reports) to the Sponsor or designee via fax or email. 
10.3.3. 
Reporting by the Sponsor 
IRBs and IECs will be informed of SUSARs according to local requirements. Cases will be 
unblinded for reporting purposes as required. 
10.4. 
Exposure in Utero During Clinical Trials 
If a patient becomes pregnant during the study, the investigator should report the pregnancy 
to the Sponsor or designee within 24 hours of being notified. The Sponsor or designee will 
then forward the Exposure in Utero form to the investigator for completion. 
The patient should be followed by the investigator until completion of the pregnancy. If the 
pregnancy ends for any reason before the anticipated date, the investigator should notify the 
Sponsor or designee. At the completion of the pregnancy, the investigator will document the 
outcome of the pregnancy. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, 
neonatal death, or congenital anomaly), the investigator should follow the procedures for 
reporting an SAE. 


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11. 
TREATMENT DISCONTINUATION/PATIENT WITHDRAWAL 
Patients may withdraw from the study at any time and for any reason. Study drug 
administration may also be discontinued at any time, at the discretion of the investigator. In 
any case, follow-up for efficacy and safety should be continued in subjects that discontinue 
therapy, but remain in the study (i.e., ODIS patients). 
11.1. 
Reasons for Early Study Drug Discontinuation 
Study drug discontinuation should be avoided as much as possible, but may be done for any 
of the following reasons: 
 Patient withdraws consent or requests early discontinuation from the study for any 
reason. Patients should be encouraged to continue to participate in the study for the 
entire duration of the study even if they choose not to take study medication any 
longer. 
 Occurrence of a clinical or laboratory AE, either serious or non-serious, at the 
discretion of the investigator. The Sponsor or designee should be notified if a patient 
discontinues study drug because of an AE or laboratory abnormality. It is 
recommended that, unless clear contraindications arise, patients be strongly 
encouraged to adhere to their treatment regimen with the study drug for the duration 
of the trial. Any interruptions of therapy should, if possible, be brief (e.g., <4 weeks) 
and only for clinically indicated reasons, such as AEs. The following should be 
considered reasons for study drug discontinuation: 
o ALT >3 × ULN and bilirubin > 1.5 × ULN 
o ALT >5 × ULN 
o ALT >3 × ULN and appearance or worsening of hepatitis 
o ALT >3 × ULN persisting for >4 weeks 
o ALT >3 × ULN and cannot be monitored weekly for 4 weeks 
 Any medical condition or personal circumstance that, in the opinion of the 
investigator, exposes the patient to risk by continuing in the study or precludes 
adherence to the protocol. 
 Sponsor discontinues the study. 
 Investigative site closure, in the event that: 
o Another investigative site cannot accommodate the patient, or  
o The patient is unable or unwilling to travel to another investigative site. 
 A TG value that is flagged as critically high, i.e., >1000 mg/dL (11.29 mmol/L), and 
confirmed as critically high by a repeat measurement (new fasting blood sample) 
within 7 days. In this case, a patient may be discontinued from study drug (with the 
option to remain ODIS) and other lipid-altering medications may be (re)initiated. If 
the TG value is flagged as >2000 mg/dL (22.58 mmol/L) then appropriate medical 
action can be taken by the investigator as soon as possible. 
Occurrence of an outcome event according to the judgment of the investigator is not 
considered a valid reason for study drug discontinuation. 


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Patients whose treatment with study medication is discontinued early, and have not 
withdrawn consent, will stay in study and will be monitored until the end of the study. 
Patients who continue in the study after ≥30 days after cessation of therapy will be 
characterized as ODIS. ODIS patients should be asked to return to the study site for an 
interim visit once the patient has been off study drug for >30 days. Procedures at this visit are 
consistent with those at Visit 5. If not contraindicated, patients will also have the option to 
restart study medication at any point once characterized as ODIS. For patients who 
discontinue study medication (e.g., for an AE that may or may not be drug-related), a brief 
therapy interruption can be followed with a re-challenge (re-initiating study medication) as 
soon as clinically appropriate; thereby allowing a causative role for study medication to be 
confirmed or ruled out and continuing a patient in the study and on study drug if appropriate. 
The reason for study drug discontinuation or interruption will be recorded on the CRF. 
11.2. 
Follow-Up after Early Study Drug Discontinuation/Lost to Follow-Up 
 Patients who prematurely discontinue study drug are not to be replaced. 
 All randomized patients must be followed up a ccording to the study schedule of 
procedures until the study end date or death, regardless of whether they discontinue 
study drug prematurely or not. Any event occurring after early study drug 
discontinuation will be recorded up through the study end date. 
 In order to follow the medical status of the patients, especially when they 
discontinued the study, investigators are encouraged to obtain information from the 
patient’s primary care practitioner (physician or any other medical care provider). 
Investigators are also requested to try as much as possible to re-contact those patients 
at the end of the trial to obtain at least their vital status as well as their status with 
respect to the primary endpoint, and thus avoid lost to follow-up for the efficacy 
assessment. 
 If patients are lost to follow-up, the CRF must be completed up to the last visit or 
contact.  


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12. 
STATISTICS 
12.1. 
Analysis Populations 
12.1.1. 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will include all patients who are randomized via the 
IWRS. All efficacy analyses, including the primary analysis, will be performed on the ITT 
population.  Patients will be analyzed according to the randomized treatment. 
12.1.2. 
Modified Intent-to-Treat Population  
The Modified Intent-to-Treat (mITT) population will include all randomized patients who 
have study drug dispensed after randomization. Groups will be defined based on t he 
randomized treatment. 
12.1.3. 
Per-Protocol Population 
The Per-Protocol (PP) population will include all mITT patients without any major protocol 
deviations, and who had ≥80% compliance while on treatment.  To be included in the PP 
population the minimum time on therapy is 90 days.   
12.1.4. 
Safety Population 
All safety analyses will be conducted based on the Safety population, which is defined as all 
randomized patients. This is the same as the ITT population.  
12.2. 
Statistical Methods 
Safety and efficacy variables will be analyzed using appropriate statistical methods to be 
described in detail in a separate Statistical Analysis Plan (SAP). The SAP will be finalized 
before study unblinding. 
12.2.1. 
Patient Disposition and Demographic/Baseline Characteristics 
The number and percentage of patients will be tabulated for each of the following categories 
for each treatment group: 
 Screened (total only); 
 Re-screened and reasons for re-screening (total only); 
 ITT overall and by stratification factors (CV risk, ezetimibe use, and geographical 
region); 
 mITT population; overall and by stratification factors (CV risk, ezetimibe use, and 
geographical region); 
 PP population; overall and by stratification factors (CV risk, ezetimibe use, and 
geographical region); 
 Safety population; 
 Patients who complete the study; 
 Patients who terminated from the trial early and the primary reason for early 
termination.  
 Patients who terminated the trial early; prior to having a confirmed primary endpoint 
event. 


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 Patients with complete follow-up, defined as those for whom all components of the 
primary endpoint have been ascertained during the entire observation period (or until 
death). 
 Patients who, at the time of study completion, were discontinued from study drug 
prematurely, but continued within the study (i.e. ODIS patients), along with the 
primary reason. 
For randomized patients who discontinued treatment with study drug, the primary reason for 
discontinuation will be listed and summarized by treatment group. 
Demographic and baseline characteristics, including age, gender, ethnicity, race, height, body 
weight, BMI, diabetes, hypertension, metabolic syndrome, overweight/obese/normal 
according to BMI, and diabetes plus obesity will be summarized using descriptive statistics 
by treatment group in the ITT population.  
Demographic data and baseline characteristics will be also compared between treatment 
groups for the mITT population and PP population. Differences in demographic and baseline 
characteristics will be tested using a chi-square test (for categorical variables) or t-test (for 
continuous variables). The p-values will be considered descriptive, primarily as an 
assessment of the balance between groups. Age in years will be calculated using the date of 
randomization (Visit 2) and the date of birth. 
12.2.2. 
Study Medication Exposure and Compliance 
Study drug exposure will be summarized by treatment group using descriptive statistics for 
each time point and overall. Overall study drug compliance will be calculated as the number 
of doses assumed to be taken relative to scheduled dosing period as follows: 
Compliance (%) = (# Capsules of total dispensed - # Capsules of total returned)  × 100 
 
                       (last dose date – first dose date + 1) × 4 capsules/day 
Overall percent compliance will be calculated per patient in the ITT and Modified ITT 
populations and summarized by treatment group using descriptive statistics. 
12.2.3. 
Concomitant Therapies 
Concomitant medication/therapy verbatim terms will be coded using the latest available 
version, prior to data base lock, of the World Health Organization Drug Dictionary and the 
Anatomical Therapeutic Chemical classification system. The numbers and percentages of 
patients in each treatment group taking concomitant medications will be summarized. All 
verbatim descriptions and coded terms will be listed for all non-study medications. 
12.2.4. 
Analysis of Efficacy 
For efficacy endpoints including CV events, only adjudicated events will be included in the 
final statistical analyses. 
12.2.4.1. 
Summary Statistics 
Summary statistics (n, mean, standard deviation, median, minimum, and maximum) for the 
baseline and post-baseline measurements, the percent changes, or changes from baseline will 
be presented by treatment group and by visit for all efficacy variables to be analyzed. The 


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summary statistics will include changes in body weight and BMI from baseline by treatment 
group and by visit. 
12.2.4.2. 
Primary Endpoint Analyses 
The primary endpoint is described in Section 9.2.1. The analysis of the primary endpoint will 
be performed using the log-rank test comparing the 2 treatment groups (AMR101 and 
placebo) and including the stratification factor “CV risk category”, use of ezetimibe and 
geographical region (Westernized, Eastern European, and Asia Pacific countries) (each as 
recorded in the IWRS at the time of enrollment) as covariates. The two-sided alpha level for 
the primary analysis will be reduced from 0.05 to account for the interim analyses based on a 
group sequential design with O’Brien-Fleming boundaries generated using the Lan-DeMets 
alpha-spending function. The hazard ratio for treatment group (AMR101 vs. placebo) from a 
Cox proportional hazard model that includes the stratification factor will also be reported, 
along with the associated 95% confidence interval. Kaplan-Meier estimates from 
randomization to the time to the primary endpoint will be plotted.  
The size and direction of the treatment effects of the individual components of the composite 
endpoint and their relative contribution to the composite endpoint will be determined as well. 
All observed data that are positively adjudicated by the CEC, including data after 
discontinuation of study treatment for patients who discontinue study drug prematurely, will 
be included in the primary analysis. 
Patients who do not experience a primary efficacy event prior to the end of the study or who 
withdraw from the study early without a preceding primary efficacy event will be censored at 
the date of their last visit/phone contact. 
The longest prespecified interval between visits (onsite or phone) is 90 days. In view of the 
up to 90-day monitoring period for CV events, the primary endpoint for patients who have a 
non-CV death within 90 days of last contact without having had an earlier CV event will be 
censored at the time of death. The primary endpoint for patients who have a non-CV death 
more than 90 days after last contact without having had an earlier CV event will be censored 
at the time of last contact. 
The primary analysis will assume that all silent MIs occurred on the date of the first tracing 
indicative of a silent MI; a second (sensitivity) analysis will assume that all silent MIs 
occurred on the day after the last prior normal ECG; and a third (sensitivity) analysis will 
assume that all silent MIs occurred at the mid-point between the last normal ECG and the 
ECG with the new MI. 
All deaths causally adjudicated as “undetermined” will be combined with those adjudicated 
as “CV deaths” for the primary analysis. A sensitivity analysis of the CV death category will 
be performed that excludes the “undetermined cause of death” cohort. 
The primary efficacy analysis will be performed on the ITT population. A sensitivity analysis 
will be performed using the mITT and PP populations. 
As a sensitivity analysis, patients who discontinue study drug prematurely will be censored 
for the primary composite endpoint analysis on t he date of drug discontinuation.  The 
primary analysis will be repeated using this censoring rule for the mITT population. 


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As a supportive analysis, a multivariable, stratified Cox proportional hazards model will be 
constructed for the primary endpoint to evaluate the treatment effect adjusting for important 
covariates.   
12.2.4.3. 
Secondary Endpoint Analyses 
The key and other secondary endpoints are listed in Section 9.2.2. The key secondary 
hypothesis will be tested as part of the confirmatory process only if the primary analysis is 
statistically significant. For the analysis of secondary efficacy endpoints, the Type 1 error 
will be controlled by testing each endpoint sequentially, starting with the key endpoint.  
Testing will be done at a significance level consistent with that used for the primary endpoint 
and will cease when a secondary endpoint is found for which treatments do not significantly 
differ.  P-values will be presented for all analyses, but they will be considered descriptive 
after the first non-significant result is obtained. 
Each of the secondary endpoints will be analyzed by the same methods described for the 
primary efficacy endpoint.  K aplan-Meier estimates, the log-rank test stratified by 
stratification factors used at randomization, and the Cox proportional hazards model 
including the stratification factors as specified above for the primary efficacy endpoint, will 
be summarized by treatment group.  In view of the 90-day monitoring period for CV events, 
the key secondary endpoint for patients who have a non-CV death within 90 da ys of last 
contact without having had an earlier CV event will be censored at the time of death. The key 
secondary endpoint for patients who have a non-CV death more than 90 da ys after last 
contact without having had an earlier CV event will be censored at the time of last contact. 
Kaplan-Meier curves stratified by each stratification factor will be presented.  These analyses 
will be conducted for the ITT population. 
12.2.4.4. 
Tertiary Endpoint Analyses 
The tertiary endpoints are listed in Section 9.2.3. Time-to-event tertiary endpoints will be 
analyzed by the same methods as described for the primary efficacy endpoint.  Kaplan-Meier 
estimates, the log-rank test stratified by stratification factors used at randomization, and the 
Cox proportional hazards model as specified for the primary efficacy endpoint, will be 
summarized by treatment group.  In view of the 90-day monitoring period for CV events, if 
applicable, tertiary endpoints for patients who have a non-CV death within 90 days of last 
contact without having had an earlier CV event will be censored at the time of death. If 
applicable, tertiary endpoints for patients who have a non-CV death more than 90 days after 
last contact without having had an earlier CV event will be censored at the time of last 
contact. Kaplan-Meier curves stratified by each of the stratification factors will be presented. 
The fasting lipid panel is tested at Screening (Visit 1 or Visit 1.1), Randomization visit 
(Visit 2; Day 0), Visit 3 (Day 120; ~4 Months) and all other follow-up visits including the 
last visit. For change from baseline to 1 year preparative ultracentrifugation measurements 
for LDL-C will be analysed, unless this value is missing.  If the LDL-C preparative 
ultracentrifugation values are missing, then another LDL-C value will be used, with 
prioritization of values obtained from LDL-C Direct measurements, followed by LDL-C 
derived by the Friedewald calculation (only for subjects with TG <400 mg/dL), and finally 
LDL-C derived using the calculation published by Hopkins University investigators (Martin 
2013).  In addition, change from baseline to day 120 in LDL-C utilizing Friedewald’s and 
Hopkins methods will be analysed, using the arithmetic mean of LDL-C obtained at Visit 2 


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(Day 0) and the preceding Visit 1 (or Visit 1.1). If one of these values is missing, the single 
available LDL-C value will be used. LDL-C according to Hopkins will be calculated at each 
visit.  
The randomization visit will be considered Baseline.  If a baseline value is not available from 
the randomization visit, then the latest screening value will be used. 
For measurements of lipids, lipoproteins, and inflammatory markers, the change from 
baseline and the percent change will be summarized at each visit.  Since these parameters are 
typically not normally distributed, the Wilcoxon rank-sum test will be used for treatment 
comparisons of the percent change from baseline, and medians and quartiles will be provided 
for each treatment group. The medians of the differences between the treatment groups and 
95% CIs will be estimated with the Hodges-Lehman method.  In addition, shift –tables may 
be generated as appropriate. 
As an additional exploratory analysis, the relationship between post-baseline biomarker 
values and treatment effects with the primary and key secondary endpoints will be assessed 
by adding biomarker values (for example, at 4 month, or at 1 year, etc.) as time-dependent 
covariates in the Cox proportional hazards model. Diagnostic plots for the proportional 
hazards assumption will be evaluated 
Weight is measured at the screening visit and at all follow-up visits, including the last visit of 
the study.  Waist circumference will be measured at the randomization visit (Visit 2; Day 0), 
Visit 5 (Day 720) and the last visit of the study.  Descriptive statistics will be presented by 
visit and treatment group for baseline, post-treatment change from baseline, and the percent 
change from baseline.  Analysis methods for repeated measurements will be used to compare 
percent change from baseline between treatments. 
New onset diabetes is defined as Type 2 di abetes newly diagnosed during the 
treatment/follow-up period (i.e. patients with no history of diabetes at randomization, with 
the test as listed in Appendix C). 
12.2.4.5. 
Exploratory Subgroup Analyses  
Analyses of the effects that patients off study drug and withdrawn from study have on the 
primary endpoint will be performed. 
Subgroup analyses of the primary and key secondary endpoints will be performed as 
described for the primary endpoint.  For each subgroup, Kaplan-Meier estimates, the log-
rank test stratified by stratification factors used at randomization (except where the subgroup 
is a stratification factor), and HRs and CIs from the Cox proportional hazards model as 
specified for the primary efficacy endpoint, will be summarized by treatment group. 
The following subgroups will be explored: 
Demographics: 
 gender; 
 age at baseline (<65 years and ≥65 years); 
 race (white and nonwhite, or any other subset with at least 10% of the total number of 
patients);  
 geographical region (Westernized, Eastern European, and Asia Pacific countries); and 


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 baseline ezetimibe use (yes/no). 
Disease Parameters: 
 CV risk category; 
 the presence/absence of diabetes at baseline; and 
 renal dysfunction at baseline (estimated glomerular filtration rate [eGFR] <60 
mL/min/1.73m2) using the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation as follows: 
eGFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 
1.159 [if black] 
Where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1 (Levey 2009). 
Treatment Parameters: 
 statin intensity at baseline (statin type and regimen)  
Statin intensity categories as defined in ACC/AHA Cholesterol Guidelines (Stone 
2013) and patient’s 10-year CV Risk Score (Goff 2013). 
Baseline Lipid and Lipoprotein Parameters: 
 LDL-C (by tertile); 
 HDL-C (by tertile, and tertile by gender); 
 TG (by tertile, and tertile by gender); 
 RLP-C (by tertile) 
 TG ≥150 mg/dL and TG <150 mg/dL; 
 TG ≥200 mg/dL and TG <200 mg/dL; 
 TG ≥ median, TG < median; 
 combined highest tertile for TG and lowest tertile for HDL-C; 
 gender-specific highest tertile for TG and lowest tertile for HDL-C; 
 TG ≥ 200 mg/dL with HDL-C ≤35 mg/dL; 
 hs-CRP (≤3 mg/L and >3 mg/L) and by gender; 
 hs-CRP (≤2 mg/L and >2 mg/L) and by gender; 
 Apo B (by tertile); and 
 non-HDL-C (by tertile). 


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A Cox proportional hazard (PH) model as mentioned above but additionally with baseline 
TG as a covariate will be fitted to the data at each interim. Diagnostic plots for the PH 
assumption will be evaluated. 
The consistency of the treatment effects in subgroups will be assessed for the primary and 
key secondary efficacy endpoints. For each subgroup variable, a Cox PH model with terms 
for treatment, stratification factors (with the exception of those subgroup variables related to 
the stratification factors, i.e., CV risk category), subgroup, and treatment-by-subgroup 
interaction will be performed.  The main treatment effect will not be tested with this model.  
P-values for testing the interaction terms < 0.15 will be considered significant. Results will 
be presented in a Forest plot. 
All subgroup analyses will be conducted for the ITT, mITT and PP populations. 
12.2.4.6. 
Interim Efficacy Analyses 
Two interim analyses are planned for the primary efficacy endpoint using adjudicated events 
when approximately 60% (967 events) and approximately 80% (1290 events) of the total 
number of primary endpoint events planned (1612) is reached. The planned interim analyses 
are based on a group-sequential design and are described in the Interim Statistical Analysis 
Plan (included as an appendix to the SAP) which will be finalized prior to performing the 
unblinded interim analyses. 
The interim results of the study will be monitored by an independent Data Monitoring 
Committee (DMC). The analyses will be performed by the independent statistical team who 
is unblinded to the treatment assignment and reported only to the DMC.  Unblinded 
information will not be released to the Sponsor before the completion of the study unless 
extraordinary circumstances arise and, under such circumstances, procedures for maintaining 
confidentiality will be described in a written agreement with the DMC. If the study is 
terminated early following interim analysis, patients will be notified promptly and brought in 
for their final close-out visit, and the final analyses of efficacy and safety will include all data 
through their final visit.  
All suspected events will be adjudicated in a blinded manner by the CEC. 
The time to event will be calculated as the time from randomization to the onset date of the 
event (as determined by the CEC). Patients who do not experience any of the above events at 
the time of data cutoff for the interim but are still in the trial will be considered censored at 
the time of their last regular contact before the interim data cutoff. 
12.2.5. 
Analysis of Safety 
All analyses of safety will be conducted on t he safety population, which is defined as all 
randomized patients. The safety assessment will be based on the frequency of AEs, physical 
exams, vital signs and safety laboratory tests. 
AEs with new onset during the study between the initiation of study drug and 30 days after 
the completion or withdrawal from study will be considered treatment-emergent (TEAEs). 
This will include any AE with onset prior to initiation of study drug and increased severity 
after the treatment initiation. 
Treatment-emergent adverse events will be summarized by system organ class and preferred 
term, and by treatment. This will include overall incidence rates (regardless of severity and 


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relationship to study drug), and incidence rates for moderate or severe AEs. A summary of 
SAEs and AEs leading to early study drug discontinuation (for ≥30 days) will be presented 
through data listings. Patients who restart study drug will not be included in the summary of 
AEs leading to discontinuation. 
Safety laboratory tests and vital signs will be summarized by post-treatment change from 
baseline for each of the parameters using descriptive statistics by treatment group. Those 
patients with significant laboratory abnormalities will be identified in data listings. 
Additional safety parameters will be summarized in data listings. 
12.3. 
Sample Size Determination 
This is an event-driven trial comparing the effect of AMR101 vs. placebo in terms of the 
composite endpoint listed above as the primary endpoint. The study has been planned to 
accrue a total of 1612 e fficacy endpoint events with two planned interim analyses when 
approximately 967 (60%) and 1290 (80%) of the events have been adjudicated. 
Sample size calculation was based on assumptions of constant hazard, asymmetric 
recruitment rate over time and without factoring for dropouts. A risk reduction corresponding 
to a hazard ratio of 0.85 (AMR101 vs. placebo) is assumed. 1612 events would be required to 
detect this hazard ratio with approximately 90% power with one-sided alpha-level at 2.5% 
and with two interim analyses. The operating characteristics of this design are identical to 
those of a corresponding group sequential design with a two-sided alpha level of 0.05. 
The recruitment period is assumed to be 4.2 years with 20% recruitment in the first year, 
40% in the second year, 20% in the third year, 19% in the fourth year and the remaining 1% 
in the last 0.2 years. The estimated maximum study duration is 6.5 years unless the trial is 
terminated early for efficacy or safety issues. A one-year event rate of 5.2% (hazard = 0.053) 
in the control arm is also assumed. Under these assumptions the number of patients to be 
enrolled is N = 7990. 
Since this is an events-driven trial, the ‘sample size’ is the number of events rather than the 
number of patients. The number of events that occur depends primarily on three factors: how 
many patients are enrolled, the combined group event rate, and how long the patients are 
followed. Because of the difficulty in predicting the combined event rate, the sponsor will 
monitor that event rate as the trial progresses. If the combined event rate is less than 
anticipated, either increasing the number of patients, extending the length of follow-up, or a 
balance of adjusting both factors may be necessary to achieve the sample size of 1612 events. 
Before completing the enrollment phase of the trial, i.e. approximately 3- to 6-months prior 
to the projected enrollment of the 7990th patient, the actual event rate based on pool ed, 
blinded accumulation of primary efficacy endpoint events would be calculated and plotted.  
If those analyses suggested the number of patients with at least 1 adjudicated, primary event 
(and appropriately accounting for patients with potential primary events for which the 
adjudication process is then incomplete) was consistent with projections, then the study could 
continue toward the protocol-specified target enrollment of 7990 patients.  However, if the 
number of such events appeared less than, and inconsistent with projections, the Sponsor 
would consider (under blinded conditions) re-calculating the number of patients needed to 
achieve the target number of events within the desired timeline or extend the follow-up 
period.  If the projected increase in number of patients was ≤25% of the original 7990 target 


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population, the Sponsor could, with documented approval of both the REDUCE-IT Steering 
Committee and the Data Monitoring Committee, extend enrollment to the revised target 
number without need for an additional protocol amendment.   Under those conditions, all 
principal investigators, ethics committees, and regulatory authorities associated with the 
protocol will be promptly notified of the action. If the projected increase in number of 
patients was more than 25% above the original 7990 target (i.e. more than 1998 additional 
patients) a formal protocol amendment would be initiated. 
Consistent with the plan stated above, an analysis and modeling of pooled, blinded primary 
efficacy endpoint events across the remainder of the trial was performed prior to the 
projected enrollment of the 7990th patient. Based on this analysis, the sample size of 7990 
randomized patients is with 95% confidence likely to result in the target 1,612 adjudicated 
primary efficacy events within 2018.  T he results of this analysis were shared with and 
approved by the REDUCE-IT Steering Committee and Data Monitoring Committee. 
As of the completion of study enrollment, the actual number of patients randomized will vary 
from the target number (either original or revised) as a result of the inherent lag between the 
date the last patient started screening and the date the last patient was randomized. 


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13. 
MONITORING, DATA MANAGEMENT, AND RECORD KEEPING 
13.1. 
Data Management 
13.1.1. 
Data Handling 
Data will be recorded at the site on CRFs. All entries on a CRF are ultimately the 
responsibility of the Investigator, who is expected to review each form for completeness and 
accuracy before signing. A CRF must be completed for each randomized patient. The CRFs 
and source documents must be made available to the Sponsor and/or its designee. 
13.2. 
Record Keeping 
The Investigator must maintain all documents and records, originals or certified copies of 
original records, relating to the conduct of this trial, and necessary for the evaluation and 
reconstruction of the clinical trial. This documentation includes, but is not limited to 
protocol, CRFs, AE reports, patient source data (including records of patients, patient visit 
logs, clinical observations and findings), correspondence with health authorities and IRB, 
consent forms, inventory of study product, Investigator’s curriculum vitae, monitor visit logs, 
laboratory reference ranges and laboratory certification or quality control procedures, and 
laboratory director curriculum vitae. 
The Investigator and affiliated institution should maintain the trial documents as required by 
the applicable regulations. The Investigator and affiliated institution should take measures to 
prevent accidental or premature destruction of documents. Clinical trial documents must be 
kept in the clinical site’s archives indefinitely, unless written authorization is obtained from 
the Sponsor. 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator and research institution agree that the Sponsor, their representatives and 
designees, the IRB or IEC, and representatives from worldwide regulatory agencies will have 
the right, both during and after the clinical trial, to review and inspect pertinent medical 
records related to the clinical trial. 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor and/or its designee(s) will perform quality control and quality assurance checks 
of all clinical trials that it sponsors. Before the enrollment of any patient in this study, the 
Sponsor or its designee will review with the investigator and site personnel the following 
documents: protocol, Investigator’s Brochure, CRFs and procedures for their completion, the 
informed consent process, and the procedure for reporting SAEs. Site visits will be 
performed by the Sponsor and/or its designees. During these visits, information recorded on 
the CRFs will be verified against source documents and requests for clarification or 
correction may be made. After the CRF data is entered by the site, the Sponsor or designee 
will review for safety information, completeness, accuracy, and logical consistency. 
Computer programs that identify data inconsistencies may be used to help monitor the 
clinical trial. If necessary, requests for clarification or correction will be sent to investigators. 
By signing the protocol, the Sponsor agrees directly or through its designee(s) to be 
responsible for implementing and maintaining quality control and quality assurance systems 
with written standard operating procedures to ensure that trials are conducted and data are 
generated, documented, and reported in compliance with the protocol, accepted standards of 
Good Clinical Practice (GCP), International Conference on Harmonisation (ICH) and other 
applicable regulations. 


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16. 
ETHICS AND GOOD CLINICAL PRACTICE COMPLIANCE 
Good Clinical Practice is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting trials that involve human patients. 
Compliance with this standard provides public assurance that the rights, safety, and well-
being of trial patients are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki, and that the clinical trial data are credible. In this study, the 2008 
version of the Declaration of Helsinki will be adhered to. It can be found on the website of 
The World Medical Association: 
http://www.wma.net/en/30publications/10policies/b3/17c.pdf 


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17. 
INFORMED CONSENT 
Prior to participation in a study, the participant, or participant’s legal representative/impartial 
witness must sign an IRB/IEC-approved written informed consent form (ICF). The approved 
written informed consent must abide to all applicable laws in regards to the safety and 
confidentiality of the patients. To obtain and document informed consent, the Investigator 
should comply with applicable regulations; adhere to GCP standards and the ethical 
principles in the Declaration of Helsinki (see Section 16). 
The language in the oral and written information about the trial, including the written 
informed consent form should be as non-technical as practical and should be understandable 
to the participant or participant’s legal representative/impartial witness, where applicable. 
Before informed consent is obtained, the Investigator should provide the participant, or 
participant’s legal representative/impartial witness ample time and opportunity to inquire 
about the trial and to decide whether or not to participate. 
All questions about the trial should be answered to the satisfaction of the participant, or the 
participant’s legal representative/impartial witness. The written ICF should be signed and 
personally dated by the participant or participant’s legal representative/impartial witness, and 
by the person who conducted the informed consent discussion. Participants will be informed 
that participation is voluntary and that he/she can withdraw from the study at any time. A 
signed copy of the consent form must be given to the participant, and this fact will be 
documented in the CRF. 
Of special concern regarding informed consent is the collection of blood samples for genetic 
analysis. Local regulations may not allow the collection of blood samples for genetic testing 
or the shipment of blood samples for genetic testing outside the region. In these cases, blood 
samples for genetic testing will not be collected, and the portion of the ICF describing the 
genetic component of the study will not be included. If blood samples for genetic testing will 
be collected, the ICF will clearly indicate that a sample will be drawn for this purpose, but 
that the participant has the right to refuse this procedure. 
18. 
PUBLICATION POLICY  
The SC is responsible for the reporting and publication of the study results. The Sponsor will 
be provided a reasonable opportunity to review such manuscripts prior to journal submission. 
The results of the study will be published irrespective of whether the endpoints are met, or 
whether the results are regarded positive or negative. 
 
Confidentiality, publication, and patent applications related to unpublished study-related 
information and unpublished information given to the site investigators by the Sponsor 
and/or its designee(s) shall be handled as set forth in the Clinical Trial Agreement. 


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19. 
FINANCING AND INSURANCE 
19.1. 
Finances 
Prior to starting the study, the Principal Investigator and/or institution will sign a Clinical 
Trial Agreement with the Sponsor and/or its designee(s). This agreement will include the 
financial information agreed upon by the parties. 
19.2. 
Insurance Compensation 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical 
trials under its sponsorship. This insurance policy is in accordance with local laws and 
requirements. The insurance of the Sponsor does not relieve the investigator and the other 
collaborators from maintaining their own liability insurance policy. An insurance certificate 
will be provided to the IRB/IEC and Competent Authority according to country specific 
regulatory requirements. 


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20. 
COMPLETION OF STUDY 
The end of the study will be at the time of the last patient-last visit of the follow-up period of 
the study. The IRB and IEC will be notified about the end of the study according to country-
specific regulatory requirements. 


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21. 
STUDY ADMINISTRATIVE INFORMATION 
21.1. 
Protocol Amendments 
Any amendments to the study protocol considered to be a substantial amendment will be 
communicated to the investigator by the Sponsor or its designee. All substantial protocol 
amendments will undergo the same review and approval process as the original protocol and 
may be implemented after it has been approved by the IRB/IEC and Competent Authority, 
unless immediate implementation of the change is necessary for patient safety. In this case, 
the situation must be documented and reported to the IRB/IEC and Competent Authority 
according to all relevant country-specific regulatory requirements. 
A protocol amendment is considered to be a substantial amendment if it is likely to affect the 
safety, physical, or mental integrity of patients in the study; the scientific value of the study; 
the conduct or management of the study; or the quality or safety of any investigational 
medicinal product (IMP) used in the study. 
Any other minor changes to the protocol not considered to be substantial amendments will 
not need prior approval of the IRB/EC and Competent Authority and will be communicated 
to the investigator by the Sponsor or its designee. 


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cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the 
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Marchioli R, Barzi F, Bomba E, et al, GISSI-Prevenzione Investigators. Early protection 
against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: 
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Sopravvivenza 
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Miller M, Cannon CP, Murphy SA, et al. Impact of triglyceride levels beyond low-density 
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Mita T, Watada H, Ogihara T, Nomiyama T, Ogawa O, Kinoshita J, Shimizu T, Hirose T, 
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Morris M, Sacks F, Rosner B. Does fish oil lower blood pressure? A meta-analysis of 
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23. 
INVESTIGATOR’S AGREEMENT 
This document is a confidential communication of Amarin. The authorized investigators 
agree to personally conduct or supervise the conduct of this investigational study in 
compliance with the current protocol, good clinical practices, and all applicable laws, 
regulations, and guidelines. No changes will be made to the protocol without prior 
notification to Amarin, except to protect the safety, rights, and welfare of the study patients, 
and always in compliance with all applicable laws, regulations, and guidelines. Acceptance 
of this document constitutes the agreement by the Investigator that no unpubl ished 
information contained herein or related to the study will be published or disclosed without 
prior written approval from Amarin. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly. 
 
 
 
 
_____________________________  
____________________ 
Signature 
 
 
 
 
Date 
Principal Investigator 
 
 
_____________________________ 
Printed Name 
 


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APPENDIX A: SCHEDULE OF PROCEDURES 
Study Day 
Screening 
Follow-Up (FU) 13 
Up to 42 
days 
before 
Day 0 
If a Visit 1.1 takes 
place, Visit 1 may 
occur up to 60 days 
before Day 02 
0 
120 
± 10 
360 
± 10 
720 
± 10 
1080 
± 10 
1440 
± 10 
1800 
± 10 
2160 
± 10 
Last 
Visit 
(LV)15 
Months of FU 
 
 
0 
4 
12 
24 
36 
48 
60 
72 
(varies) 
Years of FU 
 
 
0 
0.33 
1 
2 
3 
4 
5 
6 
(varies) 
Visit # 
1 
1.1 
2 
3 
4 
5 
6 
7 
8 
9 14 
LV 
Study Procedures: 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical, Surgical & 
Family History 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Evaluate inclusion / 
exclusion criteria 
X 1 
X 3 
X 
 
 
 
 
 
 
 
 
Physical Examination 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight, Height 4 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Waist Circumference 
 
 
X 
 
 
X 
 
 
 
 
X 
12-Lead ECG 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test 
6 
X 
 
X 
 
 
 
 
 
 
 
 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
Dosing 
at the Research Site 7 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Efficacy events 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
AE Evaluations 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Compliance Check 8 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
and 
hematology 9 
X 
X 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid profile 10 
X 
X 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Genetic testing 11 
 
 
X 
 
 
 
 
 
 
 
 
Biomarkers: hs-CRP, 
apo B, hsTNT 
 
 
 
X 
 
 
X 
 
 
 
 
X 


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Study Day 
Screening 
Follow-Up (FU) 13 
Up to 42 
days 
before 
Day 0 
If a Visit 1.1 takes 
place, Visit 1 may 
occur up to 60 days 
before Day 02 
0 
120 
± 10 
360 
± 10 
720 
± 10 
1080 
± 10 
1440 
± 10 
1800 
± 10 
2160 
± 10 
Last 
Visit 
(LV)15 
Months of FU 
 
 
0 
4 
12 
24 
36 
48 
60 
72 
(varies) 
Years of FU 
 
 
0 
0.33 
1 
2 
3 
4 
5 
6 
(varies) 
Visit # 
1 
1.1 
2 
3 
4 
5 
6 
7 
8 
9 14 
LV 
Fasting blood sample 
for archiving 12 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
1. Includes procedures and (fasting) blood samples (for example, hs-CRP, calculated creatinine clearance) as needed to determine the CV risk category (see 
inclusion criteria). 
2. Screening visit to re-evaluate inclusion/exclusion criteria for patients who are not eligible for participation based on data from Visit 1. 
3. Inclusion/exclusion criteria will be re-evaluated for selected study procedures that are performed on Visit 1.1 because patients failed to meet them at Visit 1. 
4. Height at first screening visit only. 
5. Vital signs, including systolic and diastolic blood pressure (mmHg), heart rate, respiratory rate and body temperature. Participants must be seated for at least 
5 minutes before assessments of vital signs. 
6. For women of childbearing potential. 
7. The patients will fast of at least 10 hours before arriving at the Research Site, when all fasting blood samples will be obtained. After blood samples are 
obtained, patients will be given drug with food. 
8. Review study drug compliance by unused capsule count, discuss with and counsel patients about compliance if needed; final study compliance at last visit. 
9. Safety Laboratories — Complete Blood Count: Includes RBC, Hgb, Hct, WBC and differential, and platelet count. Biochemistry includes total protein, 
albumin, alkaline phosphatase, ALT, AST, total bilirubin, glucose, calcium, electrolytes (sodium, potassium, chloride), blood urea nitrogen (BUN), serum 
creatinine, uric acid, creatine kinase, HbA1c. Safety labs may be repeated as deemed necessary by the Investigator. 
10. TG, TC, HDL-C, LDL-C, non-HDL-C, and VLDL-C. 
11. Fasting blood sample that will be stored for future genetic testing at the discretion of the sponsor. This sample is optional as local regulations may prohibit 
genetic samples to be collected or shipped outside the country, or patients may not consent. 
12. Used at the sponsor’s discretion to perform repeat analyses described in the protocol or to perform other tests related to cardiovascular health. 
13. Site personnel will contact each patient by telephone in-between Visit 2 and Visit 3 and between Visit 3 and Visit 4. After Visit 4 contact will be made every 
3 months. The purpose of the contact is to collect information about efficacy events, AEs, concomitant medications, confirm patient’s current address and 
contact information and remind patients about taking their study medication and logistics for the next visit. 
14. Office visits will continue at 360-day intervals and phone visits at 90-day intervals until study end date is determined. 
15. The last visit (LV) will be targeted to occur within 30 days after the study end date as determined by the DMC; the study end date is tentatively scheduled 
for Day 2160 but the actual date as determined by the DMC may be different.


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APPENDIX B: STANDARDIZED DEFINITIONS FOR REDUCE-IT 
CARDIOVASCULAR TRIAL ENDPOINT EVENTS 
NOTE:  The following definitions are based on the publications referenced below for the 
standardized definitions of endpoint events in cardiovascular trials. They have been edited to 
only include the endpoints relevant to this study. 
References:  
Karen A. Hicks, H. M. James Hung, Kenneth W. Mahaffey, Roxana Mehran, Steven E. 
Nissen, Norman L. Stockbridge, Shari L. Targum, Robert Temple; on be half of the 
Standardized Data Collection for Cardiovascular Trials Initiative.  Standardized Definitions 
for End Point Events in Cardiovascular Trials, May 31, 2011. 
Karen A. Hicks, James E Tcheng, Biykem Bozkurt, Bernard R. Chaitman, Donald E. Cutlip, 
Andrew Farb, Gregg C. Fonarow, Jeffrey P. Jacobs, Michael R. Jaff, Judith H. Lichtman, 
Marian C. Limacher, Kenneth W. Mchaffey, Roxana Mehran, Steven E. Nissen, Eric E. 
Smith, Shari L. Targum.  2014 A CC/AHA Key Data Elements and Definitions for 
Cardiovascular Endpoint Events in Clinical Trials. Circulation 2015;132:302-361 
23.1. 
Definition of Cardiovascular Death 
Cardiovascular death includes death resulting from an acute myocardial infarction, sudden 
cardiac death, death due to congestive heart failure (CHF), death due to stroke, death due to 
cardiovascular (CV) procedures, death due to CV hemorrhage, and death due to other 
cardiovascular causes. 
1. Death due to Acute Myocardial Infarction refers to a d eath by any mechanism 
(arrhythmia, CHF) within 30 days after a MI related to the immediate consequences of 
the MI, such as progressive CHF or recalcitrant arrhythmia.  
Mortal events that occur after a “break” (e.g., a CHF and arrhythmia-free period of at 
least a week) should be classified as CV or non-CV death, and if classified as a CV death, 
should be attributed to the immediate cause, even though the MI may have increased the 
risk of that event (e.g., the risk of arrhythmic death is increased for many months after an 
acute MI). 
Acute MI should be verified to the extent possible by the diagnostic criteria outlined for 
acute MI (see Definition of MI) 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 a death due to a CV procedure. 
2. Sudden Cardiac Death refers to a death that occurs unexpectedly, not within 30 days of 
an acute MI, and includes the following deaths: 


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a. Death witnessed and instantaneous without new or worsening symptoms 
b. Death witnessed within 60 m inutes of the onset of new or worsening cardiac 
symptoms, unless the symptoms suggest an 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 non-cardiac etiology 
f. Unwitnessed death without other cause of death (information regarding the 
patient’s clinical status preceding death should be provided, if available) 
General Considerations 
A subject seen alive and clinically stable 12-24 hours prior to being found dead 
without any evidence or information of a specific cause of death should be 
classified as “sudden cardiac death.” 
Deaths for which there is no information beyond “patient found dead at home” will be 
classified as “death due to other cardiovascular causes”. Please see Definition of 
Undetermined Cause of Death, for full details. 
3. Death due to Congestive Heart Failure refers to a death in association with clinically 
worsening symptoms and/or signs of heart failure (see Definition of Heart Failure Event). 
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 (see Definition of Transient 
Ischemic Attack and 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 (see Definition of Transient Ischemic Attack and 
Stroke), 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 (e.g., pulmonary embolism or peripheral arterial disease). 
23.2. 
Definition of Non-Cardiovascular Death 
Non-cardiovascular death is defined as any death that is not thought to be due to a 
cardiovascular cause. The following is a suggested list of non-cardiovascular causes of death 
for this trial. 
23.2.1. 
Non-malignant, Non-cardiovascular Death 
 Pulmonary 


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 Renal 
 Gastrointestinal 
 Hepatobiliary 
 Pancreatic 
 Infection (includes sepsis) 
 Non-infectious (e.g., systemic inflammatory response syndrome (SIRS)) 
 Hemorrhage that is neither cardiovascular bleeding nor a stroke  
 Accidental (e.g., physical accidents or drug overdoses) or trauma  
 Suicide 
 Prescription Drug Error (e.g., prescribed drug overdose, use of inappropriate drug, or 
drug-drug interaction) 
 Neurological process that is not a stroke or hemorrhage 
 Other non-CV, specify: _________________ 
23.2.2. 
Malignancy 
Malignancy should be coded as the cause of death if: 
o 
Death results directly from the cancer; or 
o 
Death results from a concurrent illness that could be a consequence of a cancer or 
o 
Death results from withdrawal of other therapies because of concerns relating to 
the poor prognosis associated with the cancer 
o 
Death results from an illness that is not a consequence of a cancer 
Cancer deaths may arise from cancers that were present prior to randomization or which 
developed subsequently. It may be helpful to distinguish these two scenarios (i.e. worsening of 
prior malignancy; new malignancy). 
 Suggested categorization includes the following organ systems; Lung/larynx, breast, 
leukemia/lymphoma, upper GI, melanoma, central nervous system, colon/rectum, 
renal, bladder, prostate, other/unspecified, or unknown. 
23.3. 
Definition of Undetermined Cause of Death 
Undetermined Cause of Death refers to a death not attributable to one of the above 
categories of cardiovascular death or to a non-cardiovascular cause. The inability to classify 
the cause of death is generally 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 this trial, when a cause of death is not readily apparent (e.g., found dead at 
home), the cause will be assumed to be cardiovascular in origin, unless one of the following 
two scenarios occur: 
1. There is no information or data available regarding the circumstances of death other 
than that a death has occurred. 


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2. The available data are conflicting regarding whether the death was cardiovascular or 
non-cardiovascular. 
23.4. 
Definition of Myocardial Infarction 
1. General Considerations 
The term myocardial infarction (MI) should be used when there is evidence of 
myocardial necrosis in a clinical setting consistent with myocardial ischemia. In 
general, the diagnosis of MI requires the combination of: 
 
Evidence of myocardial necrosis (either changes in cardiac biomarkers or 
postmortem pathological findings); and 
 
Supporting 
information 
derived 
from 
the 
clinical 
presentation, 
electrocardiographic changes, or the results of myocardial or coronary artery 
imaging 
The totality of the clinical, electrocardiographic, and cardiac biomarker information 
should be considered to determine whether or not a M I has occurred. Specifically, 
timing and trends in cardiac biomarkers and electrocardiographic information require 
careful analysis. The adjudication of MI should also take into account the clinical 
setting in which the event occurs. MI may be adjudicated for an event that has 
characteristics of a MI but which does not meet the strict definition because 
biomarker or electrocardiographic results are not available. 
2. Criteria for Myocardial Infarction 
a. Clinical Presentation 
The clinical presentation should be consistent with diagnosis of myocardial 
ischemia and infarction. Other findings that might support the diagnosis of MI 
should be take into account because a number of conditions are associated 
with elevations in cardiac biomarkers (e.g., trauma, surgery, pacing, ablation, 
congestive heart failure, hypertrophic cardiomyopathy, pulmonary embolism, 
severe pulmonary hypertension, stroke or subarachnoid hemorrhage, 
infiltrative and inflammatory disorders of cardiac muscle, drug toxicity, burns, 
critical illness, extreme exertion, and chronic kidney disease). Supporting 
information can also be considered from myocardial imaging and coronary 
imaging. The totality of the data may help differentiate acute MI from the 
background disease process. 
b. Biomarker Elevation 
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 f or 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 


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performing the assay are preferred over the manufacturer’s listed reference 
limits in an assay’s instructions for use. CK-MB and troponin are preferred, 
but CK may be used in the absence of CK-MB and troponin. 
For MI subtypes, different biomarker elevations for CK, CK-MB, or troponin 
will be required. The specific criteria will be referenced to the URL. 
In this study, patients may present acutely to hospitals which are not 
participating sites, it is not practical to stipulate the use of a single biomarker 
or assay, and the locally available results are to be used as the basis for 
adjudication.  
Since the prognostic significance of different types of myocardial infarctions 
(e.g., periprocedural myocardial infarction versus spontaneous myocardial 
infarction) may be different, considerations evaluating outcomes for these 
subsets of patients separately will be made. 
c. ECG Changes 
ECG changes can be used to support or confirm a MI. Supporting evidence 
may be ischemic changes and confirmatory information may be new Q waves. 
 Criteria for acute myocardial ischemia (in absence of left 
ventricular hypertrophy (LVH) and left bundle branch block 
(LBBB)): 
o ST elevation 
New ST elevation at the J point in two anatomically contiguous 
leads with the cut-off points: ≥ 0.2 mV in men (> 0.25 mV in 
men < 40 years) or ≥ 0.15 mV in women in leads V2-V3 and/or 
≥ 0.1 mV in other leads. 
o 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.  
The above ECG criteria illustrate patterns consistent with myocardial 
ischemia. In patients with abnormal biomarkers, it is recognized that lesser 
ECG abnormalities may represent an ischemic response and may be accepted 
under the category of abnormal ECG findings. 
 Criteria for pathological Q-wave 
o Any Q-wave in leads V2-V3 ≥ 0.02 seconds or QS complex in 
leads V2 and V3 
o Q-wave ≥ 0.03 seconds and ≥ 0.1 mV deep or QS complex in 
leads I, II, aVL, aVF, or V4-V6 in any two leads of a 
contiguous lead grouping (I, aVL, V6; V4-V6; II, III, and aVF) 
o R-wave 0.04 s in V1–V2 and R/S ratio >1 with a concordant 
positive T-wave in the absence of a conduction defect 
The same criteria are used for supplemental leads V7-V9, and for the Cabrera 
frontal plane lead grouping. 


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 Criteria for Prior Myocardial Infarction 
o Pathological Q-waves, as defined above 
o R-wave ≥ 0.04 seconds in V1-V2 and R/S ≥ 1 with a 
concordant positive T-wave in the absence of a conduction 
defect 
3. Myocardial Infarction Subtypes 
Several MI subtypes are commonly reported in clinical investigations and each is 
defined below: 
a. Spontaneous MI 
i. Detection of rise and/or fall of cardiac biomarkers with at least one 
value above the URL with at least one of the following: 
 Clinical presentation consistent with ischemia 
 ECG evidence of acute myocardial ischemia 
 New pathological Q waves 
 Imaging evidence of new loss of viable myocardium or new regional 
wall motion abnormality 
 Autopsy evidence of acute MI 
ii. If biomarkers are elevated from a prior infarction, then a spontaneous 
myocardial infarction is defined as: 
1. One of the following: 
 Clinical presentation consistent with ischemia 
 ECG evidence of acute myocardial ischemia 
 New pathological Q waves 
 Imaging evidence of new loss of viable myocardium or 
new regional wall motion abnormality 
 Autopsy evidence of acute MI 
AND 
2. Both of the following: 
 Evidence that cardiac biomarker values were decreasing 
(e.g., two samples 3-6 hours apart) prior to the 
suspected MI* 
 ≥ 20% increase (and > URL) in troponin or CK-MB 
between a measurement made at the time of the initial 
presentation and a further sample taken 3-6 hours later 
*If biomarkers are increasing or peak is not reached, 
then a definite diagnosis of recurrent MI is generally 
not possible. 
b. Percutaneous Coronary Intervention-Related Myocardial Infarction 
Peri-PCI MI is defined by any of the following criteria. MI associated with 
and occurring within 48 hours of PCI, with elevation of cardiac biomarker 


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values to > 5 x 99th percentile of the URL in patients with normal baseline 
values (≤99th percentile URL), or a rise of [cardiac biomarker] values ≥20% if 
baseline values are elevated and are stable or falling.  This classification also 
requires at least 1 of the following: 
a) Symptoms suggestive of myocardial ischemia (i.e., prolonged 
ischemia ≥ 20 min) 
b) New ischemic changes on ECG or new LBBB 
c) Angiographic loss of patency of a m ajor coronary artery or a s ide 
branch or persistent slow flow or no flow or embolization 
d) Imaging evidence of new loss of viable myocardium or new regional 
wall motion abnormality. 
c. Coronary Artery Bypass Grafting-Related Myocardial Infarction 
Peri-coronary artery bypass graft surgery (CABG) MI is defined by the 
following criteria. Symptoms of cardiac ischemia are not required. 
i. Biomarker elevations within 48 hours of CABG: 
 Troponin or CK-MB (preferred) > 10 x 99th percentile of the 
URL and 
 No evidence that cardiac biomarkers were elevated prior to the 
procedure; 
OR 
 Both of the following must be true: 
o ≥ 50%2 increase in the cardiac biomarker result 
o Evidence that cardiac biomarker values were decreasing 
(e.g., two samples 3-6 hours apart) prior to the 
suspected MI. 
AND 
ii. One of the following: 
 New pathological Q-waves persistent through 30 days 
 New persistent non-rate-related LBBB 
 Angiographically documented new graft or native coronary 
artery occlusion Other complication in the operating room 
resulting in loss of myocardium 
 Imaging evidence of new loss of viable myocardium 
Data should be collected in such a way that analyses using ≥ 20% or ≥ 50% could both be 
performed. 
OR 
iii. Autopsy evidence of acute MI 
d. Silent Myocardial Infarction 
Silent MI is defined by the following: 
i. No evidence of acute myocardial infarction 
AND 


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ii. Any one of the following criteria: 
 New pathological Q-waves. A confirmatory 
ECG is 
recommended if there have been no clinical symptoms or 
history of myocardial infarction. 
 Imaging evidence of a region of loss of viable myocardium that 
is thinned and fails to contract, in the absence of a n on-
ischemic cause 
 Autopsy evidence of a healed or healing MI 
(NOTE: In the case of evanescent Q waves, the last ECG will determine whether a 
silent infarction has occurred.) 
23.5. 
Sub-classification of Myocardial Infarction 
1. By the Universal MI Definition: 
a. Clinical Classification of Different Types of Myocardial Infarction 
 Type 1 
Spontaneous myocardial infarction related to ischemia due to a 
primary coronary event such as plaque erosion and/or rupture, 
fissuring, or dissection 
 Type 2 
Myocardial infarction secondary to ischemia due to either increased 
oxygen demand or decreased supply, e.g., coronary artery spasm, 
coronary 
embolism, 
anemia, 
arrhythmias, 
hypertension, 
or 
hypotension 
 Type 3 
Sudden unexpected cardiac death, including cardiac arrest, often with 
symptoms suggestive of myocardial ischemia, accompanied by 
presumably new ST elevation, or new LBBB, or evidence of fresh 
thrombus in a coronary artery by angiography and/or at autopsy, but 
death occurring before blood samples could be obtained, or at a time 
before the appearance of cardiac biomarkers in the blood 
 Type 4a 
Myocardial infarction associated with PCI 
 Type 4b 
Myocardial infarction associated with stent thrombosis as documented 
by angiography or at autopsy 
 Type 4c 
Myocardial infarction associated with stent restenosis as detected by 
angiography or at autopsy 
 
 Type 5 
Myocardial infarction associated with CABG 


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b. Sample Clinical Trial Tabulation of Randomized Patients by Types of 
Myocardial Infarction 
 
2. By Electrocardiographic Features: 
 ST-Elevation MI (STEMI) 
o Additional subcategories may include: 
 Q-wave 
 Non-Q-wave 
 Unknown (no ECG or ECG not interpretable) 
 Non-ST-Elevation MI (NSTEMI) 
o Additional subcategories may include: 
 Q-wave 
 Non-Q-wave 
 Unknown (no ECG or ECG not interpretable) 
 Unknown (no ECG or ECG not interpretable) 
*All events adjudicated as MI will be classified as STEMI, NSTEMI, 
or Unknown; however, it is acknowledged that a significant proportion 
of periprocedural (PCI or CABG) events may have missing, 
inadequate or uninterpretable ECG documentation. 
3. By Biomarker Elevation (per Universal MI Definition1): 
The magnitude of cardiac biomarker elevation can be calculated as a ratio of the peak 
biomarker value divided by the 99th percentile URL.  
The biomarker elevation can be provided for various MI subtypes, as shown in the 
example below. 
Multiples X 
99% 
MI Type 1 
(Spontaneous) 
MI Type 2 
(Secondary) 
MI Type 3* 
(Sudden death) 
MI Type 4** 
(PCI) 
MI Type 5** 
(CABG) 
Total 
Number 
1-2 X 
 
 
 
 
 
 
2-3 X 
 
 
 
 
 
 
3-5 X 
 
 
 
 
 
 
5-10 X 
 
 
 
 
 
 
>10 X 
 
 
 
 
 
 
Total Number 
 
 
 
 
 
 
 


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*Biomarkers are not available for this type of myocardial infarction since the patients 
expired before biomarker determination could be performed. 
**For the sake of completeness, the total distribution of biomarker values should be 
reported. The hatched areas represent biomarker elevations below the decision limit 
used for these types of myocardial infarction. 
 
23.6. 
Definition of Hospitalization for Unstable Angina 
Unstable angina requiring hospitalization is defined as: 
1. Ischemic discomfort (angina, or symptoms thought to be equivalent) ≥ 10 minutes in 
duration occurring 
 at rest, or 
 in an accelerating 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 2 4* hour stay (or a date change if the time of 
admission/discharge is not available). 
AND 
3. At least one of the following: 
a. New or worsening ST or T wave changes on resting ECG (in the absence of 
confounders, such as LBBB or LVH) 
 Transient ST elevation (duration <20 minutes) 
New ST elevation at the J point in two anatomically contiguous leads with 
the cut-off points: ≥0.2 mV in men (>0.25 mV in men <40 years) or ≥0.15 
mV in women in leads V2-V3 and/or ≥0.1 mV in other leads 
 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. 
b. Definite evidence of inducible myocardial ischemia as demonstrated by:  
 An early positive exercise stress test, defined as ST elevation or ≥2 mm 
ST depression prior to 5 mets  
OR 
 Stress echocardiography (reversible wall motion abnormality) OR 
 Myocardial scintigraphy (reversible perfusion defect), OR 
 MRI (myocardial perfusion deficit under pharmacologic stress). 
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. 


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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 intravenous nitrates or 
increasing dosages of β-blockers, should be considered supportive 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, would be insufficient alone to support classification as hospitalization for 
unstable angina. 
2. If subjects are admitted with suspected unstable angina, and subsequent testing 
reveals a noncardiac 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 re-hospitalization 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. 
 Re-hospitalization 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 endpoint. 
 
23.7. 
Definition of Transient Ischemic Attack and Stroke 
Transient Ischemic Attack 
Transient ischemic attack (TIA) is defined as a transient episode (< 24 hours) of neurological 
dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. 
Stroke 
Stroke is defined as an acute episode of neurological dysfunction caused by focal or global 
brain, spinal cord, or retinal vascular injury.  
Classification: 
1. Ischemic Stroke 


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Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal 
dysfunction caused by an 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. 
2. Hemorrhagic Stroke 
Hemorrhagic stroke is defined as an acute episode of focal or global cerebral or spinal 
dysfunction caused by a nontraumatic intraparenchymal, intraventricular, or 
subarachnoid hemorrhage.  
NOTE: Microhemorrhages seen on T2-weighted MRI imaging, subdural and epidural 
hemorrhages are not considered hemorrhagic strokes. 
3. Undetermined Stroke 
Undetermined stroke is defined as an acute episode of focal or global neurological 
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 ischemic or hemorrhagic. 
Stroke Disability 
Stroke disability should be measured by a reliable and valid scale in all cases, typically at 
each visit and 90 days after the event. For example, the modified Rankin Scale may be used 
to address this requirement: 
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 perform all previous activities but able to look after own affairs 
without assistance. 
3 
Moderate disability; requiring some help but able to walk without assistance. 
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 
Additional Considerations 
Evidence of vascular central nervous system injury without recognized neurological 
dysfunction may be observed. Examples include micro-hemorrhage, silent infarction, and 
silent hemorrhage.  
Subdural hematomas are intracranial hemorrhagic events and not strokes. 
The distinction between a Transient Ischemic Attack and an Ischemic Stroke is the presence 
of Infarction. Persistence of symptoms is an acceptable indicator of acute infarction. 


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23.8. 
Definition of Heart Failure Event 
A Heart Failure Event may consist of a hospitalization (a required component of this end 
point and defined below), as well as urgent outpatient visits. 
A Heart Failure Hospitalization is defined as an event that meets ALL 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 (must 
be specified and described by the protocol) 
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 heart 
failure (such as BNP > 500 pg/mL or NT-proBNP > 2,000 pg/mL). In 
patients with chronically elevated natriuretic peptides, a s ignificant 
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’ > 


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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 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. Significant 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) 
New Heart Failure/Heart Failure Not Requiring Hospitalization: 
An Urgent Heart Failure Visit is defined as an event that meets all of the following:  
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 must be met as defined in A Heart 
Failure Hospitalization above. 
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. 
23.9. 
Interventional Cardiology Definitions 
A.  Clinical Definitions 
1. Clinically-Driven Target Lesion Revascularization: Revascularization is clinically-
driven if the target lesion diameter stenosis is > 50% by quantitative coronary 
angiography (QCA) and the subject has clinical or functional ischemia which cannot 
be explained by another native coronary or bypass graft lesion. Clinical or functional 
ischemia includes any of the following: 
a. A history of angina pectoris, presumably related to the target vessel 
b. Objective signs of ischemia at rest (electrocardiographic changes) or during 
exercise test (or equivalent), presumably related to the target vessel 
c. Abnormal results of any invasive functional diagnostic test (e.g., coronary flow 
reserve [CFR] or fractional flow reserve [FFR]) 


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Comment: Target lesion revascularization of a > 70% diameter stenosis by QCA in 
the absence of the above signs or symptoms may be considered clinically-driven. 
Comment: In the absence of QCA data or if a ≤ 50% stenosis is present, TLR may be 
considered clinically-driven by the Clinical Endpoint Committee (CEC) if severe 
ischemic signs and symptoms attributed to the target lesion are present. 
2. Non-Target Lesion and Non-Target Lesion Revascularization: A lesion for which 
revascularization is not attempted or one in which revascularization is performed 
using a non-study device, respectively. 
3. Non-Target Vessel and Non-Target Vessel Revascularization: A vessel for which 
revascularization is not attempted or one in which revascularization is performed 
using a non-study device, respectively. 
4. Percutaneous Coronary Intervention (PCI) Status: 
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 should be performed on an inpatient basis and prior to 
discharge because of significant concerns that there is risk of myocardial 
ischemia, MI, and/or death. Patients who are outpatients or in the emergency 
department at the time that the cardiac catheterization is requested would warrant 
hospital admission based on their clinical presentation. 
c. Emergency:  The procedure should be performed as soon as possible because of 
substantial concerns that ongoing myocardial ischemia and/or MI could lead to 
death. "As soon as possible" refers to a patient who is of sufficient acuity that one 
would cancel a scheduled case to perform this procedure immediately in the next 
available room during business hours, or one would activate the on-call team were 
this to occur during off-hours. 
d. Salvage: The procedure is a last resort. The patient is in cardiogenic shock when 
the PCI begins (i.e., the time at which the first guide wire or intracoronary device 
is introduced into a coronary artery or bypass graft for the purpose of mechanical 
revascularization) OR within the last ten minutes prior to the start of the case or 
during the diagnostic portion of the case, the patient has also received chest 
compressions or has been on unanticipated circulatory support (e.g., intra-aortic 
balloon pump, extracorporeal mechanical oxygenation, or cardiopulmonary 
support). 
5. Percutaneous Coronary Intervention (PCI): Placement of an angioplasty guide 
wire, 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 


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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. 
23.10. 
Definition of Peripheral Vascular Intervention 
1. Peripheral Vascular Intervention (PVI): Peripheral vascular intervention is a 
catheter-based or open surgical procedure designed to improve peripheral arterial or 
venous blood flow or otherwise modify or revise vascular conduits. Procedures may 
include, but are not limited to, balloon angioplasty, stent placement, thrombectomy, 
embolectomy, atherectomy, dissection repair, aneurysm exclusion, treatment of 
dialysis conduits, placement of various devices, intravascular thrombolysis or other 
pharmacotherapies, and open surgical bypass or revision.  
In general, the intention to perform percutaneous peripheral vascular intervention is 
denoted by the insertion of a guide wire into a peripheral artery or vein. 
The target vessel(s) and the type of revascularization procedure (e.g., surgical bypass, 
thrombectomy, endarterectomy, percutaneous angioplasty, stent placement, 
thromboembolectomy, and thrombolysis) should be specified and recorded. For the 
sake of simplicity, this definition applies to the extracranial carotid artery and other 
non-cardiac arteries and veins and excludes the intracranial vessels and lymphatics. 
2. Procedural Status: Non-Elective and Elective:  
a. Non-Elective: Non-elective procedures include emergent and urgent procedures. A 
non-elective procedure is a procedure that is performed without delay, because 
there is clinical consensus that the procedure should occur imminently. Non-
elective procedures imply a degree of instability of the patient, urgency of the 
medical condition, or instability of the threatening lesion.  
 Emergent: A procedure that is performed immediately because of the acute 
nature of the medical condition (e.g., acute limb ischemia, acute aortic 
dissection), and the increased morbidity or mortality associated with a 
temporal delay in treatment. 
 Urgent: An urgent procedure is one that is not emergent but required to be 
performed on a timely basis (≤ 24 hrs) (e.g., a patient who has been stabilized 
following initial treatment of acute limb ischemia, and there is clinical 
consensus that a definitive procedure should occur within the next 24 hours). 
b. Elective: An elective procedure is one that is scheduled and is performed on a 
patient with stable disease, or in whom there is no urgency and/or increased 
morbidity or mortality associated with a planned procedure. 
23.11. 
Definition of Any Revascularization Procedure  
Any revascularization includes any arterial vascular intervention done to treat ischemia or 
prevent major ischemic events, including percutaneous or surgical intervention of the 
coronary, peripheral, or carotid arteries. Aneurysm repairs, dissection repairs, arterial-venous 
fistula or graft placement or repairs, or renal arterial intervention for hypertension or renal 
dysfunction are not included.  


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Protocol AMR-01-01-0019 
 
Confidential and Proprietary 
Amendment #2: 8 July 2016 
Page 128 of 132 
23.12. 
Definition of Cardiac Arrhythmia Requiring Hospitalization  
An arrhythmia that either results in hospitalization (≥24 hours) during or within 24 hours of 
the termination of the last episode for treatment or requires continued hospitalization for 
treatment, including any one of the following: 
1. Atrial arrhythmia – atrial fibrillation, atrial flutter, supraventricular tachycardia that 
requires cardio-version, drug therapy, or is sustained for greater than 1 minute) 
2. Ventricular arrhythmia - 
Ventricular tachycardia or ventricular fibrillation requiring 
cardio-version and/or intravenous antiarrhythmics 
3. Bradyarrhythmia - High-level AV block (defined as third-degree AV block or second-
degree AV block), junctional or ventricular escape rhythm, or severe sinus bradycardia 
(typically with heart rate < 30 bpm). The bradycardia must require temporary or permanent 
pacing. 
23.13. 
Definition of Cardiac Arrest (Sudden Cardiac Death)  
A sudden, unexpected death due to the cessation of cardiac mechanical activity, confirmed 
by the absence of a detectable pulse, unresponsiveness, and apnea (or agonal, gasping 
respirations) of presumed cardiac etiology. An arrest is presumed to be cardiac (i.e., related 
to heart disease) if this is likely, based on t he available information, including hospital 
records and autopsy data. The cardiac arrest will be further sub-classified into either: 
a) witnessed, occurring within 60 min from the onset of new symptoms, in the absence of a 
clear cause other than cardiovascular; or  
b) unwitnessed, within 24 hours of being observed alive, in the absence of pre-existing other 
non-cardiovascular causes of death;  
Note: Non-cardiac causes of cardiac arrest, such as drug overdose, suicide, drowning, 
hypoxia, exsanguination, cerebrovascular accident, subarachnoid hemorrhage, or trauma 
must not be present. 
23.14. 
Definition of Resuscitated Cardiac Arrest2 
Resuscitated Cardiac Arrest is present when there is restoration of both: 
1. Organized electrical activity, and 
2. Organized mechanical activity resulting in restoration of spontaneous circulation (defined 
as the documented presence of a measurable pulse and blood pressure at any time after 
initiation of resuscitative efforts). 
References: 
1. Thygesen K., Alpert J., Jaffe A., et al. Third Universal Definition of Myocardial 
Infarction. J Am Coll Cardiol. 2012;60(16):1581-1598. 
2. Becker LB, Aufderheide TP, Geocadin RG, Callaway CW, Lazar RM, Donnino MW, 
Nadkarni VM, Abella BS, Adrie C, Berg RA, Merchant RM, O’Connor RE, Meltzer DO, 
Holm MB, Longstreth WT, Halperin HR.  AHA Consensus Statement: Primary Outcomes 
for Resuscitation Science Sturdies: A Consensus Statement From the American Heart 


Amarin Pharma Inc. 
Protocol AMR-01-01-0019 
 
Confidential and Proprietary 
Amendment #2: 8 July 2016 
Page 129 of 132 
Association. Circulation 2011; CIR. 0b013e3182340239 published online before print 
October 3 2011, doi:10.1161/CIR.0b013e3182340239 
 


Amarin Pharma Inc. 
Protocol AMR-01-01-0019 
 
Confidential and Proprietary 
Amendment #2: 8 July 2016 
Page 130 of 132 
APPENDIX C: 
CRITERIA FOR THE DIAGNOSIS OF DIABETES 
Reference: 
American Diabetes Association. Classification and diagnosis of diabetes mellitus. Sec. 2. In 
Standards of Medical Care in Diabetes - 2015. Diabetes Care 2015; 38 (Suppl. 1):S8-S16. 
1. HbA1c ≥6.5%. The test should be performed in a laboratory using a method that is National 
Glycohemoglobin Standardization Program (NGSP) certified and standardized to the 
Diabetes Control and Complications Trial (DCCT) assay.* 
OR 
2. Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric 
intake for at least 8 hr.* 
OR  
3. 2-hr plasma glucose ≥200 mg/dL (11.1 mmol/L) during an Oral Glucose Tolerance Test 
(OGTT). The test should be performed as described by the World Health Organization, 
using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in 
water.* 
OR  
4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random 
plasma glucose ≥200 mg/dL (11.1 mmol/L). 
* In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by repeat 
testing. 


Amarin Pharma Inc. 
Protocol AMR-01-01-0019 
 
Confidential and Proprietary 
Amendment #2: 8 July 2016 
Page 131 of 132 
APPENDIX D: 
CRITERIA FOR THE DIAGNOSIS OF METABOLIC 
SYNDROME 
The diagnosis of metabolic syndrome requires the presence of three out of the following five 
specific components using the following criteria (Alberti 2009) with cut points of parameters 
as defined in Table 1 of Alberti et. al.  and listed below, and waist circumference cut points 
further guided by the Table 6 below: 
 A waist circumference ≥35 inches (88 cm) for all women, and Asian, Hispanic, or 
Latino men, and waist circumference ≥40 inches (102 cm) for all other men; 
 Elevated TG (TG ≥150 mg/dL); 
 Reduced HDL-C (HDL-C <40 mg/dL if male; HDL-C <50 mg/dL if female); 
 Elevated blood pressure (systolic ≥130 mmHg and/or diastolic ≥85 mmHg, OR an 
antihypertensive therapy with medical history of hypertension; 
 Elevated fasting glucose (fasting glucose ≥100 mg/dL, OR on drug therapy for 
elevated glucose. 
 
 


Amarin Pharma Inc. 
Protocol AMR-01-01-0019 
 
Confidential and Proprietary 
Amendment #2: 8 July 2016 
Page 132 of 132 
Table 6.  Current Recommended Waist Circumference Thresholds for Abdominal 
Obesity by Organization and Population (Alberti et. al. Table 2) 
Organization 
Population 
(Reference) 
Waist Circumference Threshold 
Men 
(cm) 
Women 
(cm) 
IDF (4) 
Europid 
≥94 
≥80 
WHO (7) 
Caucasian 
≥94 
(increased risk) 
≥80 
≥102 
(still higher risk) 
≥88 
AHA/NHLBI (ATP III)* (5) 
US 
≥102 
≥88 
Health Canada (8,9) 
Canada 
≥102 
≥88 
European Cardiovascular 
Societies (10) 
European 
≥102 
≥88 
IDF (4) 
Asian 
(including Japanese) 
≥90 
≥80 
WHO (11) 
Asian 
≥90 
≥80 
Japanese Obesity Society 
Japanese 
≥85 
≥90 
Cooperative Task Force (13) 
China 
≥85 
≥80 
IDF (4) 
Middle East, 
Mediterranean 
≥94 
≥80 
IDF (4) 
Sub-Saharan 
African 
≥94 
≥80 
IDF (4) 
Ethnic Central & 
South American 
≥90 
≥80 
IDF=International Diabetes Federation; WHO=World Health Organization; AHA/NHLBI (ATP III)=American Heart 
Association/National 
Heart, 
Lung, 
and 
Blood 
Institute 
Adult 
Treatment 
Panel 
III; 
*Recent AHA/NHLBI guidelines for metabolic syndrome recognize an increased risk for cardiovascular disease and 
diabetes at waist-circumference thresholds of ≥94 cm in men and ≥80 cm in women and identify these as optional cut 
points for individuals or populations with increased insulin resistance. 
 


Amarin Pharma Inc. 
Explanation of Changes- AMR-01-01-0019 Amendment 1 
Confidential 
 
16 May 2013 
Page 1 of 4 
EXPLANATION OF CHANGES DOCUMENT 
STUDY NUMBER: AMR-01-01-0019 
AMENDMENT NUMBER 1 
PROTOCOL TITLE: A Multi-Center, Prospective, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Evaluate the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients with Cardiovascular Disease 
or at High Risk for cardiovascular Disease: REDUCE-IT (Reduction of Cardiovascular Events with EPA – Intervention Trial) 
AMENDMENT 1 DATE: 16 May 2013 
REASON FOR CHANGES:  
This protocol amendment includes changes based on feedback and comments from regi onal regulatory agencies (including US FDA-
approved labeling), ethics committees, investigators, and the RE DUCE-IT Steering Committee. Major protocol changes are included 
in the summary of changes.  Editorial ch anges, clarifications, and corrections were  also made throughout the protocol, but have  not 
been included in this summary.  
Protocol Location 
Summary of Change 
Reason for Change 
 
Throughout Protocol 
 
Synopsis Objectives 
 
Inclusion Criteria #1 and #2 
Laboratory data changes or additions: 
 
Fasting TG level >200 mg/dL 
(2.26 mmol/L) and <500 mg/dL 
(5.64 mmol/L) 
 
Deletion of the lower end 
fasting TG level requirement. 
Increase in the required fasting TG level at 
screening to increase the overall proportion 
of patients enrolled with TG at or above the 
200 mg/dL level. 
 
Added SI Units for all laboratory values. 
 
The lower end fasting TG level information is 
no longer relevant. 
 
Secondary Objectives and Endpoints 
Clarified secondary efficacy statements 
regarding unstable angina by adding 
“determined to be caused by myocardial 
Further clarify objective and endpoints. 


Amarin Pharma Inc. 
Explanation of Changes- AMR-01-01-0019 Amendment 1 
Confidential 
 
16 May 2013 
Page 2 of 4 
Protocol Location 
Summary of Change 
Reason for Change 
ischemia by invasive/non‐invasive 
testing and requiring emergent 
hospitalization”. 
 
Inclusion Criterion #3, CV Risk Category 1 
Deletion of “one or more” and addition 
of “>50%” and “at least” two major 
epicardial coronary arteries. 
Further clarify and define inclusion criteria. 
 
Inclusion Criterion #6 
“Effective” was deleted and 
“acceptable” was added to define the 
method of birth control. 
Last sentence was deleted “Effective 
methods of avoiding pregnancy 
are….etc”. 
Required change as per Canada regulators. 
 
Inclusion Criterion #8 
 
Section 7.2.2. Patient Restrictions 
The wording changed to “Agree to 
follow a physician recommended diet 
and to maintain it through the duration 
of the study.” 
Required change as per Canada regulators. 
 
Exclusion Criterion #10 
Updated to read: “Known 
hypersensitivity to any ingredients of 
the study product or placebo. Known 
hypersensitivity to fish and or shell fish.” 
Canada and the Netherlands required the 
exclusion of patients with allergies to the 
study product, placebo or seafood.  This will 
be adopted across the entire study.  
Modification to better conform with FDA‐
approved label. 
 
Exclusion Criterion #12 
Added “malabsorption syndrome 
and/or chronic diarrhea (Note: patients 
who have undergone gastric/intestinal 
bypass surgery are considered to have 
malabsorption, hence are excluded; 
patients who have undergone gastric 
banding are allowed to enter the trial).” 
Added clarity for investigators. 
 
Exclusion Criterion #13 
 
Additional details of a wash‐out were 
added for patients taking niacin or 
fibrates. 
Added clarity for investigators. 
 
 


Amarin Pharma Inc. 
Explanation of Changes- AMR-01-01-0019 Amendment 1 
Confidential 
 
16 May 2013 
Page 3 of 4 
Protocol Location 
Summary of Change 
Reason for Change 
Added Netherlands specific exclusion 
for patients currently taking >300 
mg/day of EPA/DHA. 
Required change as per The Netherlands 
regulators. 
 
Exclusion Criterion #17 
Creatine kinase exclusion changed to >5 
x ULN (from >10 x ULN previously). 
Required change as per Canada regulators 
and adopted for all countries. 
 
Sample Size Determination Synopsis  
 
Section 12.3. Sample Size Determination 
Updated with additional text. 
Added to clearly define conditions under 
which the addition of patients would require 
a protocol amendment. 
 
Section 1.3. Study AMR‐01‐01‐0017 
(ANCHOR Study) 
Included the ANCHOR study results and 
data table.  
Updated with ANCHOR study results; at the 
time the original REDUCE‐IT protocol was 
written, ANCHOR clinical study report was 
not available.  
 
Section 1.4. Clinical Safety 
Updated the most commonly reported 
adverse events in hypertriglyceridemia 
studies completed by Amarin. 
Update with current expected adverse 
events; at the time the original REDUCE‐IT 
protocol was written, the expected events 
were taken from a combination of past 
Amarin CNS population studies and 
hypertriglyceride population studies. As all 
the hypertriglyceridemia population data are 
available, new expected events have been 
added, consistent with FDA‐approved label. 
 
Section 6.1.1.2. Screening Visit (Visit 1.1) 
Extended length of the screening Visit 1 
to randomization, from 42 days to 60, 
for patients that have had a Visit 1.1. 
Increased to include time to send and receive 
laboratory sample results and to then 
schedule next visits for patients with multiple 
screening visits. 
 
Section 6.2. Telephone Follow‐up Contact 
Additional phone contact with patients 
at Day 270 +/‐ 5 days. 
Ensure patients are contacted at least every 3 
months throughout study. 
 
Section 6.3.1.3. Genetic Testing 
Additional information added on 
anonymity of genetic testing and the 
ability for patients to decline testing 
prior to sample analysis. 
Added for clarity. 
 
Section 6.3.1.6. Blinding of Laboratory 
Added the allowance for the central 
Added for enhanced patient safety. 


Amarin Pharma Inc. 
Explanation of Changes- AMR-01-01-0019 Amendment 1 
Confidential 
 
16 May 2013 
Page 4 of 4 
Protocol Location 
Summary of Change 
Reason for Change 
Results 
laboratory to notify sites of all hsTnT 
results. 
 
Section 6.3.1.7. Flagging of Critical Lab 
Values 
 
Section 11.1. Reasons for Early Study Drug 
Discontinuation 
 
Added an additional flag from the 
central laboratory to site of TG values 
>2000 mg/dL (22.58 mmol/L) during the 
blinded phase of the study.  
Added for enhanced patient safety. 
 
Section 10.2.1. Serious Adverse Events 
Further definition added around 
endpoint event reporting and site 
responsibility to inquire with their 
institution/IRB about their specific 
reporting requirements for these 
events. 
Added for clarity. 
 
Section 12.2.4.4. Tertiary Endpoints 
Added “All tertiary analyses will be 
conducted for the ITT population. No 
multiple testing adjustments will be 
made.” 
Further define tertiary endpoints. 
 
Section 12.2.4.5. Exploratory Subgroup 
Analyses 
Updated subgroup analyses detail for 
primary and key secondary endpoints. 
Further define planned exploratory subgroup 
analyses. 
 
Section 18 Publication Policy 
Paragraph was updated to conform to 
Steering Committee publication policies. 
Updated based on Steering Committee 
feedback. 
 
APPENDIX B: Standardized definitions for 
endpoint events in cardiovascular trials.  
The appendix was replaced with a 
section from the CEC charter. 
Updated to reflect the Clinical Event 
Committee Charter (updated FDA guidelines). 
 


Amarin Pharma Inc. 
AMR-01-01-0019 Amendment 2 
Confidential 
Explanation of Changes 
 
8 July 2016 
Page 1 of 9 
EXPLANATION OF CHANGES DOCUMENT 
STUDY NUMBER: AMR-01-01-0019 
AMENDMENT NUMBER 2 
PROTOCOL TITLE: A Multi-Center, Prospective, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group Study to Evaluate the Effect of AMR101 on Cardiovascular Health 
and Mortality in Hypertriglyceridemic Patients with Cardiovascular Disease or at High Risk for 
Cardiovascular Disease: REDUCE-IT (Reduction of Cardiovascular Events with EPA – 
Intervention Trial) 
PROTOCOL AMENDMENT 2 FINAL; DATE: 8 July 2016 
REASON FOR CHANGES:  
This protocol amendment includes changes to update the content with newly available scientific 
background information and feedback and comments from the United States Food and Drug 
Administration (FDA), ethics committees, investigators, and the REDUCE-IT Steering 
Committee. Major protocol changes are included in the summary of changes table below.  
Editorial changes, clarifications, and corrections were also made throughout the protocol, but 
have not been included in this summary.  
Protocol Location 
Summary of Change 
Reason for Change 
 
Section 1 (Introduction 
and Background 
Information) 
Updated the regulatory status of AMR101 
in the US. 
Provided updated 
background information 
 
Section 1.2 (Summary of 
Completed Amarin-
Sponsored Clinical 
Studies of AMR101 in 
Patients with 
Hypertriglyceridemia) 
Removed summary of previous Amarin-
sponsored studies in patients with central 
nervous system disorders; added a 
summary of the MARINE study. 
Provided updated and 
relevant information 
related to clinical 
development 
 
Section 1.4 (Rationale) 
Updated medical need with statistics from 
2016 AHA publications. 
Updated the results from recent genetic 
studies and recently completed relevant 
cardiovascular outcomes studies.   
Provided updated 
background information 


Amarin Pharma Inc. 
AMR-01-01-0019 Amendment 2 
Confidential 
Explanation of Changes 
 
8 July 2016 
Page 2 of 9 
Protocol Location 
Summary of Change 
Reason for Change 
 
Section 2 (Study 
Objectives),  
 
Section 9.2.1 (Primary 
Endpoint) and  
 
Synopsis 
The following wording “to evaluate the 
effect of 4 g/day AMR101 for preventing 
the occurrence of a first major 
cardiovascular event of the composite 
endpoint that includes:”, was rewritten as 
follows: “to evaluate the effect of 4 g/day 
AMR101 on the time from randomization 
to first occurrence of any component of 
the composite of the following major 
cardiovascular (CV) events:”. 
Included silent MI under nonfatal 
myocardial infarction (MI). 
Clarification 
 
Section 2 (Study 
Objectives),  
 
Section 9.2.2 (Secondary 
Endpoints) and  
 
Synopsis 
Per FDA comments, the composite of 
hard major adverse coronary event 
(MACE) endpoints (CV death, non-fatal 
MI, non-fatal stroke) was designated as 
the “key secondary endpoint” and 
secondary endpoints were streamlined 
and re-ordered to further elucidate primary 
and key secondary findings.   
 
Again in concert with FDA comments, 
several former secondary endpoints were 
moved to tertiary endpoints with 
definitions of such tertiary endpoints 
around metabolic syndrome and new-
onset hypertension provided. 
 
The “other” secondary objectives were 
designated and re-ordered as follows:  
 
Composite of CV death or 
nonfatal MI (including silent MI); 
 
Fatal or nonfatal MI (including 
silent MI); 
 
Non-elective coronary 
revascularization represented as 
the composite of emergent or 
urgent classifications; 
 
CV death; 
 
Unstable angina determined to be 
caused by myocardial ischemia by 
invasive/non-invasive testing and 
requiring emergent 
hospitalization;  
 
Fatal or nonfatal stroke; 
 
Composite of total mortality, 
nonfatal MI (including silent MI), 
or nonfatal stroke; 
 
Total mortality. 
For consistency with 
Statistical Analysis Plan 
(SAP) 
 
 


Amarin Pharma Inc. 
AMR-01-01-0019 Amendment 2 
Confidential 
Explanation of Changes 
 
8 July 2016 
Page 3 of 9 
Protocol Location 
Summary of Change 
Reason for Change 
 
Section 2 (Study 
Objectives),  
 
Section 9.2.3 (Tertiary 
Endpoints), and 
 
Synopsis 
The tertiary objectives and endpoints were 
designated, re-ordered, and in some 
cases more clearly defined.  
 
Examples include: 
Adding remnant lipoprotein cholesterol to 
the list of lipids, lipoproteins, and 
inflammatory markers to be assessed. 
 
Added tertiary endpoints: Ischemic stroke, 
hemorrhagic stroke, incidence of new 
onset hypertension, primary endpoint in 
the subset of patients with impaired 
glucose metabolism, key secondary 
endpoint in the subset of patients with 
impaired glucose metabolism and 
specifically classified revascularization 
procedures. Definition was provided 
around metabolic syndrome as part of a 
composite. 
 
Some components of composite 
endpoints which were previously 
secondary were moved to tertiary and 
reordered.   
For consistency with the 
SAP 
 
 
Section 3.4 (Study 
Duration) 
 
Section 7.1.1 (Treatment 
Regimen, Dosage, and 
Duration) 
 
Synopsis Study Design 
and Duration 
Updated enrollment duration 
(approximately 4.2 years) and total study 
duration (approximately 6.5 years). 
Extension of the expected 
enrollment period and 
total study period and for 
consistency with the SAP 
and iSAP 
 
Section 3.6 (Number of 
Patients) 
Clarified that additional patients may be 
enrolled beyond the projected 7990 if the 
number of events contributing to the 
primary endpoint appears less than, and 
inconsistent with, projections. 
Clarification  
 
Section 3.10 
(Stratification) 
 
Section 7.1.2.2 (Drug 
Randomization) 
Added condition to stratification: If the 
enrollment exceeds 7990 patients, new 
patients will be limited to Cardiovascular 
Risk Category 1. 
For clarification if 
enrollment exceeds pre-
specified 7990 patients 
 
Section 4.2 and 
 
Synopsis 
Added the following bullet point to 
Exclusion Criterion 13: Patients are 
excluded if they use proprotein convertase 
subtilisin kexin 9 (PCSK9) inhibitors during 
the screening period (after Visit 1) and/or 
plan to use during the treatment/follow-up 
periods of the study. To be eligible for 
participation in the study, patients cannot 
have taken a PCSK9 inhibitor within 90 
days prior to their screening visit. 
For clarification of patients 
who would be excluded 
from study participation on 
the basis of concurrent 
medication usage. 
 
Section 5.1 (Steering 
Committee) 
Revised description of the composition of 
the Steering Committee. 
Clarification 


Amarin Pharma Inc. 
AMR-01-01-0019 Amendment 2 
Confidential 
Explanation of Changes 
 
8 July 2016 
Page 4 of 9 
Protocol Location 
Summary of Change 
Reason for Change 
 
Section 5.2 (Study 
Operations Committee) 
Updated meeting frequency from 
monthly/bimonthly to periodic. 
For flexibility of meeting 
schedule 
 
Section 5.3 (Clinical 
Endpoints Committee 
[CEC]) 
Change the name of the CEC from 
“Clinical Events Committee” to “Clinical 
Endpoints Committee” and added 
requirement of adjudication of events for 
tertiary endpoints. 
For consistency with CEC 
Charter 
 
Section 5.4 (Data 
Monitoring Committee 
[DMC]) 
Clarification of description of Data 
Monitoring Committee (DMC) activities. 
For consistency with DMC 
Charter, SAP and iSAP 
 
Section 6.1 (Assessment 
Schedule) 
Added statement on supporting patient 
protocol adherence (compliance with 
office and phone visit schedule). 
Advisement to 
investigators to promote 
protocol adherence 
 
Section 6.1.2.3 (Visits 4, 
5, 6, 7, 8, and 9) 
 
Appendix A: Schedule of 
Procedures 
Added procedures for Visit 8 and 9 
Extension of the expected 
study period 
 
Sections 6.1.2.4 
(Additional Visits) 
 
Section 6.1.2.5 (Last 
Visit – End of Study) 
 
Section 6.2 (Telephone 
Follow-up Contact) 
 
Appendix A: Schedule of 
Procedures 
Changed expected end of study date to 
Day 2160. 
Extension of the expected 
study period 
 
Section 6.1.2.5 (Last 
Visit – End of Study) 
Changed study completion window for all 
patients of 30 days from study end date to 
a target of 30 days from study end date 
Clarification 
 
Section 6.2 (Telephone 
Follow-up Contact) 
Added timing of additional planned 
telephone contacts; 
Clarified the frequency of additional 
telephone contacts to occur every 90 days 
Extension of the expected 
study period; 
Clarification 
 
Section 6.3.1 (Clinical 
Laboratory Procedures) 
Deletion of allowance for eligibility if 
exclusion criteria are deemed not clinically 
significant by the investigator 
Clarification of 
requirement 
 
Section 6.3.1.2 (Fasting 
Lipid Profile) 
Direct measurement of low-density 
lipoprotein cholesterol (LDL-C) was added 
to Visits 2 and 4 
Added measurement to 
existing biosamples 
 
Section 6.3.1.2 (Fasting 
Lipid Profile) 
 
Section 12.2.4.4 (Tertiary 
Endpoints) 
Addition of calculation of Hopkins LDL-C 
Additional analysis 
variable based on LDL-C 
measurements 
 
Section 6.3.1.3 (Genetic 
testing) 
Added list of potential genetic tests 
Inclusion of detail on 
genetic tests 
 
Section 6.3.1.5 
(Additional Laboratory 
Tests) 
Changed 12 mL blood draw to 10 mL 
blood draw;  
 
Clarified that serum will be archived. 
 
Added list of potential bioassays (non-
genetic and genetic). 
 
Correction of blood 
sample volume; 
 
Clarification 
 
Description of potential 
bioassay uses of samples 


Amarin Pharma Inc. 
AMR-01-01-0019 Amendment 2 
Confidential 
Explanation of Changes 
 
8 July 2016 
Page 5 of 9 
Protocol Location 
Summary of Change 
Reason for Change 
 
Section 6.3.2.7 
(Electrocardiogram 
[ECG]) 
Added instruction that all post-
randomization ECG results are to be sent 
to the CEC for assessment of silent 
myocardial infarction (MI). 
Clarification of process 
 
Section 7.1.3 
(Compliance Control) 
Added instruction on study drug dose 
decrease: If dose is decreased for a 
patient (with Medical Monitor [MM] 
approval), the study drug dose should be 
increased back to 4 capsules as soon as 
medically appropriate. 
Clarification of process 
 
Section 7.2.1 
(Concomitant 
Medications during 
Treatment/Follow-Up 
Period) 
Added instruction on statin 
discontinuation: If it becomes necessary to 
discontinue statin therapy, patients may 
(with MM approval) remain in the study 
and on study medication; statin therapy 
should be resumed when medically 
appropriate. 
 
Added instruction on post randomization 
initiation of medications that were 
excluded for non-stable dosage ≥28 days 
prior to screening, if medically warranted. 
 
Added PCSK9 inhibitors to the list of non-
study drug related, non-statin, lipid-
altering medications and supplements, 
and foods are prohibited during the study. 
Clarification of process 
 
 
 
 
 
 
 
Clarification of process 
 
 
 
 
Clarification of process 
 
Section 8.2 
(Pharmaceutical 
Formulations) 
Update the capsule shell components of 
AMR101 1 g capsules and placebo 
capsules. 
Update capsule shell 
components to represent 
nominal “dry shell” formula 
weight 
 
Section 9.1 
(Specification of 
Variables and 
Procedures) 
Clarification added that only adjudicated 
events will be used in the final efficacy 
statistical analysis. Also added reference 
to Appendix C for metabolic syndrome. 
Clarification and to provide 
a location of additional 
relevant information 
 
Section 10.2 (Adverse 
Events) 
For causality assessments, clarified 
definition of “Yes” as (related, probably 
related, possibly related). 
Clarification of definition 
 
Section 10.3.1 (Initial 
Reports) 
Specified follow-up period for SAE 
reporting for patients who are Off Drug In 
Study (ODIS) (28 days following study 
completion). 
Clarification of process 
 
Section 11 (Treatment 
discontinuation/patient 
withdrawal) 
Clarified that follow-up for efficacy and 
safety should be continued “in subjects 
that discontinued therapy, but remain in 
the study (i.e., ODIS patients)”. 
Clarification of process 


Amarin Pharma Inc. 
AMR-01-01-0019 Amendment 2 
Confidential 
Explanation of Changes 
 
8 July 2016 
Page 6 of 9 
Protocol Location 
Summary of Change 
Reason for Change 
 
Section 11.1 (Reasons 
for Early Study Drug 
Discontinuation) 
Added reason for early study drug 
discontinuation: Investigative site closure. 
 
Added requirement of ≥30 days 
discontinuation of study drug for patient to 
qualify as ODIS. 
 
Added description of re-challenge (re-
initiating study drug) after study drug 
discontinuation as soon as clinically 
appropriate. 
Clarification of process 
 
 
Clarification of process 
 
 
 
Clarification of process 
 
Section 12.1.1 (Intent-to-
Treat Population) 
Renamed the Randomized Population to 
the Intent-to-Treat population; clarified 
definition. 
For consistency with the 
population description and 
SAP 
 
Section 12.1.2 (Modified 
Intent-to-Treat 
Population) 
Added definition of Modified Intent-to-
Treat (mITT) population. 
For consistency with SAP 
 
Section 12.1.3 (Per-
Protocol Population) 
Updated definition of Per-Protocol 
population. 
Following the addition of 
the mITT population and 
for consistency with SAP 
 
Section 12.1.4 (Safety 
Population) 
Updated definition of Safety Population: 
patients will be analyzed based on 
treatment received if different from that 
assigned by randomization. 
Clarification 
 
Section 12.2.1 (Patient 
Disposition/Baseline 
Characteristics) 
Modified or added descriptions of 
variables to be analyzed, methods, and 
analysis populations. 
For consistency with SAP 
 
Section 12.2.2 (Study 
Medication Exposure 
and Compliance) 
Clarified the methods for calculating study 
medication exposure and compliance. 
For consistency with SAP 
 
Section 12.2.3 
(Concomitant Therapies) 
Clarified the codes to be used for 
summary and presentation of concomitant 
medications. 
For consistency with SAP 


Amarin Pharma Inc. 
AMR-01-01-0019 Amendment 2 
Confidential 
Explanation of Changes 
 
8 July 2016 
Page 7 of 9 
Protocol Location 
Summary of Change 
Reason for Change 
 
Section 12.2.4.2 
(Primary Endpoint) 
Revised statistical methods for primary 
endpoint analysis to account for change in 
interim analyses: the 2-sided alpha level 
for the log-rank test will be reduced from 
0.05 to account for the interim analyses 
based on a group sequential design.  
 
Added information on analysis populations 
for the primary and sensitivity analyses of 
the primary endpoint. 
 
Added a paragraph that describes how 
patients who have a non-CV death within 
90 days versus patients who have a non-
CV death more than 90 days after last 
contact without having had an earlier CV 
event will be censored. 
 
Added a paragraph defining the analysis 
and sensitivity analysis for silent MI.  
 
Added language which specifies that all 
observed data will be included in the 
primary analysis. 
 
Added language explaining that all deaths 
adjudicated as “undetermined” will be 
combined with those adjudicated as “CV 
deaths” for the primary analysis. 
Additionally, a sensitivity analysis of the 
CV death category will be done excluding 
“undetermined” deaths. 
For consistency with SAP 
 
 
 
 
 
 
For consistency with SAP 
 
 
 
For consistency with SAP 
 
 
 
 
 
 
Clarification of process 
 
 
Clarification of process 
 
 
 
Clarification of process 
 
Section 12.2.4.3 
(Secondary Endpoints) 
Revised statistical methods for analysis of 
secondary endpoints to describe 
sequential testing and updated methods. 
 
Added a paragraph that describes how 
patients who have a non-CV death within 
90 days versus patients who have a non-
CV death more than 90 days after last 
contact without having had an earlier CV 
event will be censored. 
For consistency with SAP 
 
 
 
For consistency with SAP 


Amarin Pharma Inc. 
AMR-01-01-0019 Amendment 2 
Confidential 
Explanation of Changes 
 
8 July 2016 
Page 8 of 9 
Protocol Location 
Summary of Change 
Reason for Change 
 
Section 12.2.4.4 (Tertiary 
Endpoints) 
Added calculation of Hopkins LDL-C to 
tertiary endpoint analyses. 
 
 
Added a paragraph that describes how 
patients who have a non-CV death within 
90 days versus patients who have a non-
CV death more than 90 days after last 
contact without having had an earlier CV 
event will be censored. 
 
Added an explanation of an additional 
exploratory analysis on the relationship 
between post-baseline biomarker values 
and treatment effect with the primary and 
key secondary endpoint.   
Additional analysis 
variable based on LDL-C 
measurements 
 
For consistency with SAP 
 
 
 
 
 
 
For consistency with SAP 
 
Section 12.2.4.5 
(Exploratory Subgroup 
Analyses 
Updated the analysis populations (mITT 
and PP) for the subgroup analyses. 
 
The Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) 
equation was designated as the equation 
that would be used to evaluate renal 
dysfunction with an estimated glomerular 
filtration rate [eGFR] of 60 mL/min/1.73m2 
set as the lower limit of normal. 
For consistency with SAP 
 
 
For consistency with SAP 
 
Section 12.2.4.6 (Interim 
Efficacy Analyses) 
Added an additional interim analysis to 
occur after approximately 80% of the total 
primary endpoint events are reached. 
 
Added condition for unblinded information 
to be released to the Sponsor before 
completion of the study under 
extraordinary circumstances. 
 
Added description of statistical methods to 
be used for the interim analyses. 
For consistency with iSAP 
 
 
 
Clarification of process 
 
 
 
 
For consistency with SAP 
 
Section 12.2.5 (Analysis 
of Safety) 
Clarified definition of TEAEs to be 
consistent with SAP. 
 
Revised text to describe planned safety 
analysis for patients who discontinued 
study drug for at least 30 days due to 
AE/SAE.  Patients who restart drug will 
not be included in the summary. 
Clarification of planned 
safety analysis 
 
Section 12.3 (Sample 
Size Determination) and 
Synopsis 
Clarified sample size calculation and 
assumptions. 
 
Provided a brief update on the analysis 
completed. 
For consistency with iSAP 
 
 
Updated information 
 
Section 22 (References) 
Updated the references cited in the main 
body of the protocol. 
Revised set of references 
according to content 
changes 


Amarin Pharma Inc. 
AMR-01-01-0019 Amendment 2 
Confidential 
Explanation of Changes 
 
8 July 2016 
Page 9 of 9 
Protocol Location 
Summary of Change 
Reason for Change 
 
Appendix A: Schedule of 
Procedures 
Added columns to describe Day 2160 Visit 
and Last Visit. 
Extension of the expected 
study period 
 
Appendix B: 
Standardized Definitions 
for Endpoint Events in 
Cardiovascular Trials 
Updated per new version of Standardized 
Definitions for Endpoint Events in 
Cardiovascular Trials (Hicks 2015). 
 
 
 
Consistent with FDA comments, the 
definitions were updated to make them 
specific to the REDUCE-IT study by 
removing ambiguous language and 
deleting definitions that do not apply to the 
study (i.e., some interventional cardiology 
definitions).  Also, language clarifying that 
undetermined deaths will be classified as 
death due to cardiovascular causes 
unless one of two scenarios occur: 
there is no information or data available 
regarding the circumstances of death 
other than that a death has occurred; or 
the available data are conflicting regarding 
whether the death was cardiovascular or 
non-cardiovascular. 
 
Updated to the current 
definitions for 
standardized 
cardiovascular endpoint 
events 
 
Clarification of definitions 
and for consistency with 
SAP 
 
Appendix C: Criteria for 
the Diagnosis of 
Diabetes 
Updated source to new version of 
guideline. 
Update of current source 
 
Appendix D: Criteria for 
the Diagnosis of 
Metabolic Syndrome 
This appendix was added to provide the 
criteria and waist circumference cut-points 
for abdominal obesity used for the 
diagnosis of metabolic syndrome as 
published by Alberti et al. in 2009. 
Addition of a new 
resource related to 
evaluation of certain 
tertiary endpoints. 
 


™
 
 
 
STATISTICAL ANALYSIS PLAN 
A Multi-Center, Prospective, Randomized, Double-Blind, 
Placebo-Controlled, Parallel-Group Study to Evaluate the Effect of AMR101 
on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients 
with Cardiovascular Disease or at High Risk for Cardiovascular Disease: 
REDUCE-IT (Reduction of Cardiovascular Events with EPA – Intervention Trial) 
 
Investigational Product: AMR101 (icosapent ethyl [ethyl-EPA]) 
Protocol Number: AMR-01-01-0019 
 
Sponsor: 
Amarin Pharma Inc. 
1430 Route 206 
Bedminster, New Jersey 07921, USA 
Telephone: +1-908-719-1315 
Facsimile: +1-908-719-3012 
 
Final: 8 July 2016 
Version Number: Final v 1.0 
 
  
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Amarin Pharma Inc., except to the extent that disclosure would be required by law 
and for the purpose of evaluating and/or conducting a clinical trial for Amarin Pharma Inc. 
You are allowed to disclose the contents of this document only to your Institutional Review 
Board or Independent Ethics Committee and study personnel directly involved with 
conducting this study. Persons to whom the information is disclosed must be informed that 
the information is confidential and proprietary to Amarin Pharma Inc. and that it may not be 
further disclosed to third parties. 


 
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Confidential and Proprietary 
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Page 2 of 68  
SIGNATURE PAGE 
TRIAL TITLE: A Multi-Center, Prospective, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group Study to Evaluate the Effect of AMR101 on Cardiovascular 
Health and Mortality in Hypertriglyceridemic Patients with Cardiovascular Disease or at High 
Risk for Cardiovascular Disease: REDUCE-IT (Reduction of Cardiovascular Events with 
EPA – Intervention Trial) 
 
We, the undersigned, have reviewed and approved this Statistical Analysis Plan for Protocol 
AMR-01-01-0019. 
 
Signature 
Date 
 
 
[Name / signature redacted]                    
[Signed (11 July 2016)] 
Senior Director, Biostatistics and Data Management 
Amarin Pharma Inc. 
 
 
[Name / signature redacted]                    
[Signed (11 July 2016)] 
Executive Director, Clinical Development 
Amarin Pharma Inc.  
 
 
[Name / signature redacted]                    
[Signed (11 July 2016)] 
Executive Director, Clinical Development  
Amarin Pharma Inc. 
 
 
[Name / signature redacted]                    
[Signed (15 July 2016)] 
President of R&D and Chief Scientific Officer, SVP 
Amarin Pharma Inc. 
 
 
[Name / signature redacted]                    
[Signed (19 July 2016)] 
Principal Investigator 


 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................ 6 
1.
 
INTRODUCTION ......................................................................................................... 8 
2.
 
STUDY OBJECTIVES AND TRIAL DESIGN ......................................................... 9 
3.
3.1 
Study Objective(s) ...................................................................................................... 9 
3.2 
Study Design............................................................................................................ 12 
 
Efficacy Assessments ........................................................................................ 13 
3.2.1
 
Safety Endpoints ............................................................................................... 16 
3.2.2
 
STATISTICAL METHODOLOGY ........................................................................... 17 
4.
4.1 
Determination of Sample Size .................................................................................. 17 
4.2 
Analysis Sets ........................................................................................................... 18 
 
Intent-to-Treat Population (ITT).......................................................................... 18 
4.2.1
 
Modified Intent-to-Treat Population (mITT) ........................................................ 18 
4.2.2
 
Per Protocol Population (PP) ............................................................................. 18 
4.2.3
 
Safety Population .............................................................................................. 18 
4.2.4
4.3 
Statistical Considerations ......................................................................................... 19 
 
General Statistical Considerations ..................................................................... 19 
4.3.1
 
Missing Data ...................................................................................................... 19 
4.3.2
 
Baseline ............................................................................................................. 20 
4.3.3
 
Study Day .......................................................................................................... 20 
4.3.4
 
Visit Windows .................................................................................................... 20 
4.3.5
 
Multiplicity .......................................................................................................... 20 
4.3.6
4.4 
Interim Analyses ...................................................................................................... 21 
4.5 
Final Analysis Following an Interim Analysis Early Stop Decision ............................ 22 
4.6 
Summary of Study Population Data ......................................................................... 22 
 
Patient Disposition ............................................................................................. 22 
4.6.1
 
Protocol Deviations ............................................................................................ 23 
4.6.2
 
Demographics and Baseline Characteristics ...................................................... 23 
4.6.3
 
Cardiovascular Risk Category............................................................................ 23 
4.6.4
 
Smoking and Alcohol History ............................................................................. 24 
4.6.5


 
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Cardiovascular History and Procedures, Family History, and Other 
4.6.6
Significant Medical History ................................................................................. 24 
 
Study Medication Administration and Compliance ............................................. 24 
4.6.7
 
Discontinuation of Study Drug ........................................................................... 25 
4.6.8
 
Early Termination from the Study ....................................................................... 25 
4.6.9
 Medications of Special Interest .......................................................................... 25 
4.6.10
 Prior and Concomitant Medications ................................................................... 25 
4.6.11
4.7 
Efficacy Analyses ..................................................................................................... 26 
 
Primary Efficacy Endpoint .................................................................................. 26 
4.7.1
 
Components of Primary Endpoint ...................................................................... 28 
4.7.2
 
Analysis of Secondary Efficacy Endpoints ......................................................... 29 
4.7.3
 
Analysis of Tertiary Endpoints ........................................................................... 30 
4.7.4
 
Exploratory Analysis of Subgroups .................................................................... 33 
4.7.5
4.8 
Safety Analyses ....................................................................................................... 35 
 
Adverse Events ................................................................................................. 35 
4.8.1
 
Clinical Laboratory Evaluation ........................................................................... 37 
4.8.2
 
Adverse Events of Special Interest .................................................................... 38 
4.8.3
 
Vital Signs and Patient Measurements .............................................................. 38 
4.8.4
 
12-Lead ECG ..................................................................................................... 38 
4.8.5
 
Physical Examination ......................................................................................... 39 
4.8.6
 
Childbearing Potential and Pregnancy Tests ..................................................... 39 
4.8.7
 
REFERENCES ........................................................................................................... 40 
5.
 
APPENDICES ............................................................................................................ 41 
6.
6.1 
Appendix A: Interim Statistical Analysis Plan (iSAP) ................................................ 41 
6.2 
Appendix B: Potential Genetic and Non-Genetic Bioassays ..................................... 66 
6.3 
Appendix C: Criteria for the Diagnosis of Metabolic Syndrome ................................ 67 
 


 
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LIST OF TABLES 
Table 1.  Examples of Recomputed Alpha Levels for Final Analysis .................................... 22 
Table 2.  Current Recommended Waist Circumference Thresholds for Abdominal 
Obesity by Organization and Population (adapted from Alberti et. al. Table 
2) ....................................................................................................................... 68 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
1.
Abbreviation or Term 
Definition 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
apo B 
Apolipoprotein B 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CABG 
Coronary artery bypass graft 
CBC 
Complete blood count 
CEC 
Clinical Endpoint Committee 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CRF 
Case Report Form 
CV 
Cardiovascular 
CVD 
Cardiovascular disease 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
EPA 
Eicosapentaenoic acid 
Hct 
Hematocrit 
HDL-C 
High-density lipoprotein cholesterol 
Hgb 
Hemoglobin 
HR 
Hazard ratio 
hs-CRP 
High-sensitivity C-reactive protein 
hsTnT 
High-sensitivity troponin T 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
iSAP 
Interim Statistical Analysis Plan 


 
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Abbreviation or Term 
Definition 
LDL-C 
Low-density lipoprotein cholesterol 
MI 
Myocardial infarction 
mITT 
Modified Intent-to-Treat 
NCEP 
National Cholesterol Education Program 
PP 
Per Protocol 
PTCA 
Percutaneous transluminal coronary angioplasty 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SOC 
System Organ Class 
TC 
Total cholesterol 
TEAE 
Treatment-emergent adverse event 
TG 
Triglycerides 
TIA 
Transient Ischemic Attack 
WBC 
White blood cell 


 
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INTRODUCTION 
2.
This Statistical Analysis Plan (SAP) has been developed based on Protocol AMR-01-01-0019 
(Amendment #2 Final Version 3.0 d ated 8 July 2016). The SAP describes the statistical 
methods to be used for the final analysis and reporting of efficacy and safety data collected 
during the entire conduct of Protocol AMR-01-01-0019, and has been developed and finalized 
prior to database lock and unblinding of the clinical database for Study AMR-01-01-0019. A 
separate Interim Statistical Analysis Plan (iSAP) (Appendix A) describes the planned interim 
analyses that will be solely used for interim decision making by the independent Data 
Monitoring Committee (DMC). If additional analyses are required to supplement the planned 
analyses described in this SAP, they will be identified in the Clinical Study Report (CSR). 
This SAP is being written with consideration of the recommendations outlined in the 
International Conference on H armonisation (ICH) E9 Guideline entitled Guidance for 
Industry: Statistical Principles for Clinical Trials and the most recent ICH E3 Guideline 
entitled Guidance for Industry: Structure and Content of Clinical Study Reports. 


 
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STUDY OBJECTIVES AND TRIAL DESIGN 
3.
3.1 
Study Objective(s) 
The primary objective is, in patients at low-density lipoprotein cholesterol (LDL-C) goal 
while on s tatin therapy, with established cardiovascular disease (CVD) or at high risk for 
CVD, and hypertriglyceridemia (fasting triglycerides [TG] 200* mg/dL and <500 mg/dL 
[2.26 mmol/L and <5.64 mmol/L]), to evaluate the effect of 4 g/day AMR101 on the time 
from randomization to first occurrence of any component of the composite of the following 
major cardiovascular (CV) events: 
 CV death; 
 Nonfatal myocardial infarction (MI), (including silent MI; electrocardiograms [ECGs] 
will be performed annually for the detection of silent MIs); 
 Nonfatal stroke; 
 Coronary revascularization; or 
 Unstable 
angina 
determined 
to 
be 
caused 
by 
myocardial 
ischemia 
by 
invasive/non-invasive testing and requiring emergent hospitalization. 
(*The fasting TG lower limit of ≥150 mg/dL, as defined in the original protocol, was changed 
via protocol amendment #1 dated 16 May 2013 to ≥200 mg/dL.  All randomized patients will 
be included in the final analyses).   
The secondary objectives of this study are the following: 
The key secondary objective is to evaluate the effect of therapy on the time from 
randomization to the first occurrence of the composite of CV death, nonfatal MI (including 
silent MI), or nonfatal stroke. 
Other secondary objectives for this study are to evaluate the effect of therapy on time from 
randomization to the first occurrence of: 
 Composite of CV death or nonfatal MI (including silent MI); 
 Fatal or nonfatal MI (including silent MI); 
 Non-elective coronary revascularization represented as the composite of emergent or 
urgent classifications; 
 CV death; 
 Unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization;  
 Fatal or nonfatal stroke; 
 Composite of total mortality, nonfatal MI (including silent MI), or nonfatal stroke; 
 Total mortality. 


 
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The tertiary objectives for this study are to evaluate the effect of therapy on the following. 
Where applicable and unless specified otherwise, endpoints represent time from 
randomization to the first occurrence of the individual or composite endpoints: 
 The total CV events analysis defined as the time from randomization to occurrence of 
the first and all recurrent major CV events defined as CV death, nonfatal MI 
(including silent MI), nonfatal stroke, coronary revascularization, or unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization; 
 Primary composite endpoint in the subset of patients with diabetes mellitus at 
baseline; 
 Primary composite endpoint in the subset of patients with metabolic syndrome at 
baseline as defined in A Joint Interim Statement of the International Diabetes 
Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and 
Blood Institute; American Heart Association; World Heart Federation; International 
Atherosclerosis Society; and International Association for the Study of Obesity 
(Alberti 2009); with cut points of parameters as defined in Table 1 of Alberti et al. and 
waist circumference cut points further guided by Table 2 of Alberti et. al. and 
specifically set at ≥35 inches (88 cm) for all women and Asian, Hispanic, or Latino 
men, and ≥40 inches (102 cm) for all other men (see Appendix C in Section 6.3); 
 Primary composite endpoint in the subset of patients with impaired glucose 
metabolism at baseline (Visit 2 FBG of 100-125 mg/dL); 
 Key secondary composite endpoint in the subset of patients with impaired glucose 
metabolism at baseline (Visit 2 FBG 100-125 mg/dL); 
 Composite of CV death, nonfatal MI (including silent MI), nonfatal stroke, cardiac 
arrhythmia requiring hospitalization of ≥24 hours, or cardiac arrest; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), or unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization, nonfatal stroke, or PVD requiring intervention, 
such as angioplasty, bypass surgery, or aneurism repair; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization, PVD requiring intervention, or cardiac arrhythmia 
requiring hospitalization of ≥24 hours; 


 
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 New CHF; 
 New CHF as the primary cause of hospitalization; 
 Transient ischemic attack (TIA);  
 Amputation for PVD; 
 Carotid revascularization; 
 All coronary revascularizations defined as the composite of emergent, urgent, elective, 
or salvage; 
 Emergent coronary revascularizations; 
 Urgent coronary revascularizations; 
 Elective coronary revascularizations; 
 Salvage coronary revascularizations; 
 Cardiac arrhythmias requiring hospitalization of ≥24 hours; 
 Cardiac arrest; 
 Ischemic stroke; 
 Hemorrhagic stroke; 
 Fatal or nonfatal stroke in the subset of patients with a history of stroke prior to 
baseline; 
 New onset diabetes, defined as Type 2 di abetes newly diagnosed during the 
treatment/follow-up period;  
 New onset hypertension, defined as blood pressure ≥140 mmHg systolic OR 
≥90 mmHg diastolic newly diagnosed during the treatment/follow-up period; 
 Fasting TG, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apo B, hs-CRP (hsCRP and 
log[hsCRP]), hsTnT, and RLP-C (to be estimated from standard lipid panel, RLP-C = 
TC – HDL-C – LDL-C [Varbo 2014]) (based on ITT estimands):  
o Assessment of the relationship between baseline biomarker values and 
treatment effects within the primary and key secondary composite endpoints, 
o Assessment of the effect of AMR101 on each marker, 


 
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o Assessment of the relationship between post-baseline biomarker values and 
treatment effects within the primary and key secondary composite endpoints 
by including post-baseline biomarker values (for example, at 4 months, or at 1 
year) as a covariate; 
 Change in body weight; 
 Change in waist circumference. 
3.2 
Study Design 
This is a Phase 3b, m ulti-center, multi-national, prospective, randomized, double-blind, 
placebo-controlled, parallel-group study. 
This is an event driven trial comparing the effect of AMR101 vs. control, in terms of the 
composite endpoint listed above as the primary efficacy endpoint. The study has been planned 
to accrue a total of 1612 efficacy endpoint events with two planned interim analyses when 
approximately 967 (60%) and 1290 (80%) of the events have occurred and been adjudicated. 
The study includes patients with established CVD (CV Risk Category 1) and patients ≥50 
years old with diabetes and at least one additional risk factor for CVD but with CVD not 
established (CV Risk Category 2). 
Sample size calculation was based on assumptions of constant hazard, asymmetric 
recruitment rate over time and without factoring for dropouts. A risk reduction corresponding 
to a hazard ratio of 0.85 (AMR101 vs. control) is assumed. 1612 events would be required to 
detect this hazard ratio with approximately 90% power with one-sided alpha-level at 2.5% 
and with two interim analyses. 
The recruitment period is assumed to be approximately 4.2 years with 20% recruitment in the 
first year, 40% in the second year, 20% in the third year, 19% in the fourth year and the 
remaining 1% in the last 0.2 years. The expected maximum study duration is estimated at 6.5 
years unless the trial is terminated early for efficacy or safety issues. A one-year event rate of 
5.2% (hazard = 0.053) in the control arm is also assumed. Under these assumptions the 
number of patients to be enrolled is N = 7990. 
Randomized treatment assignment to either 4 g/day AMR101 or placebo in a 1:1 ratio will be 
provided using the internet via an interactive web response system (IWRS). Randomization 
will be stratified by CV Risk Category 1 or 2 (defined in the inclusion criteria of the study 
protocol), use of ezetimibe, and by geographical region (Westernized, Eastern European, and 
Asia Pacific countries). 
Approximately 70% of randomized patients will be in CV Risk Category 1, a nd 
approximately 30% of randomized patients will be in CV Risk Category 2. Enrollment of 
patients within a CV risk category will be stopped when the planned number of patients in 
that risk category is reached or, if the enrollment target is extended beyond 7990 patients (as 


 
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described in Section 4.1), then only CV Risk Category 1 will be included in further 
enrollment. 
Study drug AMR101 or placebo capsules will be taken daily (with food) as two capsules in 
the morning and two capsules in the evening (twice-per-day dosing regimen). 
The study schedule and assessments to be performed are described in the study protocol. 
 
Efficacy Assessments 
3.2.1
The primary endpoint and the majority of the secondary and tertiary endpoints are based on 
clinical events related to CVD and mortality. All events occurring between randomization and 
the study end date (inclusive) will be recorded. All suspected efficacy endpoint events will be 
adjudicated by a Clinical Endpoints Committee (CEC) based on the criteria detailed in the 
CEC Charter. The CEC members are blinded to study treatment allocation. For efficacy 
endpoints including CV events, only adjudicated events will be included in the final statistical 
analyses. 
3.2.1.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the time from randomization to the first occurrence of the 
composite of the following clinical events: 
 CV death; 
 Nonfatal MI (including silent MI; ECGs will be performed annually for the detection 
of silent MIs); 
 Nonfatal stroke; 
 Coronary revascularization;  
 Unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization. 
The first occurrence of any of these major adverse cardiovascular events during the follow-up 
period of the study will be included in the incidence. 
All deaths casually adjudicated as “undetermined” will be combined with those adjudicated as 
“CV deaths” for the primary analysis. A sensitivity analysis of the CV death category will be 
performed that excludes the “undetermined cause of death” cohort. 
For silent MIs, the primary analysis will assume that all silent MIs occurred on the date of the 
first tracing indicative of a silent MI; a second (sensitivity) analysis will assume that all silent 
MIs occurred on the day after the last prior normal ECG; and a third (sensitivity) analysis will 
assume that all silent MIs occurred at the mid-point between the last normal ECG and the 
ECG with the new MI. 


 
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3.2.1.2 Secondary Efficacy Endpoints 
The key secondary efficacy endpoint is the time from randomization to the first occurrence of 
the composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke.  
Other secondary efficacy endpoints are time from randomization to the first occurrence of the 
individual or composite endpoints as follows (to be tested in the order listed): 
 Composite of CV death or nonfatal MI (including silent MI); 
 Fatal or nonfatal MI (including silent MI); 
 Non-elective coronary revascularization represented as the composite of emergent or 
urgent classifications; 
 CV death; 
 Unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization; 
 Fatal or nonfatal stroke; 
 Composite of total mortality, nonfatal MI (including silent MI), or nonfatal stroke; 
 Total mortality. 
For the secondary endpoints that count a single event, the time to first occurrence of this type 
of event will be counted for each patient. For secondary endpoints that are composites of two 
or more types of events, the time to first occurrence of any of the event types included in the 
composite will be counted for each patient. 
For the secondary endpoints as well as the tertiary endpoints mentioned below, the main 
analysis will combine all deaths casually adjudicated as “undetermined” with those 
adjudicated as “CV deaths” and use the date of the first tracing indicative of a silent MI as the 
onset date for silent MI, similar to the primary efficacy analysis described above. Similarly, 
the sensitivity analyses as described for the primary composite endpoint will also be carried 
out for the secondary and tertiary endpoints. 
3.2.1.3 Tertiary Efficacy Endpoints 
The following tertiary endpoints will be evaluated as supporting efficacy analyses. Where 
applicable and unless specified otherwise, endpoint analyses will be conducted as time from 
randomization to the first occurrence of the individual or composite endpoints. 
 Total CV events analysis defined as the time from randomization to occurrence of the 
first and all recurrent major CV events defined as CV death, nonfatal MI (including 
silent MI), nonfatal stroke, coronary revascularization, or unstable angina determined 
to be caused by myocardial ischemia by invasive/non-invasive testing and requiring 
emergent hospitalization;  
 Primary composite endpoint in subset of patients with diabetes mellitus at baseline; 


 
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 Primary composite endpoint in the subset of patients with metabolic syndrome at 
baseline as defined in A Joint Interim Statement of the International Diabetes 
Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and 
Blood Institute; American Heart Association; World Heart Federation; International 
Atherosclerosis Society; and International Association for the Study of Obesity 
(Alberti 2009); with cut points of parameters as defined in Table 1 of Alberti et al. and 
waist circumference cut points further guided by Table 2 of Alberti et al. and 
specifically set at ≥35 inches (88 cm) for all women and Asian, Hispanic, or Latino 
men, and ≥40 inches (102 cm) for all other men (see Appendix C in Section 6.3); 
 Primary composite endpoint in the subset of patients with impaired glucose 
metabolism at baseline (Visit 2 FBG of 100-125 mg/dL); 
 Key secondary composite endpoint in the subset of patients with impaired glucose 
metabolism at baseline (Visit 2 FBG 100-125 mg/dL); 
 Composite of CV death, nonfatal MI (including silent MI), nonfatal stroke, cardiac 
arrhythmia requiring hospitalization of ≥24 hours, or cardiac arrest; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), or unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization, nonfatal stroke, or PVD requiring intervention, 
such as angioplasty, bypass surgery, or aneurism repair; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization, PVD requiring intervention, or cardiac arrhythmia 
requiring hospitalization of ≥24 hours; 
 New CHF; 
 New CHF as the primary cause of hospitalization; 
 Transient ischemic attack (TIA); 
 Amputation for PVD; 
 Carotid revascularization; 
 All coronary revascularizations defined as the composite of emergent, urgent, elective, 
or salvage; 
 Emergent coronary revascularizations; 
 Urgent coronary revascularizations; 


 
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 Elective coronary revascularizations; 
 Salvage coronary revascularizations; 
 Cardiac arrhythmias requiring hospitalization of ≥24 hours; 
 Cardiac arrest; 
 Ischemic stroke; 
 Hemorrhagic stroke; 
 Fatal or nonfatal stroke in the subset of patients with a history of stroke prior to 
baseline; 
 New onset diabetes, defined as Type 2 di abetes newly diagnosed during the 
treatment/follow-up period;  
 New onset hypertension, defined as blood pressure ≥140 mmHg systolic OR ≥90 mm 
Hg diastolic newly diagnosed during the treatment/follow-up period; 
 Fasting TG, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apo B, hs-CRP (hsCRP and 
log[hsCRP]), hsTnT, and RLP-C (to be estimated from standard lipid panel, RLP-C = 
TC – HDL-C – LDL-C [Varbo 2014]) (based on ITT estimands):  
o Assessment of the relationship between baseline biomarker values and treatment 
effects within the primary and key secondary composite endpoints, 
o Assessment of the effect of AMR101 on each marker, 
o Assessment of the relationship between post-baseline biomarker values and 
treatment effects within the primary and key secondary composite endpoints by 
including post-baseline biomarker values (for example, at 4 months, or at 1 year) 
as a covariate; 
 Change in body weight;  
 Change in waist circumference. 
Where applicable and unless specified otherwise, for the tertiary endpoints that count a single 
event, the time from randomization to the first occurrence of this type of event will be counted 
in each patient. Similarly, where applicable and unless specified otherwise, for tertiary 
endpoints that are composites of two or more types of events, the time from randomization to 
the first occurrence of any of the event types included in the composite will be counted for 
each patient. 
 
Safety Endpoints 
3.2.2
Safety assessments will include adverse events (AEs), clinical laboratory measurements 
(chemistry, hematology), 12-lead electrocardiograms (ECGs), vital signs (seated systolic and 
diastolic blood pressures, heart rate, respiration rate, and body temperature), weight, waist 
circumference, and physical examinations as per the study protocol.  


 
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A complete medical, surgical and family history will be completed at Visit 1. 
 
STATISTICAL METHODOLOGY 
4.
4.1 
Determination of Sample Size 
The initial sample size estimation (protocol v1.0) was based on the assumption that the 
primary composite endpoint (time from randomization to the first occurrence of CV death, 
non-fatal MI, non-fatal stroke, coronary revascularization, or unstable angina requiring 
hospitalization) would be relatively reduced by approximately 15% with AMR101 from an 
event rate by 4 years of 20.8% (5.2% per year) in the placebo group (which corresponds to a 
hazard ratio of 0.85). The updated sample size calculation is based on assumptions of constant 
hazard, asymmetric recruitment rate over time and without factoring for dropouts. A risk 
reduction corresponding to a hazard ratio of 0.85 (AMR101 vs. control) is assumed. 1612 
events would be required to detect this hazard ratio with approximately 90% power with two-
sided alpha-level at 5% and with two interim analyses.  
The recruitment period is assumed to be approximately 4.2 years with 20% recruitment in the 
first year, 40% in the second year, 20% in the third year, 19% in the fourth year and the 
remaining 1% in the last 0.2 years. The expected maximum study duration is estimated at 6.5 
years unless the trial is terminated early for efficacy or safety issues. A one-year event rate of 
5.2% (hazard = 0.053) in the control arm is also assumed. Under these assumptions the 
number of patients to be enrolled is N = 7990. 
Two interim analyses are planned after approximately 60% (967) and approximately 80% 
(1290) of the primary events have occurred (see iSAP in Section 6.1 [Appendix A] for 
description of the interim analyses). 
Since this is an events-driven trial, the ‘sample size’ is the number of events rather than the 
number of patients. The number of events that occur depends primarily on three factors: how 
many patients are enrolled, the combined group event rate, and how long the patients are 
followed. Because of the difficulty in predicting the combined event rate, the sponsor will 
monitor that event rate as the trial progresses. If the combined event rate is less than 
anticipated, either increasing the number of patients, extending the length of follow-up, or a 
balance of adjusting both factors may be necessary to achieve the sample size of 1612 events. 
Before completing the enrollment phase of the trial, i.e. approximately 3 to 6 months prior to 
the projected enrollment of the 7990th patient, the actual event rate based on pooled, blinded 
accumulation of primary efficacy endpoint events would be calculated and plotted.  If those 
analyses suggested the number of patients with at least 1 a djudicated, primary event (and 
appropriately accounting for patients with potential primary events for which the adjudication 
process is then incomplete) was consistent with projections, then the study could continue 
toward the protocol-specified target enrollment of 7990 patients.  However, if the number of 
such events appeared less than and inconsistent with projections, the Sponsor would consider 
(under blinded conditions) re-calculating the number of patients needed to achieve the target 


 
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number of events within the desired timeline or extend the follow-up period.  If the projected 
increase in number of patients was ≤25% of the original 7990 target population, the Sponsor 
could, with documented approval of both the REDUCE-IT Steering Committee and the DMC, 
extend enrollment to the revised target number without need for an additional protocol 
amendment. Under those conditions, all principal investigators, ethics committees, and 
regulatory authorities associated with the protocol will be promptly notified of the action. If 
the projected increase in number of patients was more than 25% above the original 7990 
target (i.e. more than 1998 additional patients) a formal protocol amendment would have been 
initiated. 
Consistent with the plan stated above, an analysis and modeling of pooled, blinded primary 
efficacy endpoint events across the remainder of the trial was performed prior to the projected 
enrollment of the 7990th patient.  Based on this analysis, the sample size of 7990 randomized 
patients is with 95% confidence likely to result in the target 1,612 a djudicated primary 
efficacy events within 2018.  T he results of this analysis were shared with and approved by 
the REDUCE-IT Steering Committee and DMC. 
As of the completion of study enrollment, the actual number of patients randomized will vary 
from the target number as a result of the inherent lag between the date the last patient started 
screening and the date the last patient was randomized. 
4.2 
Analysis Sets 
 
Intent-to-Treat Population (ITT) 
4.2.1
The Intent-to-Treat (ITT) population will include all patients who are randomized via the 
IWRS. All efficacy analyses, including the primary analysis, will be performed on the ITT 
population. Patients will be analysed according to the randomized treatment. 
 
Modified Intent-to-Treat Population (mITT) 
4.2.2
The Modified Intent-to-Treat (mITT) population will include all randomized patients who 
have study drug dispensed after randomization. Groups will be defined based on t he 
randomized treatment. 
 
Per Protocol Population (PP) 
4.2.3
The Per-Protocol (PP) population will include all mITT patients without any major protocol 
deviations, and who had ≥80% compliance while on t reatment.  To be included in the PP 
population the minimum time on therapy is 90 days.   
 
Safety Population 
4.2.4
All safety analyses will be conducted based on the Safety population, which is defined as all 
randomized patients. This is the same as the ITT population.   


 
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4.3 
Statistical Considerations 
 
General Statistical Considerations 
4.3.1
All statistical analyses and data summaries are to be generated according to this SAP. Any 
deviations from this SAP will be documented in the CSR. 
All null hypotheses will be defined as no treatment difference. All statistical tests for the 
efficacy outcomes will be performed at the two-sided 5% significance level, unless otherwise 
noted. The iSAP will utilize one-sided testing for efficacy at the 0.025 level for interim 
analyses, the operating characteristics of which are identical to those of a corresponding group 
sequential design with a two-sided alpha level of 0.05. 
Summary statistics will be presented by treatment group and by visit where appropriate. Data 
will be presented “as-observed”, unless otherwise specified. Continuous data will be 
summarized with descriptive statistics: count (n), number of missing values (n-missing), 
mean, standard deviation (SD), median, minimum, and maximum. Categorical data will be 
described using frequencies and percentages, including a category for missing values where 
appropriate. Percentages are based on t he number of patients in the analysis set. All 
meaningful patient data collected in the database will be listed. Listings will be sorted by 
patient within center/site. 
 
Missing Data 
4.3.2
Only measurements obtained at each study visit will be used in presenting tabular data 
summaries, unless otherwise stated. Unless otherwise stated, observed data will be presented 
in tables and listings without imputation of missing values. All measurements, including 
unscheduled or repeated assessments, will be presented in data listings. 
Medications, except study drug, with missing stop dates will be considered in concurrent use 
with study drug during the study period and counted in the summary table of concomitant 
medications unless the start date of the medication was after study completion or after 
discontinuation from study. 
Adverse events with missing onset dates will be considered treatment-emergent for 
randomized patients if the adverse event stop date is after randomization. Adverse events with 
missing stop dates will be considered treatment-emergent for randomized patients. If only the 
year is present for AE stop dates, then December 31 w ill be used as the month and day, 
respectively. If only the day is missing, the first of the month will be used for all start dates 
and the last day of the month will be used for all end dates. 
Missing AE relationship will be presented as ‘related’ in tables and missing in listings. In 
addition, tables that describe the collected data and that include a ‘missing’ relationship 
category where appropriate will be presented. Missing AE intensity/severity will be presented 
in a ‘missing’ category in tables and as missing in listings.  


 
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Event or censoring dates used in the time-to-event analysis of efficacy endpoints will be 
imputed to the first of the month only if the day is missing and the month and year are both 
known. However, for events that occurred in the same month as randomization, the day will 
be imputed as the date of randomization. For event or censoring with missing months or 
years, the event or censoring date will be imputed to the last known date without a previous 
event, or January 1 if only year is known, whichever is later. 
 
Baseline 
4.3.3
In general, the baseline value will be defined as the last non-missing measurement obtained 
prior to the dispensing drug, unless otherwise specified. If the baseline value is missing, the 
value obtained at the screening visit will be used as the baseline value. 
Lipid, lipoprotein, and inflammatory marker baseline values will be derived variables. LDL-C 
may be obtained by various methods at each visit; therefore, the baseline value obtained via 
Preparative Ultracentrifugation will be used, unless this value is missing. If the LDL-C 
Preparative Ultracentrifugation value is missing, then another LDL-C value will be used, with 
prioritization of values obtained from LDL-C Direct measurements, followed by LDL-C 
derived by the Friedewald calculation (only for subjects with TG < 400 mg/dL), and finally 
LDL-C derived using the calculation published by Hopkins University investigators (Martin 
2013). For all other lipid, lipoprotein, and inflammatory marker parameters, wherever 
possible, baseline will be derived as the arithmetic mean of the Visit 2 (Day 0) value and the 
preceding Visit 1 ( or Visit 1.1) value. If only one of these values is available, the single 
available value will be used as baseline. 
 
Study Day 
4.3.4
For purposes of calculating study day, the day of randomization is defined as Day 0. Study 
Day will be calculated as [date of event – date of randomization + 1]. 
 
Visit Windows 
4.3.5
Nominal study visits (days or weeks relative to Baseline) as collected per the protocol 
schedule of events will be used to summarize data. Ranges for study day intervals 
(“windows”) will not be used to re-assign visit numbers in relation to the start of therapy. If 
there is more than one valid measurement for a selected visit after the baseline visit, the 
average of the values collected will be used. However, for any safety analyses intended to 
identify outliers (including, but not limited to, shift tables), the most extreme value instead of 
the average of the values collected will be used; and values from all visits (including 
unscheduled measurements) will be included in these analyses. 
 
Multiplicity 
4.3.6
There is a single primary efficacy endpoint (a composite of CV death, nonfatal MI, nonfatal 
stroke, coronary revascularization, or hospitalization for unstable angina) and one primary 
comparison (Placebo vs. 4 g /day AMR101) defined in the primary objective. Formal 


 
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statistical testing for key and other secondary endpoints will be performed for the final 
analysis, either at the planned completion at 1612 primary events or in case of an early stop 
for efficacy at one of the two interim analyses, and will be carried out in a hierarchical fashion 
if and only if the primary endpoint meets statistical significance. The hierarchy of secondary 
endpoints is given in Section 3.2.1.2. 
The planned interim analyses are based on a group sequential design with O’Brien-Fleming 
boundaries generated using the Lan-DeMets alpha-spending function at approximately 60% 
and 80% of the targeted 1612 events. The use of the spending-function allows for possible 
deviations from the planned event number at the time of the interim. If the interim analyses 
are carried out exactly at the planned 60% and 80% milestones, then the resulting one-sided 
alpha-levels at each of the two interim analyses and the final analysis are: 
 0.0038 at the 60% milestone (967 events), 
 0.0110 at the 80% milestone (1290 events), and 
 0.0211 at the 100% milestone (1612 events). 
A complete description of the group sequential design details is described in the iSAP 
(Appendix A). 
The alpha level for the final analysis either at the planned completion at 1612 primary events 
or in case of an early stop for efficacy will be obtained from the O’Brien-Fleming boundaries 
generated using the Lan-DeMets alpha-spending function. If the primary efficacy endpoint 
test described in Section 4.7.1.1 meets statistical significance at this alpha-level, then the 
testing will be carried out hierarchically for the key secondary and the other secondary 
endpoints at the same alpha level used for the primary endpoint. All analysis beyond the 
primary or the last endpoint meeting statistical significance at this alpha-level will be 
considered as exploratory. Further details on the alpha-level to be used for the final analysis 
are given in Section 4.5.  
Since the results from the analysis of the tertiary endpoints are intended to be supportive 
rather than pivotal evidence of drug efficacy and safety, all tertiary efficacy endpoint analysis 
will be considered exploratory and statistical testing will be carried out at the nominal 5% 
level without adjustment. 
4.4 
Interim Analyses 
Two interim analyses are planned for the primary efficacy endpoint using adjudicated events 
when adjudication of approximately 60% (967 events) and approximately 80% (1290 events) 
of the total number of primary endpoint events planned (1612) is reached. The planned 
interim analyses are based on a  group-sequential design and are described in the iSAP 
(Appendix A). 
The interim results of the study will be monitored by an independent DMC. The analyses will 
be performed by an independent statistical team that is unblinded to the treatment assignment 
and will be reported only to the DMC. The unblinded information will not be released to the 


 
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Sponsor before the completion of the study unless extraordinary circumstances arise and, 
under such circumstances, procedures for maintaining confidentiality will be described in a 
written agreement with the DMC.  
If the study is terminated early following an interim analysis, patients will be notified 
promptly and brought in for their final close-out visit, and the final analyses of efficacy and 
safety will include all data through their final visit. Further details are given in Section 4.5.  
4.5 
Final Analysis Following an Interim Analysis Early Stop Decision 
If the decision is taken to terminate the study at one of the two planned interim analyses, the 
study will enter the closeout phase. During this phase, which extends from the DMC interim 
analysis meeting until the final database lock, additional adjudicated events may arrive. The 
final analysis, being based on the totality of the evidence, will include these additional events, 
resulting in an increase in the information fraction (of the pre-specified 1612 events) from 
what the information was at the time of the interim decision making. The significance level 
for the formal hypothesis testing at the final analysis will then be recomputed from the Lan-
DeMets error spending function at the new information fraction while ignoring the look at 
which the efficacy boundary was crossed for the DMC decision-making purpose (Whitehead, 
1992). A few examples of the recomputed alpha level used for the final analysis are given in 
the Table below: 
Table 1.  Examples of Recomputed Alpha Levels for Final Analysis 
Early Stop 
IA Number 
Number of 
Events at IA 
Decision 
Number of 
Additional Events 
at Closeout 
Final Analysis 
Total Number 
of Events 
α Level 
1 
967 
33 
1000 
0.0088 
1 
967 
50 
1017 
0.0095 
2 
1290 
40 
1330 
0.0272 
2 
1290 
60 
1350 
0.0286 
IA=interim analysis 
4.6 
Summary of Study Population Data 
 
Patient Disposition 
4.6.1
The number and percentage of patients will be tabulated for each of the following categories 
for each treatment group: 
 Screened (total only); 
 Re-screened and reasons for re-screening (total only); 
 ITT overall and by stratification factors (CV risk, ezetimibe use, and geographical 
region); 


 
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 mITT population; overall and by stratification factors (CV risk, ezetimibe use, and 
geographical region); 
 PP population; overall and by stratification factors (CV risk, ezetimibe use, and 
geographical region); 
 Safety population; 
 Patients who complete the study; 
 Patients who terminated from the trial early and the primary reason for early 
termination.  
 Patients who terminated the trial early; prior to having a confirmed primary endpoint 
event. 
 Patients with complete follow-up, defined as those for whom all components of the 
primary endpoint have been ascertained during the entire observation period (or until 
death). 
 Patients who, at the time of study completion, were discontinued from study drug 
prematurely, but continued within the study (i.e. ODIS patients), along with the 
primary reason. 
 
Protocol Deviations 
4.6.2
All instances of protocol non-compliance will be tracked during the study and a list of 
protocol deviations will be reviewed in a blinded manner by the Sponsor prior to database 
lock.  Major deviations resulting in exclusion of the patient from the Per Protocol population 
will be determined. Protocol deviations will be presented in a data listing and summarized by 
type using counts and percentages by treatment group. 
 
Demographics and Baseline Characteristics 
4.6.3
Demographic and baseline characteristics, including age, gender, ethnicity, race, height, body 
weight, 
body 
mass 
index 
(BMI), 
diabetes, 
hypertension, 
metabolic 
syndrome, 
overweight/obese/normal according to BMI, and diabetes plus obesity will be summarized 
using descriptive statistics by treatment group in the ITT population. 
Demographic data and baseline characteristics will be also compared between treatment 
groups for the mITT population and PP population. Differences in demographic and baseline 
characteristics will be tested using a ch i-square for categorical variables and a t-test for 
continuous measures. The p-values will be considered descriptive, primarily as an assessment 
of the balance between groups. Age in years will be calculated using the date of 
randomization (Visit 2) and the date of birth.  
 
Cardiovascular Risk Category 
4.6.4
Factors determining the cardiovascular risk category (1 or 2) at randomization will be 
summarized by treatment group using counts and percentages for the ITT and Modified ITT 
populations.   


 
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Smoking and Alcohol History 
4.6.5
Smoking status (Never/Former/Current) and Alcohol use (Never/Former/Current) will be 
presented by treatment group using counts and percentages for the ITT and mITT populations.  
In addition, the average number of drinks per day for former and current alcohol users will be 
summarized with descriptive statistics.  The number and percentage of patients with a history 
of alcoholism, previous treatment for alcoholism, and number of years since treatment was 
completed will be presented. 
 
Cardiovascular History and Procedures, Family History, and Other Significant 
4.6.6
Medical History 
Counts and percentages of patients with each type of cardiovascular disease history will be 
presented by treatment group for the ITT and Modified ITT populations. 
Counts and percentages of patients with a history of cardiovascular procedures (percutaneous 
transluminal coronary angioplasty [PTCA]/stent, coronary artery bypass graft [CABG], 
Implantable Cardioverter/Defibrillator, Permanent Pacemaker, Carotid Revascularization and 
Aorto-iliac or Peripheral Arterial Intervention) will be presented by treatment group for the 
ITT population. For PTCA/Stent and CABG, whether the procedure was emergent and 
whether it was successful will be reported. For Carotid Revascularization and Aorto-iliac or 
Peripheral Arterial Intervention, whether it was performed with a catheter or surgically will be 
presented. 
The number and percentage of patients with a family history of premature coronary heart 
disease will be summarized by treatment group for the ITT and mITT populations. For 
patients with a family history, the number and percentage with a male first degree relative < 
55 years, female first degree relative < 65 years, or both male and female will be presented. 
Other significant medical history will be listed by patient. 
 
Study Medication Administration and Compliance 
4.6.7
Study drug exposure will be summarized by treatment group using descriptive statistics for 
each time point and overall. 
Overall study drug compliance will be calculated as the number of doses assumed to be taken 
relative to scheduled dosing period as follows: 
Compliance (%) = (# Capsules of total dispensed - # Capsules of total returned)  ×  100 
 
                       (last dose date – first dose date + 1) × 4 capsules/day 
Overall percent compliance will be calculated per patient in the ITT and mITT populations 
and summarized by treatment group using descriptive statistics. 


 
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Discontinuation of Study Drug 
4.6.8
A Kaplan-Meier analysis of the time to premature discontinuation of study drug will be 
presented by treatment arm.  A temporary discontinuation followed by re-starting study drug 
will not be considered a discontinuation in this analysis.  Event probabilities at 6-month 
intervals and the median time to event (if estimable) will be presented.  The log-rank test will 
be used to compare treatment groups.   
 
Early Termination from the Study 
4.6.9
A Kaplan-Meier analysis of the time to early termination will be presented by treatment arm.  
The date of termination for patients who do not complete the study due to any reason besides 
death will be used as the event date.  Patients who do not terminate early or who terminate 
due to death will be censored at the date of death or last contact.  Event probabilities at 
6-month intervals and the median time to event (if estimable) will be presented.  The log-rank 
test will be used to compare treatment groups.   
 
Medications of Special Interest 
4.6.10
At each scheduled visit (on site or by phone contact), information on changes in ezetimibe, 
statins, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers 
(ARBs)/beta blockers, and anti-diabetic drugs will be collected. For each medication type, the 
number and percentage of patients who started a new medication, discontinued a medication, 
increased the dose or decreased the dose of a medication will be presented by visit/phone 
contact. The overall number of patients with at least one of the above changes during the 
study will also be summarized by medication type. 
 
Prior and Concomitant Medications 
4.6.11
Non-study medications will be coded using the latest available version prior to database lock 
of the World Health Organization Drug Dictionary (WHO-DRUG) and the Anatomical 
Therapeutic Chemical (ATC) classification system. Coding includes the anatomical main 
group (ATC 1st Level), therapeutic class (ATC 3rd Level), and preferred term. All verbatim 
descriptions and coded terms will be listed for all non-study medications. 
Prior medications are defined as non-study medications with a stop date before the 
randomization date.  
Concomitant medications are defined as non-study medications with a stop date on or after 
the date of randomization. Medications that started prior to randomization but continued 
during study will also be defined as concomitant. Ongoing medications without stop dates are 
considered concomitant. 
Medications with partial onset/stop dates that indicate that the medication could be 
concomitant in relation to the date of randomization are classified as concomitant. Otherwise, 
they are classified as prior medications. 


 
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The numbers and percentages of patients in each treatment group taking concomitant 
medications will be summarized by ATC therapeutic class and preferred term. For each 
patient, multiple records of the same concomitant medication will be counted only once 
within each therapeutic class and preferred term. 
Listings will be provided for both prior and concomitant medications. 
4.7 
Efficacy Analyses 
 
Primary Efficacy Endpoint 
4.7.1
4.7.1.1  Primary Analysis 
The primary efficacy endpoint is the time from randomization to the first occurrence of any 
component of the composite of the following adjudicated clinical events: 
 CV death, 
 Nonfatal MI (including silent MI; ECGs will be performed annually for the detection 
of silent MIs), 
 Nonfatal stroke, 
 Coronary revascularization, 
 Unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization. 
All observed data that are positively adjudicated by the CEC, including data after 
discontinuation of study treatment for patients who discontinue study drug prematurely, will 
be included in the primary analysis.   
Suspected endpoint events are adjudicated by the CEC without knowledge of the treatment. 
Counts and Kaplan-Meier estimates of the percentage of patients experiencing each type of 
adjudicated event by study completion, along with overall counts for each type, will be 
presented by treatment arm. A separate table of the number of events that are ruled out by the 
CEC will also be displayed. 
The event time will be calculated as the (date of first event – date of randomization + 1 day) 
for patients who experience one or more of the primary endpoint events. The following 
provides detailed considerations for determining the date of event/date of censoring: 
 Patients who do not experience a primary efficacy event prior to the end of the study 
or withdrawal from the study early without a preceding primary efficacy event will be 
censored at the date of their last visit/phone contact. 
 Patients who die with an adjudicated undetermined cause of death and without a 
preceding endpoint event will be considered to have an adjudicated CV death and this 
will be included as an event in the primary analysis. 


 
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 In view of the 90-day monitoring period for CV events, patients who have a non-CV 
death within 90 days of last contact without having had an earlier CV event will be 
censored at the time of death. Patients who have a non-CV death more than 90 days 
after last contact without having had an earlier CV event will be censored at the date 
of their last visit/phone contact. 
 The primary analysis of silent MI will assume that all silent MIs occurred on the date 
of the first tracing indicative of a silent MI. 
Kaplan-Meier estimates will be used to summarize the time to the first event of the composite 
endpoint. Event probabilities at 6-month intervals and the median time to event (if estimable) 
will be presented. The log-rank test, stratified by stratification variables at randomization (CV 
risk category, use of ezetimibe, and geographical region [Westernized, Eastern European, and 
Asia Pacific countries]), will be used to compare the time-to-event between treatment groups. 
The two-sided alpha level for the primary analysis will be reduced from 0.05 to account for 
the interim analyses based on a  group sequential design with O’Brien-Fleming boundaries 
generated using the Lan-DeMets alpha-spending function. 
The hazard ratio (HR) comparing the two treatment groups along with a confidence interval 
(CI) adjusted for the interim analyses and p-value will be calculated from a s tratified Cox 
proportional hazards (PH) model with treatment as the only covariate, and stratified by CV 
risk category at baseline, use of ezetimibe at baseline, and geographical region (Westernized, 
Eastern European, and Asia Pacific countries). Kaplan-Meier curves stratified by each of the 
stratification variables will be presented. 
The primary efficacy analysis will be performed on t he ITT population. A corresponding 
sensitivity analysis will be performed using the mITT and PP populations. 
4.7.1.2 Other Sensitivity, Supportive, and Exploratory Analyses for the Primary 
Efficacy Endpoint 
As a sensitivity analysis, patients who discontinue study drug prematurely will be censored 
for the composite endpoint analysis on the date of drug discontinuation. The primary analysis 
will be repeated using this censoring rule for the mITT population. 
In the primary analysis, the date of first ECG indicative of a silent MI will be taken as the date 
for that silent MI. The following sensitivity analyses regarding this definition will be carried 
out both on the ITT and mITT populations: 
1. Date of silent MI = Date of last normal ECG + 1; and 
2. Date of silent MI = Mid-point between date of last normal ECG and date of first 
indicative ECG. 
In the primary analysis, deaths with undetermined cause and without a preceding primary 
endpoint event constituent will be regarded as CV deaths. A sensitivity analysis where 
patients are censored for these cases will be carried out both on the ITT and the mITT 
populations. 


 
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Since the primary efficacy endpoint is a composite of five cardiovascular events, recurrence 
of such events within each patient is possible. For this reason, a supportive analysis using a 
Cox proportional-hazard with the counting-process formulation of Andersen and Gill 
(Andersen and Gill, 1982) will be carried out to model the recurrent cardiovascular events. 
Since death is a terminating event, the modified Wei-Lin-Weissfeld (WLW) method (Wei, 
Lin, and Weissfeld, 1989) for analysis of recurrent events in presence of death proposed by Li 
and Lagakos (Li and Lagakos, 1997) will also be carried out as a supportive analysis. Both 
analyses will be carried out for the ITT and mITT populations. 
As an exploratory and supportive analysis, a stratified Cox proportional hazards model will be 
constructed for the primary endpoint to evaluate the treatment effect adjusting for important 
baseline covariates. Stratification variables will include CV risk category at baseline, use of 
ezetimibe at baseline, and geographical region (Westernized, Eastern European, and Asia 
Pacific countries). The model will include treatment and any of the following variables that 
are identified by a stepwise selection procedure: 
 Gender; 
 Age at baseline (<65 or ≥65 years); 
 Race (White and non-White); 
 Presence/absence of diabetes at baseline; 
 Baseline LDL-C (by tertile); 
 Baseline HDL-C (by tertile); 
 Baseline non-HDL-C (by tertile); 
 Baseline TG (by tertile); 
 Baseline hs-CRP (≤3 mg/L and >3 mg/L); 
 Baseline Apo B (by tertile); 
 Baseline RLP-C (by tertile); 
 Hopkins calculated LDL-C at baseline (by tertile); 
 Waist/height ratio at baseline; and 
 Waist circumference at baseline. 
The minimum p-value to enter will be 0.05 and selected variables with p < 0.10 will remain in 
the model. The hazard ratio (HR), 95% confidence interval (CI) and p-value comparing the 
two treatment groups, and the hazard ratio, 95% CI and p-value for each covariate in the final 
model will be presented. 
 
Components of Primary Endpoint 
4.7.2
The time to first occurrence of each of the five component events of the primary endpoint will 
be analyzed by the same methods described for the primary endpoint. Kaplan-Meier 


 
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estimates, the log-rank test stratified by stratification factors used at randomization, and the 
Cox proportional hazards model including the stratification factors as specified above for the 
primary efficacy endpoint, will be summarized by treatment group. Kaplan-Meier curves 
stratified by each stratification factor will be presented. These analyses will be conducted for 
the ITT, mITT and PP populations. 
Similarly, the rules for determining date of event/date of censoring for the primary efficacy 
endpoint (Section 4.7.1) will be applied to the components of primary endpoints. For the CV 
death endpoint, patients who do not die from CV causes will be censored at death from non-
CV causes or last visit/phone contact as described in Section 4.7.1.1. For all other events 
(nonfatal MI [including silent MI], nonfatal stroke, coronary revascularization, and 
hospitalization for unstable angina determined to be caused by myocardial ischemia by 
invasive/non-invasive testing), patients who do not experience the event will be censored at 
death or last visit/phone contact, consistent with that described in Section 4.7.1.1.  
In addition, a recurrent event analysis using Andersen-Gill and Li-Lagakos methods will be 
carried out for the individual primary event constituents other than CV death. 
 
Analysis of Secondary Efficacy Endpoints 
4.7.3
The key secondary hypothesis will be tested as part of the confirmatory process only if the 
primary analysis is statistically significant. For the analysis of secondary efficacy endpoints, 
the Type 1 error will be controlled by testing each endpoint sequentially, starting with the key 
endpoint. Testing will be done at a significance level consistent with that used for the primary 
endpoint and will cease when a secondary endpoint is found for which treatments do not  
significantly differ. P-values will be presented for all analyses, but they will be considered 
descriptive after the first non-significant result is obtained. 
Each of the secondary endpoints will be analyzed by the same methods described for the 
primary efficacy endpoint. Kaplan-Meier estimates, the log-rank test stratified by 
stratification factors used at randomization, and the Cox proportional hazards model including 
the stratification factors as specified above for the primary efficacy endpoint, will be 
summarized by treatment group. Kaplan-Meier curves stratified by each stratification factor 
will be presented. Similarly, the rules for determining date of event/date of censoring for the 
primary efficacy endpoint (Section 4.7.1) will be applied to the secondary endpoints. These 
analyses will be conducted for the ITT population.  
4.7.3.1 Key Secondary Efficacy Endpoint 
If the primary analysis is statistically significant, then the key secondary efficacy endpoint, 
which is the time from randomization to the first occurrence of the composite of CV death, 
nonfatal MI (including silent MI), or nonfatal stroke will be tested first. 


 
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4.7.3.2 Other Secondary Efficacy Endpoints 
Other secondary efficacy endpoints are the time from randomization to the first occurrence of 
each of the events described below.  If the primary and key secondary endpoints are 
statistically significant, the remaining secondary endpoints will be tested in the following 
order: 
 Composite of CV death or nonfatal MI (including silent MI); 
 Fatal or nonfatal MI (including silent MI); 
 Non-elective coronary revascularization represented as the composite of emergent or 
urgent classifications; 
 CV death; 
 Unstable angina determined to be caused by myocardial ischemia by invasive/non-
invasive testing and requiring emergent hospitalization; 
 Fatal or nonfatal stroke; 
 Composite of total mortality, nonfatal MI (including silent MI), or nonfatal stroke;  
 Total mortality. 
 
Analysis of Tertiary Endpoints 
4.7.4
All tertiary analyses will be conducted for the ITT population. No multiple testing 
adjustments will be made. Time-to-event tertiary endpoints will be analyzed by the same 
methods as described for the primary efficacy endpoint. Kaplan-Meier estimates, the log-rank 
test stratified by stratification factors used at randomization, and the Cox proportional hazards 
model as specified for the primary efficacy endpoint, will be summarized by treatment group. 
Kaplan-Meier curves stratified by each of the stratification factors will be presented. 
Similarly, the rules for determining date of event/date of censoring for the primary efficacy 
endpoint (Section 4.7.1) will be applied to the tertiary endpoints. The following are the 
tertiary time-to-event endpoints: 
 Total CV events analysis defined as the time from randomization to occurrence of the 
first and all recurrent major CV events defined as CV death, nonfatal MI (including 
silent MI), nonfatal stroke, coronary revascularization, or unstable angina determined 
to be caused by myocardial ischemia by invasive/non-invasive testing and requiring 
emergent hospitalization; 
 Primary composite endpoint in subset of patients with diabetes mellitus at baseline; 
 Primary composite endpoint in the subset of patients with metabolic syndrome at 
baseline as defined in A Joint Interim Statement of the International Diabetes 
Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and 
Blood Institute; American Heart Association; World Heart Federation; International 
Atherosclerosis Society; and International Association for the Study of Obesity (Alberti 


 
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2009); with cut points of parameters as defined in Table 1 of Alberti et al. and waist 
circumference cut points further guided by Table 2 of Alberti et al. and specifically set 
at ≥35 inches (88 cm) for all women and Asian, Hispanic, or Latino men, and ≥40 
inches (102 cm) for all other men (see Appendix C in Section 6.3); 
 Primary composite endpoint in the subset of patients with impaired glucose metabolism 
at baseline (Visit 2 FBG of 100-125 mg/dL); 
 Key secondary composite endpoint in the subset of patients with impaired glucose 
metabolism at baseline (Visit 2 FBG 100-125 mg/dL); 
 Composite of CV death, nonfatal MI (including silent MI), nonfatal stroke, cardiac 
arrhythmia requiring hospitalization of ≥24 hours, or cardiac arrest; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), or unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization, nonfatal stroke, or PVD requiring intervention, such 
as angioplasty, bypass surgery, or aneurism repair; 
 Composite of CV death, nonfatal MI (including silent MI), non-elective coronary 
revascularizations (defined as emergent or urgent classifications), unstable angina 
determined to be caused by myocardial ischemia by invasive/non-invasive testing and 
requiring emergent hospitalization, PVD requiring intervention, or cardiac arrhythmia 
requiring hospitalization of ≥24 hours; 
 New CHF; 
 New CHF as the primary cause of hospitalization; 
 Transient ischemic attack (TIA); 
 Amputation for PVD; 
 Carotid revascularization; 
 All coronary revascularizations defined as the composite of emergent, urgent, elective, 
or salvage; 
 Emergent coronary revascularizations; 
 Urgent coronary revascularizations; 
 Elective coronary revascularizations; 
 Salvage coronary revascularizations; 
 Cardiac arrhythmias requiring hospitalization of ≥24 hours; 


 
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 Cardiac arrest; 
 Ischemic stroke; 
 Hemorrhagic stroke; 
 Fatal or nonfatal stroke in the subset of patients with a history of stroke prior to 
baseline; 
 New onset diabetes, defined as Type 2 di abetes newly diagnosed during the 
treatment/follow-up period;  
 New onset hypertension, defined as blood pressure ≥140 mmHg systolic OR 
≥90 mmHg diastolic newly diagnosed during the treatment/follow-up period; 
 Fasting TG, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apo B, hs-CRP (hsCRP and 
log[hsCRP]), hsTnT, and RLP-C (to be estimated from standard lipid panel, RLP-C = 
TC – HDL-C – LDL-C [Varbo 2014]) (based on ITT estimands):  
o 
Assessment of the relationship between baseline biomarker values and 
treatment effects within the primary and key secondary composite endpoints, 
o 
Assessment of the relationship between post-baseline biomarker values and 
treatment effects within the primary and key secondary composite endpoints by 
including post-baseline biomarker values (for example, at 4 m onths, or at 1 
year) as a covariate. 
Continuous tertiary endpoints include: 
 Change from baseline and percent change from baseline in fasting TG, TC, LDL-C, 
HDL-C, non-HDL-C, VLDL-C, apo B, hs-CRP (hsCRP and log[hsCRP]), hsTnT, and 
RLP-C (to be estimated from standard lipid panel, RLP-C = TC – HDL-C – LDL-C 
[Varbo 2014]) (based on ITT estimands); 
 Change in body weight; 
 Change in waist circumference. 
The fasting lipid panel is tested at Screening (Visit 1 or Visit 1.1), Randomization visit (Visit 
2; Day 0), Visit 3 (Day 120; ~4 Months) and all other follow-up visits including the last visit. 
For change from baseline to 1-year Preparative Ultracentrifugation measurements for LDL-C 
will be analysed, unless this value is missing. As described in Section 4.3.3, if the LDL-C 
Preparative Ultracentrifugation values is missing, then another LDL-C value will be used, 
with prioritization of values obtained from LDL-C Direct measurements, followed by LDL-C 
derived by the Friedewald calculation (only for subjects with TG <400 mg/dL), and finally 
LDL-C derived using the calculation published by Hopkins University investigators (Martin 
2013). In addition, change from baseline to day 120 i n LDL-C utilizing Friedewald’s and 
Hopkins methods will be analysed, using the arithmetic mean of LDL-C obtained at Visit 2 
(Day 0) and the preceding Visit 1 (or Visit 1.1). If one of these values is missing, the single 
available LDL-C value will be used. LDL-C according to Hopkins will be calculated at each 
visit. 


 
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The randomization visit will be considered Baseline. If a baseline value is not available from 
the randomization visit, then the latest screening value will be used. 
For measurements of lipids, lipoproteins, and inflammatory markers, the change from 
baseline and the percent change will be summarized at each visit. Since these parameters are 
typically not normally distributed, the Wilcoxon rank-sum test will be used for treatment 
comparisons of the percent change from baseline, and medians and quartiles will be provided 
for each treatment group. The medians of the differences between the treatment groups and 
95% CIs will be estimated with the Hodges-Lehman method. In addition, shift–tables may be 
generated as appropriate. 
As an additional exploratory analysis, the relationship between post-baseline biomarker 
values and treatment effects with the primary and key secondary composite endpoints will be 
assessed by adding biomarker values (for example, at 4 month, or at 1 year, etc.) as time-
dependent covariates in the Cox proportional hazards model. Diagnostic plots for the 
proportional hazards assumption will be evaluated. 
Weight is measured at the screening visit and at all follow-up visits, including the last visit of 
the study. Waist circumference will be measured at the randomization visit (Visit 2; Day 0), 
Visit 5 (Day 720) and the last visit of the study. Descriptive statistics will be presented by 
visit and treatment group for baseline, post-treatment change from baseline, and the percent 
change from baseline. Analysis methods for repeated measurements will be used to compare 
percent change from baseline between treatments. 
 
Exploratory Analysis of Subgroups 
4.7.5
Analyses of the effects of patients off study drug and withdrawn from study have on primary 
endpoint will be performed. 
Subgroup analyses of the primary and key secondary endpoints will be performed as 
described for the primary endpoint. For each subgroup, Kaplan-Meier estimates, the log-rank 
test stratified by stratification factors used at randomization (except where the subgroup is a 
stratification factor), and HRs and CIs from the Cox proportional hazards model as specified 
for the primary efficacy endpoint, will be summarized by treatment group. 
The following subgroups will be explored: 
Demographic Parameters: 
 gender; 
 age (<65 years and ≥65 years); 
 race (white and non-white, or any other subset with at least 10% of the total number of 
patients);  
 geography (Westernized, Eastern European, and Asia Pacific countries); and 


 
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 baseline ezetimibe use (yes/no). 
Disease Parameters: 
 CV risk category; 
 the presence/absence of diabetes at baseline; and 
 renal dysfunction (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73m2) 
using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 
as follows: 
eGFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 
1.159 [if black] 
Where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
Treatment Parameters: 
 statin intensity at baseline (statin type and regimen)  
Statin intensity categories as defined in ACC/AHA Cholesterol Guidelines (Stone 2013) 
and patient’s 10-year CV Risk Score (Goff 2013) will be considered. 
Baseline Lipid and Lipoprotein Parameters: 
 LDL-C (by tertile); 
 HDL-C (by tertile, and tertile by gender); 
 TG (by tertile, and tertile by gender);  
 RLP-C (by tertile); 
 TG ≥150 mg/dL and TG <150 mg/dL; 
 TG ≥200 mg/dL and TG <200 mg/dL; 
 TG ≥ median, TG < median; 
 combined highest tertile for TG and lowest tertile for HDL-C; 
 gender-specific highest tertile for TG and lowest tertile for HDL-C; 


 
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 TG ≥ 200 mg/dL with HDL-C ≤35 mg/dL; 
 hs-CRP (≤3 mg/L and >3 mg/L) and by gender; 
 hs-CRP (≤2 mg/L and >2 mg/L) and by gender; 
 Apo B (by tertile); and 
 non-HDL-C (by tertile). 
Adjustment for Baseline TG Level: Following a protocol amendment, dated May 2013, only 
patients with qualifying TG ≥200 mg/dL were enrolled in the study. Prior to this, patients with 
qualifying TG levels as low as approximately 135 mg/dL were enrolled. In order to account 
and adjust for the fact the follow-up times may be different depending on the baseline TG 
level, a Cox PH model as mentioned above but additionally with baseline TG as a covariate 
will be fitted to the data at each interim. Diagnostic plots for the PH assumption will be 
evaluated. 
The consistency of the treatment effects in subgroups will be assessed for the primary and key 
secondary efficacy endpoints. For each subgroup variable, a Cox proportional hazards model 
with terms for treatment, stratification factors (with the exception of those subgroup variables 
related to the stratification factors, i.e., CV risk category), subgroup, and treatment-by-
subgroup interaction will be performed. The main treatment effect will not be tested with this 
model. P-values for testing the interaction terms <0.15 will be considered significant. Results 
will be presented in a Forest plot. 
All subgroup analyses will be conducted for the ITT, mITT and PP populations. 
4.8 
Safety Analyses 
All safety analysis summaries will be tabulated by treatment received (if different from 
randomized treatment assignment) and based on the Safety Analysis population. The baseline 
values for all safety variables are from assessments obtained on Day 0 (the randomization 
visit). If the value on Day 0 is not available, the nearest prior assessment at Screening will be 
used as baseline value. No formal statistical comparisons of treatment groups will be made for 
safety data. 
A list of potential biomarker assays (genetic and non-genetic) to be analysed is included in 
Appendix B. 
 
Adverse Events 
4.8.1
AEs are recorded from the time the informed consent is signed until study participation is 
complete. Adverse events with onset on or after the date of dispensing study drug for each 
patient will be considered treatment-emergent (TEAEs). This will include any AE with onset 
prior to initiation of study drug and increased severity after the treatment initiation. 


 
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By design of this study, serious AEs (SAEs) that are endpoint events will only be recorded for 
the endpoint determination and not captured as SAEs. Following adjudication, if the event is 
determined to not meet the criteria for an event, the event will be evaluated as an SAE. 
Adverse events will be coded using the most recent available Medical Dictionary for 
Regulatory Activities (MedDRA) Version. Coding includes system organ class (SOC) and 
preferred term (PT). All AEs will be listed by patient and by SOC and PT; these listings will 
present detailed information concerning adverse events, including the verbatim description, 
time of onset and resolution, severity, relationship to study drug, action taken, and outcome.  
Pre-treatment AEs: 
Pre-treatment-emergent AEs will be defined as any AE that started before the patient’s 
randomization. (An AE that was ongoing at the time of randomization and subsequently 
increased in severity is also considered treatment-emergent.) Pre-treatment AEs will be listed 
separately from TEAEs. 
Treatment-emergent AEs: 
For each patient, the following AEs will be defined as TEAEs: 
 AEs occurring after randomization; 
 AEs occurring within 30 days after the completion or withdrawal from study; 
 AEs started prior to randomization but worsened in severity following randomization; 
 AEs with partial onset dates if the AE stop date is after randomization and the dates do 
not definitively place the AE start date before randomization; and 
 AEs with completely missing onset dates. 
The frequency and percentage of patients with any TEAEs will be summarized. TEAEs will 
be presented by SOC and PT. At each summary level, a patient will be counted only once for 
each TEAE he/she experiences within that level, regardless of how many occurrences of that 
TEAE that patient experienced. The percentage of patients having had at least one TEAE at 
each level will be calculated. 
An overall summary of patients with at least one TEAE, severe TEAE, related TEAE, SAE, 
related SAE, TEAE leading to discontinuation of study drug, adjudicated as a clinical event, 
and leading to death will be presented by treatment group. Tabular summaries by SOC and 
preferred term will include all AEs, severe TEAEs, related TEAEs, serious TEAEs (SAEs), 
related SAEs, TEAEs leading to permanent study drug discontinuation, TEAEs that were 
adjudicated as events, and TEAEs leading to death. 
For the purpose of analysis, TEAEs with a reported relatedness of related, probably related, or 
possibly related will be characterized as “Related”. AEs assessed as “Not Related” will be 
classified as not related to study drug. In instances where a patient may have had multiple 
TEAEs with differing levels of severity or relatedness, the most severe or most related event, 


 
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respectively, will be reported for the severity and relatedness tables. For the purpose of 
analysis, missing AE relationship will be presented as ‘related’ in tables and missing in 
listings. In addition, tables that describe the collected data and that include a ‘missing’ 
relationship category where appropriate will be presented. Missing AE severity will be 
presented in a ‘missing’ category in tables and as missing in listings. 
Pre-randomization AEs and TEAEs will be listed separately. In addition, listings will be 
provided of SAEs and AEs meeting criteria for adjudication (including whether the event was 
adjudicated as an endpoint or ruled out). Deaths will be presented in a listing that includes the 
AE leading to death, demographic data, details of study treatment, and relationship of the AE 
leading to death to the study drug. 
 Clinical Laboratory Evaluation 
4.8.2
Samples for the clinical laboratory procedures will be collected after fasting for at least 10 
hours. For the purposes of this study, fasting is defined as nothing by mouth except water (and 
any essential medications). 
The safety parameters are analyzed by a certified clinical laboratory at screening (Visit 1 or 
Visit 1.1), Randomization visit (Visit 2; Day 0), Visit 3 (Day 120; ~4 Months) and all other 
follow-up visits including the last visit: 
 Hematology with complete blood count (CBC), including red blood cell (RBC) count, 
hemoglobin (Hgb), hematocrit (Hct), white blood cell (WBC) count, white cell 
differentials (Neutrophils, Lymphocytes, Monocytes, Eosinophils and Basophils), and 
platelet count; and 
 Biochemistry panel including total protein, albumin, alkaline phosphatase, alanine 
aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), total 
bilirubin, glucose, calcium, electrolytes (sodium, potassium, chloride), blood urea 
nitrogen (BUN), serum creatinine, uric acid, creatine kinase, and HbA1c. 
Clinical laboratory parameters will be summarized using descriptive statistics. Mean and 
mean change from baseline values will be presented at each study visit.  C hange from 
baseline will be calculated as post-baseline measurement minus baseline measurement.  If 
either the baseline or post-baseline value is missing, the observation will not be included in 
the change from baseline summary. 
Each laboratory result will be classified as low (L), normal (N), and high (H) at each visit 
according to the laboratory-supplied normal range. The shift from baseline will be presented 
for each post-baseline visit and overall post-baseline visits.  If multiple measurements for a 
test parameter are available for a post-baseline patient-visit, the most extreme value will be 
included in the shift table. For shift from baseline to overall post-baseline visits, values from 
all visits (including unscheduled measurements) will be included. The chemistry shift table 
will include fasting lipid parameters.  (The continuous lipid values are presented as part of the 
efficacy analysis.) 


 
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All laboratory results will be listed by patient, parameter, and time point. 
 
Adverse Events of Special Interest 
4.8.3
Bleeding-related adverse events, glucose control (fasting blood glucose and HbA1c), and 
indicators of hepatic disorders (e.g., ALT or AST increases >3 × ULN, total bilirubin 
increases of ≥2 × ULN) will be summarized separately and compared between treatment 
groups. 
 
Vital Signs and Patient Measurements 
4.8.4
Vital signs include systolic and diastolic blood pressures (mmHg), heart rate, respiration rate, 
and body temperature. Blood pressure should be measured for all patients at screening (Visit 
1/ Visit 1.1), Randomization visit (Visit 2; Day 0) and all other follow-up visits including the 
last visit (end of the study. The end of the study will be at the time of the last patient’s last 
visit of the follow-up period of the study). 
Height is measured only at the screening visit (Visit 1). Vital signs (respiration, heart rate, 
temperature, systolic and diastolic blood pressure), height, and BMI by gender will be 
summarized descriptively at each scheduled visit. Mean and mean change from baseline 
values will be presented in a similar manner as for laboratory variables. Change from baseline 
will be calculated as post-baseline measurement minus baseline measurement. If either the 
baseline or post-baseline value is missing, the observation will not be included in the change 
from baseline summary.  If there is more than one valid measurement for a selected visit after 
the baseline visit, the average of the values collected will be used.  
All vital signs, height, and BMI, will be listed by patient, parameter, and time point. 
 
12-Lead ECG 
4.8.5
Twelve-lead ECG parameters including Heart Rate (bpm), PR Interval (msec), QRS Interval 
(msec), QT Interval (msec), and QTc Interval (msec) are measured, and Overall Interpretation 
and Silent MI (Yes/No) are summarized for all patients at Screening (Visit 1), Randomization 
visit (Visit 2; Day 0) and all other follow-up visits including the last visit of the study. 
ECG parameters will be summarized using descriptive statistics. Mean and mean change from 
baseline values will be presented for every scheduled assessment. Change from baseline will 
be calculated as the post-baseline measurement minus the baseline measurement. If either the 
baseline or post-baseline value is missing, the observation will not be included in the change 
from baseline summary. In addition, counts and percentages for ECG overall interpretation 
(normal, abnormal, clinically significant and not clinically significant) and whether MI was 
present will be presented for each scheduled assessment.  
ECG results will be listed by patient, parameter and time point. 


 
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Physical Examination 
4.8.6
The physical examination includes assessment of general appearance, skin, and specific head 
and neck, heart, lung, abdomen, extremities, and neuromuscular systems. A physical 
examination is performed at Randomization Visit (Visit 2; Day 0) and all other follow-up 
visits including the last visit of the study.  
The results (normal, abnormal, or not done) by body system of the full physical examination 
at the Randomization visit (Visit 2; Day 0) and follow-up visits will be summarized with 
descriptive statistics by treatment group and visit. For physical examinations performed at 
post-randomization time points, the number and percent of patients with no change or any 
significant changes since the previous examination will be presented by treatment received. In 
addition, a shift table will be included to summarize the number and percent of patients with 
changes from Day 0 to each post-randomization visit by body system for each treatment 
group. The number and percent of patients with normal and abnormal results (clinically 
significant vs. not clinically significant) for each body system will be presented by treatment 
group. 
All physical examinations will be presented in a data listing. 
 
Childbearing Potential and Pregnancy Tests 
4.8.7
A urine pregnancy test will be administered to women of childbearing potential at the 
screening and randomization visits. The urine pregnancy tests will be performed at the 
Research Site utilizing marketed test kits, or at a certified clinical laboratory. Childbearing 
potential and urine pregnancy test results will be included in a data listing. 


 
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REFERENCES 
5.
Alberti K, et. al. Harmonizing the Metabolic Syndrome: A Joint Interim Statement of the 
International Diabetes Federation Task Force on Epidemiology and Prevention; 
National Heart, Lung, and Blood Institute; American Heart Association; World Heart 
Federation; International Atherosclerosis Society; and International Association for 
the Study of Obesity. Circulation. 2009;120:1640-1645. 
Andersen PK and Gill RD. Cox's Regression Model for Counting Processes: A Large Sample 
Study. Ann. Statist. 1982;10 (4):1100-1120. 
DeMets D L, Lan KK. Interim Analysis: the Alpha Spending Function Approach. Stat Med 
1994;13 (13-14): 1341–52. 
Goff DC, Lloyd-Jones DM, Bennett G, et al. ACC/AHA Prevention Guideline: 2013 
ACC/AHA Guideline on the Assessment of Cardiovascular Risk: A Report of the 
American College of Cardiology/American Heart Association Task Force on Practice 
Guidelines. Circulation. 2014;129:S74–S75. 
Li, QH and Lagakos SW. Use of the Wei–Lin–Weissfeld Method for the Analysis of a 
Recurring and a Terminating Event. Statistics in Medicine 1997;16, 925–940. 
Martin SS, Blaha MJ, Elhazly MB, et al. Comparison of a novel method vs the Friedewald 
equation for estimating low-density lipoprotein cholesterol levels from the standard 
lipid profile. JAMA. 2013;310:2061–2068.  
Stone NJ, Robinson J, Lichtenstein AH, et al. ACC/AHA Prevention Guideline: 2013 
ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce 
Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines. 
Circulation. 2014;129:S46–S48. 
Varbo A, Benn M, Tybjærg-Hansen A, Nordestgaard BG.  Reply to letters regarding article, 
"Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart 
disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart 
disease without inflammation".  Circulation. 2014;129:e656. 
Wei LJ, Lin DY, and Weissfeld L. Regression analysis of multivariate incomplete failure time 
data by modeling marginal distributions. Journal of the American Statistical 
Association.  1989;84:1065–1073. 
Whitehead, J. Overrunning and underrunning in sequential clinical trials. Control Clin Trials. 
1992;13, 2:106-21. 


 
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APPENDICES 
6.
6.1 
Appendix A: Interim Statistical Analysis Plan (iSAP) 
 


 
INTERIM STATISTICAL ANALYSIS PLAN (iSAP) 
A Multi-Center, Prospective, Randomized, Double-Blind, 
Placebo-Controlled, Parallel-Group Study to Evaluate the Effect of AMR101 
on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients 
with Cardiovascular Disease or at High Risk for Cardiovascular Disease: 
REDUCE-IT (Reduction of Cardiovascular Events with EPA – Intervention Trial) 
 
 
Investigational Product: AMR101 (icosapent ethyl [ethyl-EPA]) 
Protocol Number: AMR-01-01-0019 
 
 
Sponsor: 
Amarin Pharma Inc. 
1430 Route 206 
Bedminster, New Jersey 07921, USA 
Telephone: +1-908-719-1315 
Facsimile: +1-908-719-3012 
 
Final: 8 July 2016 
Version Number: Final v 1.0 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the 
written consent of Amarin Pharma Inc., except to the extent that disclosure would be 
required by law and for the purpose of evaluating and/or conducting a clinical trial for 
Amarin Pharma Inc. You are allowed to disclose the contents of this document only to 
your Institutional Review Board or Independent Ethics Committee and study personnel 
directly involved with conducting this study. Persons to whom the information is 
disclosed must be informed that the information is confidential and proprietary to Amarin 
Pharma Inc. and that it may not be further disclosed to third parties. 
 
 


 
 
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Page 2 of 24 
SIGNATURE PAGE 
TRIAL TITLE: A Multi-Center, Prospective, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group Study to Evaluate the Effect of AMR101 on Cardiovascular 
Health and Mortality in Hypertriglyceridemic Patients with Cardiovascular Disease or at 
High Risk for Cardiovascular Disease: REDUCE-IT (Reduction of Cardiovascular 
Events with EPA – Intervention Trial) 
 
We, the undersigned, have reviewed and approved this Interim Statistical Analysis Plan 
for protocol AMR-01-01-0019. 
 
Signature 
Date 
 
 
[Name / signature redacted]                    
[Signed (8 July 2016)] 
Biostatistician, Data Management Service 
Cytel, Inc. 
 
 
[Name / signature redacted]                    
[Signed (8 July 2016)] 
President, Executive Management 
Cytel, Inc. 
 
 
[Name / signature redacted]                    
[Signed (11 July 2016)] 
Senior Director, Biostatistics and Data Management 
Amarin Pharma Inc. 
 
 
[Name / signature redacted]                    
[Signed (15 July 2016)] 
President of R&D and Chief Scientific Officer, SVP 
Amarin Pharma Inc. 
 
 
[Name / signature redacted]                    
[Signed (19 July 2016)] 
Principal Investigator 


 
 
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Page 3 of 24 
TABLE OF CONTENTS 
1 
Introduction ................................................................................................................. 6 
2 
Trial Design ................................................................................................................ 7 
2.1 
Group Sequential Design Details ......................................................................... 7 
3 
Analysis Population .................................................................................................... 9 
4 
Interim Data Analysis Plan at the 60% and 80% Milestones ................................... 10 
4.1 
Safety Analysis ................................................................................................... 10 
4.2 
Efficacy Analysis ............................................................................................... 10 
4.2.1 
Formal Test for the Primary Efficacy Endpoint ......................................... 10 
4.2.2 
Supportive Analyses for Primary Efficacy Analysis .................................. 12 
4.2.2.1 
Estimation of Hazard Ratio ................................................................. 12 
4.2.2.2 
Adjustment for Baseline Triglyceride (TG) Level .............................. 12 
4.2.2.3 
Adjustments for Unadjudicated Events ............................................... 12 
4.2.3 
Hazard Ratio for Composite “Hard” MACE and Individual Components of 
the Composite Primary Endpoint ................................................................ 13 
4.2.4 
Analysis within Subgroups Defined by Stratification Factors .................... 13 
4.2.5 
Progress in the Control Group .................................................................... 13 
4.3 
Lipid and Lipoprotein Parameters ...................................................................... 14 
5 
The Use of Conditional and Predictive Power .......................................................... 16 
6 
Decisions following the Interim Analyses ................................................................ 18 
6.1 
Decision Tree ..................................................................................................... 18 
7 
Statistical Inference Following an Stop Early at an Interim analysis ....................... 20 
8 
References ................................................................................................................. 21 
9 
Appendix ................................................................................................................... 23 
9.1 
Predictive Probability Calculation ..................................................................... 23 
9.2 
Simulations to calculate 𝑪𝑪 and 𝑷𝑷 .................................................................. 23 
 


 
 
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LIST OF TABLES AND FIGURES 
Table 1: Group Sequential Boundaries according to planned interim analyses, power = 
0.897.................................................................................................................................... 8 
Table 2: Group Sequential Boundaries according to minor deviation from planned interim 
analyses - example 1, power = 0.898 .................................................................................. 8 
Table 3: Group Sequential Boundaries according to minor deviation from planned interim 
analyses - example 2, power = 0.897 .................................................................................. 8 
 
Figure 1: Flow Chart to Guide Interim Decision-Making ................................................ 19 


 
 
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Page 5 of 24 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
 
Adverse event 
CEC 
 
Clinical Endpoint Committee 
CP 
 
Conditional power 
CV 
 
Cardiovascular 
CVD  
Cardiovascular disease 
DMC  
Data Monitoring Committee 
GSD  
Group-sequential design 
HR 
 
Hazard ratios 
IA 
 
Interim analyses 
iSAP  
interim Statistical Analysis Plan 
ITT 
 
Intent-to-Treat 
K-M 
 
Kaplan-Meier 
LDL-C 
Low density lipoprotein cholesterol-C 
MACE  
Major adverse cardiovascular events 
MI 
 
Myocardial infarction 
PH 
 
Proportional hazards 
PP 
 
Predictive power 
SAP 
 
Statistical Analysis Plan 
TG 
 
Triglycerides 


 
 
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1 
INTRODUCTION 
This interim Statistical Analysis Plan (iSAP) has been developed based on the Protocol 
AMR-01-01-0019 (Amendment #2 Final Version 3.0 da ted: 8 July 2016 and the 
Statistical Analysis Plan (SAP), Final Version 1.0 dated: 8 July 2016). This iSAP 
describes analysis methods to be used by the independent Data Monitoring Committee 
(DMC) and the independent statistical team for carrying out unblinded efficacy and 
safety analysis at the two planned interim analyses (IA) during a group sequential trial. 
Unblinded data will only be available to the DMC and the independent statistical team 
supporting the interim analyses. Unblinded information will not be released to the 
Sponsor before the completion of the study unless extraordinary circumstances arise and, 
under such circumstances, procedures for maintaining confidentiality will be described in 
a written agreement with the DMC.  The analyses described in this iSAP are only to be 
used for interim decision making for early stop or continuation of the trial to the planned 
completion and not to be used for supporting efficacy and safety claims. A separate SAP 
has been developed that describes the final analysis that would support such claims. 
Clinical trial REDUCE-IT (protocol AMR-01-01-0019) is a multi-center, prospective, 
randomized, double-blind, placebo-controlled, parallel-group study to evaluate the effect 
of AMR101 (icosapent ethyl [ethyl-EPA], 4 g/day) vs. control in patients at low density 
lipoprotein-cholesterol (LDL-C) goal while on statin therapy with established 
cardiovascular disease (CVD) or at high risk for CVD. The primary efficacy endpoint 
will be evaluated in terms of the time from randomization to first occurrence of the 
composite major cardiovascular (CV) event that includes: 
1. CV death; 
2. Nonfatal myocardial infarction (MI), including silent MI; 
3. Nonfatal stroke; 
4. Coronary revascularization; or 
5. Unstable angina determined to be caused by myocardial ischemia by 
invasive/non-invasive testing and requiring emergent hospitalization. 
In this document, components 1-3 above are referred to as “hard” major adverse 
cardiovascular events (MACE) components while components 4 and 5 are referred to as 
“other” MACE components 
This is an event driven trial, i.e. targeting a fixed number of major CV events listed above 
and follows a group sequential design (GSD) with two planned interim analyses at 
approximately 60% and 80% of the targeted major CV events. 


 
 
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Page 7 of 24 
2 
TRIAL DESIGN 
This is an event driven trial comparing the effect of AMR101 vs. control, in terms of the 
composite endpoint listed above as the primary efficacy endpoint. The study has been 
planned to accrue a total of 1612 e fficacy endpoint events with two planned interim 
analyses when approximately 967 (60%) and 1290 (80%) of the events have occurred and 
been adjudicated. The study includes patients with established CVD (CV Risk Category-
1) and patient ≥ 50 years old with diabetes and at least one additional risk factor for CVD 
but with CVD not established (CV Risk Category-2). 
Sample size calculation was based on assumptions of constant hazard, asymmetric 
recruitment rate over time and without factoring for dropouts. A risk reduction 
corresponding to a hazard ratio (HR) of 0.85 (AMR101 vs. control) is assumed. 1612 
events would be required to detect this HR with approximately 90% power with one-
sided alpha-level at 2.5% and with two interim analyses. 
The recruitment period is assumed to be approximately 4.2 years with 20% recruitment in 
the first year, 40% in the second year, 20% in the third year, 19% in the fourth year and 
the remaining 1% in the last 0.2 years. The expected maximum study duration is 
estimated at 6.5 years unless the trial is terminated early for efficacy or safety issues. A 
one-year event rate of 5.2% (hazard = 0.053) in the control arm is also assumed. Under 
these assumptions the number of patients to be enrolled is N=7990. 
2.1 
Group Sequential Design Details 
The planned interim analyses are based on a GSD with O’Brien-Fleming boundaries 
generated using the Lan-DeMets (DeMets 1994) alpha-spending function. The use of the 
spending-function allows for possible deviations from the planned event number at the 
time of the IA. If the interim analyses are carried out exactly at the planned 60% and 80% 
milestones, then the resulting one-sided alpha-levels and boundaries based on a Z-test 
and corresponding HR for each of the two interim analyses and the final analysis are 
given in Table 1. In case of a deviation, as an example, if the first interim is carried out 
after 58% of the events and the second at 80% then the one-sided alpha-levels will be 
0.0032 and 0.009 respectively with corresponding upper bounds on HRs being 0.837 and 
0.881 respectively. For reference, Table 2 and Table 3 provide examples of possible 
deviation, if the planned 60% interim (Table 1) occurs at 50% (Table 2) or 55% (Table 3) 
of primary events with completed adjudication. 


 
 
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Table 1: Group Sequential Boundaries according to planned interim analyses, 
power = 0.897 
Look 
Information 
Fraction 
No. of 
Events 
Cumulative 
Alpha 
(1-sided) 
Spent 
Efficacy 
Boundary 
(Z-score) 
Efficacy 
Boundary 
(HR) 
Efficacy 
Boundary 
(1-sided 
P-value) 
1 
0.60 
967 
0.0038 
-2.669 
0.842 
0.0038 
2 
0.80 
1290 
0.0122 
-2.289 
0.880 
0.0110 
3 
1.00 
1612 
0.0250 
-2.031 
0.904 
0.0211 
Table 2: Group Sequential Boundaries according to minor deviation from planned 
interim analyses - example 1, power = 0.898 
Look 
Information 
Fraction 
No. of 
Events 
Cumulative 
Alpha 
(1-sided) 
Spent 
Efficacy 
Boundary 
(Z-score) 
Efficacy 
Boundary 
(HR) 
Efficacy 
Boundary 
(1-sided 
P-value) 
1 
0.50 
806 
0.0015 
-2.963 
0.812 
0.0015 
2 
0.80 
1290 
0.0122 
-2.266 
0.881 
0.0117 
3 
1.00 
1612 
0.0250 
-2.028 
0.904 
0.0213 
Table 3: Group Sequential Boundaries according to minor deviation from planned 
interim analyses - example 2, power = 0.897 
Look 
Information 
Fraction 
No. of 
Events 
Cumulative 
Alpha 
(1-sided) 
Spent 
Efficacy 
Boundary 
(Z-score) 
Efficacy 
Boundary 
(HR) 
Efficacy 
Boundary 
(1-sided 
P-value) 
1 
0.55 
887 
0.0025 
-2.805 
0.828 
0.0025 
2 
0.80 
1290 
0.0122 
-2.276 
0.881 
0.0114 
3 
1.00 
1612 
0.0250 
-2.029 
0.904 
0.0212 
 


 
 
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3 
ANALYSIS POPULATION 
All interim data analysis will be carried out on the Intent-to-Treat (ITT) population 
except for the safety analysis where all analysis will be based on the safety population. 
Each of the ITT and safety populations will be as defined in the protocol/SAP.  


 
 
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Page 10 of 24 
4 
INTERIM DATA ANALYSIS PLAN AT THE 60% AND 80% MILESTONES 
Described here is an analysis plan consisting of a sequence of analyses to be performed at 
each IA time point, in order to aid decision making regarding whether the trial should 
continue or be terminated. However, the entire sequence of analyses described below in 
Sections 4.1 through 4.3, and the predictive power (PP) calculation in Section 5, will be 
performed and presented to the DMC irrespective of the result of the singular formal 
hypothesis test. Figure 1 in Section 6 provides a graphical display of the hierarchical 
sequence of analyses and serves as a guide for the DMC in making its recommendation to 
either continue or stop the trial. 
4.1 
Safety Analysis 
Safety analyses will be carried at the interim analyses based on the safety population. 
All adverse events (AEs) will be tabulated by treatment with summary measures. P-
values from tests of independence using Fisher’s exact test or the Chi-square test will be 
provided for flagging purpose. No multiplicity adjustment is needed here. The definition 
of AEs and their classification is defined in the SAP for the final analysis. 
Summary measures at each visit and change from baseline will be presented for other 
safety parameters: electrocardiogram, vital signs including systolic and diastolic blood 
pressure, hematology and biochemistry clinical laboratory parameters. Summary tables 
will be accompanied by appropriate plots to best visualize the data. 
The safety analyses could result in three possible outcomes as shown in Figure 1. 
 The DMC has safety concerns that warrant immediate termination of the trial; 
 The DMC has safety concerns that warrant continuing the trial for additional 
safety follow-up regardless of the efficacy outcomes; or 
 The DMC has no safety concerns currently warranting action. 
4.2 
Efficacy Analysis 
In this section we provide details of the analysis methods to be used for the different 
efficacy analyses at each of the two IA time points. 
4.2.1 Formal Test for the Primary Efficacy Endpoint 
This is the only formal hypothesis testing that will be carried out as part of the two 
interim analyses. All other analyses described in this iSAP are either supportive to the 
primary analysis or for the purpose of informal consistency and robustness check. The 
formal hypothesis test results will only be used for the purpose of DMC’s decision 
making. The final efficacy analysis is described in Sections 4.5 and 4.7 in the SAP and 
consists of a hierarchical sequence of formal hypothesis tests with strong alpha control, to 
be performed in a hierarchical fashion on t he secondary endpoints should the primary 
endpoint demonstrate statistical significance. 


 
 
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Page 11 of 24 
The primary efficacy endpoint is the time to first occurrence of any component of the 
composite of the following adjudicated events 
1. CV death; 
2. Nonfatal MI (including silent MI; electrocardiograms [ECGs] will be performed 
annually for the detection of silent MIs); 
3. Nonfatal stroke; 
4. Coronary revascularization; or 
5. Unstable angina determined to be caused by myocardial ischemia by 
invasive/non-invasive testing and requiring emergent hospitalization. 
In this document, components 1-3 above are referred to as “hard” MACE components 
while components 4 and 5 are referred to as “other” MACE components. 
All suspected events will be adjudicated in a blinded manner by the Clinical Endpoint 
Committee (CEC) and only events that are confirmed by the CEC will be included in this 
analysis. 
The following are detailed considerations for determining the date of event/date of 
censoring for the primary analysis: 
 Patients who withdraw from the study early and do not experience any of the 
primary efficacy events prior to withdrawal will be considered censored at the last 
visit/phone contact before withdrawal. 
 Patients who do not experience any of the primary efficacy events prior to the 
interim cutoff date but are still in the trial will be considered censored at the date 
of their last visit/phone contact before the interim data cutoff. 
 Patients who die with an adjudicated undetermined cause of death and without a 
preceding endpoint event will be considered to have an adjudicated CV death and 
this will be included as an event in the primary analysis. 
 In view of the 90-day monitoring period for CV events, patients who have a non-
CV death within 90 days of last contact without having had an earlier CV event 
will be censored at the time of death. Patients who have a non-CV death more 
than 90 da ys after last contact without having had an earlier CV event will be 
censored at the date of their last visit/phone contact. 
 The primary analysis of silent MI will assume that all silent MIs occurred on the 
date of the first tracing indicative of a silent MI. 
In order to test the hypothesis of superiority of the AMR101 group vs. the control group, 
an unblinded analysis will consist of fitting Kaplan-Meier (K-M) curves to the time to 
composite event and using a stratified log-rank test to test for the difference. The one-
sided alpha-level corresponding to the IA will be used as the significance level for the 
log-rank test here. Thus, for example, if the first interim is conducted after 60% of the 
events then the above test will meet statistical significance if the one-sided stratified log-
rank test p-value <0.0038 as reflected in Table 1. 


 
 
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The following randomization stratification factors will be used in the stratified log-rank 
test: 
1. Geographical location (Western, Eastern European and Asia Pacific); 
2. CV risk group: Patients with established CVD (CV Risk Category-1) and Patients 
≥ 50 years old with diabetes and at least one additional risk factor for CVD but 
CVD not established (CV Risk Category-2); and, 
3. Use of ezetimibe. 
All stratified analyses mentioned in this document will be based on the above three 
variables. 
4.2.2 Supportive Analyses for Primary Efficacy Analysis 
4.2.2.1 Estimation of Hazard Ratio 
In addition to the stratified log-rank test described in Section 4.2.1 and in order to provide 
an estimate of the treatment effect, we will estimate the corresponding HR (point estimate 
and confidence interval) between the AMR101 and the control groups for the primary 
composite event. Since this is not part of a formal hypothesis test, a 95% two-sided 
confidence interval will be presented. Estimation will be carried out using a stratified Cox 
proportional hazards (PH) model fitted to the time to composite event, stratified by the 
factors mentioned in Section 4.2.1, and with treatment as the only covariate. Diagnostic 
plots for the proportional hazards assumption will be evaluated. 
4.2.2.2 Adjustment for Baseline Triglyceride (TG) Level 
Following a protocol amendment, dated May 2013, only patients with a qualifying TG 
level ≥200 mg/dL were enrolled in the study. Prior to this, patients with qualifying TG 
levels as low as approximately 135 mg/dL were permitted to enroll. In order to account 
and adjust for the fact the follow-up times may be different depending on the baseline TG 
level, a Cox PH model as mentioned above but additionally with baseline TG as a 
covariate will be fitted to the data at each interim. Diagnostic plots for the proportional 
hazards assumption will be evaluated. 
4.2.2.3 Adjustments for Unadjudicated Events 
A data cut-off date prior to the IA will be decided on b y the sponsors and the DMC. 
Certain events may remain unadjudicated at this point. Summary measures by treatment 
group and investigators’ classification (primary or otherwise) of these unadjudicated 
events will be presented to the DMC. Additionally, adjusted survival curves (Cook 2000) 
and corresponding log-rank test and hazard estimation will be provided. 
Cook’s methodology (Cook 2000) is based on a ssuming that the probability that a 
reported event will be adjudicated as primary event constituent depends only on i ts 
investigator-reported classification and is unrelated to treatment, time of event or the 
subject’s prior event history. Under these assumptions, the results of adjudication for all 
events for which the adjudication is complete are used to estimate the probability of an 
unadjudicated event to be adjudicated as a primary event constituent. Once these 


 
 
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probabilities are estimated, the data with only confirmed events (as used for the primary 
efficacy analysis above) will be augmented with the unadjudicated events data while 
allocating the events according to the estimated probabilities. Then a valid analysis using 
the K-M estimator, the log-rank statistic, and the Cox PH model can be performed using 
the augmented data. As an alternative, the estimated probabilities can be used as weights 
in the generalized K-M estimator, the generalized log-rank test and in the weighted Cox 
PH model. Technical details are available in (Cook 2000, Cook 2004). The estimates of 
the survival probabilities and regression parameters are shown to be unbiased in Cook 
and Kosorok (Cook 2004). 
4.2.3 Hazard Ratio for Composite “Hard” MACE and Individual Components of 
the Composite Primary Endpoint 
Hazard ratios for AMR101 vs. control will be estimated separately for the 3-component 
“hard” MACE composite endpoint as well as for each of the “hard” and the “other” 
MACE individual components using a stratified Cox PH model with treatment as the 
only covariate. 95% confidence intervals will be used. 
4.2.4 Analysis within Subgroups Defined by Stratification Factors 
The Cox PH models to be used for the previous analyses use the stratification variables to 
fit separate baseline hazard functions for each stratum while assuming that the stratum-
wise HRs between the AMR101 and the control groups are the same. Here we consider 
an analysis where HRs are estimated individually for each marginal stratum level of each 
of the three stratification factors. Thus we estimate the HRs with 95% confidence 
intervals for each stratum within: 
1. Each of the three geographical regions; 
2. For each of the two CV risk groups; and 
3. For each of the two groups based on ezetimibe use. 
Thus seven HR estimates will be obtained, each from a stratified Cox PH model with 
treatment as the only covariate. Stratification in this case will be based on the other two 
stratification variables. For marginal stratum, where the cell-size is small, an unstratified 
analysis will be carried out as an alternative. 
4.2.5 Progress in the Control Group 
One of the inclusion criteria of this trial is that the patients be on a stable dose of statin 
therapy (with or without ezetimibe) prior to randomization and following randomization. 
In view of the importance of the statin-alone group response being consistent with 
expectations, two methods of comparing the control group in terms of the primary 
composite event endpoint and in terms of the composite of CV death, non-fatal MI and 
nonfatal stroke (hard MACE) with historical data will be employed. The historical data 
will be obtained from different studies having at least one of the two CV-risk populations 
(Section 4.2.1) on statin therapy. 
First, the annualized (time-averaged) control group event rates will be compared to that 
from the historical data stratified by CV-risk group. This will be done both in terms of the 


 
 
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composite primary endpoint as well as its five individual components, whenever the 
required information is available from the historical data. Pooling of historical data from 
different studies will not be carried out. 
Second, cumulative incidence (%) of the primary composite endpoint and that of the 
composite “hard” MACE endpoint will be plotted for the control group arm alongside the 
corresponding cumulative incidence (%) plots that are available from peer-reviewed 
literature on individual historical studies. Variations in primary endpoint definitions will 
be allowed and pooling of data from individual studies will not be carried out. 
At minimum, the following articles (studies) will be considered for the historical data: 
1. Intensive Blood Glucose and Vascular Outcomes in Patients with Type 2 
Diabetes, the ADVANCE collaborative group (Patel 2008) 
2. Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus, The 
ACCORD study group (Ginsberg 2010)  
3. Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary 
Syndromes (Cannon 2004) 
4. Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of 
Atherothrombotic Events (Bhatt 2006) 
5. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes 
in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre 
randomised placebo-controlled trial (Colhoun 2004) 
6. Impact of Triglyceride Levels Beyond Low-Density Lipoprotein Cholesterol 
After Acute Coronary Syndrome in the PROVE IT-TIMI 22 Trial (M. Miller et al. 
[2008]) 
7. Angiotensin-Converting–Enzyme Inhibition in Stable Coronary Artery Disease, 
The PEACE trial investigators (Braunwald 2004) 
8. High-Dose Atorvastatin vs. Usual-Dose Simvastatin for Secondary Prevention 
After Myocardial Infarction, The IDEAL Study: A Randomized Controlled Trial 
(Pedersen 2005) 
Other studies completed before the time of the interim analyses may also be included. A 
detailed explanation for inclusion/exclusion of studies will be provided in the interim data 
analysis report. 
In addition to the above analyses comparing the entire REDUCE-IT control group 
responses (by CV-risk category and overall) to historical outcomes data, other potential 
analyses may employ case-matched subsets from the control group in REDUCE-IT for 
comparison to populations with similar attributes from published historical data. 
4.3 
Lipid and Lipoprotein Parameters 
Descriptive analysis of these parameters will be included as part of the IA and may be 
used for interim decision-making only at the discretion of the DMC. 


 
 
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These parameters will be summarized by treatment group and visit in terms of the raw 
data and also expressed as change and percent-change from baseline. Tables will be 
accompanied by plots where appropriate. 


 
 
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5 
THE USE OF CONDITIONAL AND PREDICTIVE POWER 
As a means to predict the future of the trial, given the interim data, we consider 
calculation of conditional power (CP) and predictive power (PP). While the CP provides 
a frequentist means to this, the PP is based on Bayesian calculations where one starts with 
a prior belief on the effect of the treatment which is then updated once the data is 
available. Through these calculations one can study the impact of departures from design 
assumptions, such as lags in efficacy response, loss to follow-up, or differences in 
stratum-wise HRs, into predicting the probability of success given the interim data. In 
this section we describe how PP may be incorporated into the interim decision-making 
for possibly overruling an early efficacy-stopping decision despite meeting all the 
necessary efficacy criteria. 
Figure 1 shows that stopping at an IA for efficacy may be possible if there is strong and 
clear evidence in support of the efficacy and safety of AMR101. However, in spite of 
having such evidence, it may be worthwhile to continue the trial if the results at the final 
analysis are expected to provide even stronger evidence of efficacy, for example, in terms 
of one or more of the three individual components of the “hard” MACE composite 
endpoint meeting statistical significance. This situation could be expected if the 
predictive power calculated at the interim for an individual hard MACE component is 
sufficiently high (>90%). 
In the remainder of this section we summarize how CP and PP are computed. Additional 
technical details are provided in the Appendix. In the context of this iSAP, HR for the 
composite event and that for its five individual components will be used to estimate the 
effect of AMR101 compared to control. We describe the PP calculation process in terms 
of the composite event, calculations for the individual components are similar. 
The hazard functions for the two arms are assumed to be piece-wise constant, i.e., 
constant over a small time interval but allowed to change from one time interval to the 
next. A prior distribution for each of the piece-wise constant hazards are assumed. For 
this we propose to use the Gamma-process priors (Nieto-Barajas 2002). Priors reflecting 
different HRs between the two treatment arms will be considered in order to assess the 
sensitivity of the predictive power to prior assumptions. Other scenarios such as lag in 
treatment response and different stratum-wise HRs will also be considered. 
Once the unblinded interim data is obtained, the posterior (updated prior) distribution of 
the piece-wise constant hazards will be obtained. A Monte-Carlo simulation will follow 
where at each run, hazard functions will be sampled for each of the treatment groups 
using the posterior distributions. These hazard functions will then be used to generate the 
part of the data that is yet to be observed. The interim data and the generated data will 
then be considered as a “proxy” for the final data and will be used to test the primary 
efficacy hypothesis. Using the proxy data if the hypothesis is rejected the decision value 
will be 1, otherwise 0. This generation of the missing or incomplete data will be carried 
out several times for each set of sampled hazard functions. The average of the binary 
decision variable over all these runs is then the Bayesian CP. Averaging the Bayesian CP 


 
 
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over several sets of hazard functions sampled from the posterior is then the Bayesian PP. 
Details of this computation are given in the Section 9 (Appendix). 
At interim analyses, the DMC may conduct/request additional analyses at their discretion, 
such as conditional power analyses, as estimations of possible power at study completion. 


 
 
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6 
DECISIONS FOLLOWING THE INTERIM ANALYSES 
At each IA, one of the following recommendations may be given by the DMC: 
1. 
Continue trial as planned; 
2. 
Stop for success; or 
3. 
Stop for safety issues. 
In Figure 1, we outline the hierarchy of analysis results that is intended to be followed for 
interim decision-making by the DMC. This sequence of analyses is discussed in Section 4 
and Section 5. It consists of the safety analysis (Section 4.1), Efficacy Analysis 
(Section 4.2) which includes one formal hypothesis test, and computation of Predictive 
Power (Section 5). Descriptive analysis of Lipid and Lipoprotein parameters (Section 
4.3) may additionally be used for interim decision-making at the discretion of the DMC. 
6.1 
Decision Tree 
The following decision tree in Figure 1 is provided to aid the DMC members for 
decision-making based on the interim analyses. Thus if the results from the safety 
analysis described in Section 4.1 do not warrant stopping the trial for safety issues or 
additional follow-up of patients then the interim decision rule is based on interim results 
of the efficacy analysis described in Section 4.2. If the formal hypothesis test for efficacy 
meets statistical significance at the corresponding interim alpha-level (Section 2.1) and 
other supportive analyses depicted in Figure 1 provide strong and consistent efficacy 
results, then the DMC may recommend early stopping for efficacy. 


 
 
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Figure 1: Flow Chart to Guide Interim Decision-Making 
 
SafelY Outcomes 
[] 5.lftty issues th.lt 
stopping tilt trill? 
f 
Stop Trial 
SafelY Outcomes 
for 5.lftty ISSuti 
[] 5.lftty iSSUtStNt Wlfrllnt lIcldition.11 pttitnt follow-up? 
/ 
Formal Hypothesis Test for 
Primary S component composite endpoint 
[] StrUified logrllnk ttit mUlS m tistiulsignificlince? 
YES 
ES 
Informal Robustness Ch 
3 
"Hard" MACE HR 
NO 
[] 95" CI Upptf bourod ( n 
t
ES 
0 
Additional Considerations 
[] HRs lind 95" (Is for irwlMdulil compontnts of tht prilNry endpoint 
[] HRs lIrod 95" (I for prilNry endpoint by rtgion 
[] HRs lIrod 95" (15 for prim,uy tndpoint byCV risk cmgory 
Continue Trial 
[] (ompositt prilNry endpoint lIrwl 3 compantn! h.lrd MACE eYent rlittS 
for tilt control urn cornj)llred similn populations frf)lT1 otlltr trills 
of elur evidence of effimV/5lIftty It tilt Interim 
[] un.adjudimed event tn.alysis fOf prilT1.loryendpoint 
[] Prtdictivt power fOf prilNry and 3-compontnt "hard" MACE endpoint! 
[] Blinded condition.al power calcuilition 
[] Upid lind Upoprotein 
I \ 
Stop for Efficacy 
OR 
- - --
Continue Trial 
Safety Outcomes 
o 
issues tlut 
stopping tht 
f 
5(op Trial 
Safely Outcomes 
o 
issuts thn 
follow-up? 
/ 
Formal HVPOlhesls Test for 
Primary S componem composite endpolm 
[] Strulfitd logrink ttst metts sllltistiulslgnlficu.ct7 
YEl 
El 
Informal Robustness Ch 
3 component' "Hard" MACE HR 
NO 
o 95" ( I Upptf bourld < n 
t
El 
0 
Additional Considerations 
[] ItRs ind 95" ( 15 for indil'iduill compontntS of lilt prilNry tndpoinl 
[] tlRs ind 95" ( I for pri INIY endpoint by region 
[] HRs irld 95" (15 for prirNry endpoint byCV risk COIttgolY 
Continue Trial 
[] Compositt prirNlY endpoint incl 3 component lurd MA( E tYent 
for tht control urn 
similu popuiitions frl)fl'l othtr 1I1i1ls 
Luk of dur evidence of efnmY{51fety ill tht Inttrim 
[] Un.adJudiWtd tytnt an.aiysis Ill! pdrNry endpoint 
[] PIed/elM pcM'tr fll! prilNry and 3-compontnt "Nrd" MA( E tndpoinu 
[] Blinded condition.al power cOilculiulon 
[] Upid and UpoprOltin pmmtltrs 
I \ 
Stop for Efficacy 
OR 
Cominue Trial 
- - - -


 
 
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7 
STATISTICAL INFERENCE FOLLOWING AN STOP EARLY AT AN 
INTERIM ANALYSIS 
If the decision is taken to terminate the study at one of the two planned interim analyses, 
the study will enter the closeout phase. During this phase that extends from the interim 
analysis meeting of DMC until the final database lock, additional adjudicated events may 
arrive. The final analysis, being based on the totality of the evidence, will include these 
additional events, resulting in an increase in the information fraction (of the pre-specified 
1612 events) from what the information was at the time of the IA. The significance level 
for the formal hypothesis testing at the final analysis will then be recomputed from the 
Lan-DeMets error spending function at the new information fraction. Stage-wise adjusted 
p-values and confidence intervals consistent with group sequential boundaries computed 
using the Lan-DeMets spending function (Tsiatis 1984, Kim 1987) will be calculated. 


 
 
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8 
REFERENCES 
Bhatt, D. L., et al. 2006. “Clopidogrel and Aspirin Versus Aspirin Alone for the 
Prevention of Atherothrombotic Events.” N. Engl. J. Med. 354 (16): 1706–17. 
Braunwald, E., M. J. Domanski, S. E. Fowler, N. L. Geller, B. J. Gersh, J. Hsia, M. A. 
Pfeffer, M. M. Rice, Y. D. Rosenberg, and J. L. Rouleau. 2004. “Angiotensin-
Converting-Enzyme Inhibition in Stable Coronary Artery Disease.” N. Engl. J. 
Med. 351 (20): 2058–68. 
Cannon, C. P., et al. 2004. “Intensive Versus Moderate Lipid Lowering with Statins After 
Acute Coronary Syndromes.” N. Engl. J. Med. 350 (15): 1495–1504. 
Colhoun, H. M., et al. 2004. “Primary Prevention of Cardiovascular Disease with 
Atorvastatin in Type 2 Diabetes in the Collaborative Atorvastatin Diabetes Study 
(CARDS): Multicentre Randomised Placebo-Controlled Trial.” Lancet 364 
(9435): 685–96. 
Cook, T. D. 2000. “Adjusting Survival Analysis for the Presence of Unadjudicated Study 
Events.” Control Clin Trials 21 (3): 208–22. 
Cook, Thomas D., and Michael R. Kosorok. 2004. “Analysis of Time-to-Event Data with 
Incomplete Event Adjudication.” Journal of the American Statistical Association 
99 (468). Taylor & Francis, Ltd.: 1140–52.  
DeMets, D. L., and K. K. Lan. 1994. “Interim Analysis: the Alpha Spending Function 
Approach.” Stat Med 13 (13-14): 1341–52. 
Ginsberg, H. N., et al. 2010. “Effects of Combination Lipid Therapy in Type 2 Diabetes 
Mellitus.” N. Engl. J. Med. 362 (17): 1563–74. 
Kim, K., and D. L. DeMets. 1987. “Confidence Intervals Following Group Sequential 
Tests in Clinical Trials.” Biometrics 43 (4): 857–64. 
Kosorok MR, Lee BL, and Fine JP. 2004. Robust inference for univariate proportional 
hazards frailty regression models. Ann. Statist. 32 (4): 1448-1491. 
Lewis, J. A. 1999. “Statistical Principles for Clinical Trials (ICH E9): an Introductory 
Note on an International Guideline.” Stat Med 18 (15): 1903–42. 
Miller, M., C. P. Cannon, S. A. Murphy, J. Qin, K. K. Ray, and E. Braunwald. 2008. 
“Impact of Triglyceride Levels Beyond Low-Density Lipoprotein Cholesterol 
After Acute Coronary Syndrome in the PROVE IT-TIMI 22 Trial.” J. Am. Coll. 
Cardiol. 51 (7): 724–30. 
Nieto-Barajas, L.E. & Walker S.G. 2002. “Markov Beta and Gamma Processes for 
Modelling Hazard Rates.” Scandinavian Journal of Statistics 29: 413–24. 
Patel, A., et al. 2008. “Intensive Blood Glucose Control and Vascular Outcomes in 
Patients with Type 2 Diabetes.” N. Engl. J. Med. 358 (24): 2560–72. 


 
 
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Pedersen, T. R., et al. 2005. “High-Dose Atorvastatin Vs Usual-Dose Simvastatin for 
Secondary Prevention After Myocardial Infarction: the IDEAL Study: a 
Randomized Controlled Trial.” JAMA 294 (19): 2437–45. 
Schmidli, H., F. Bretz, and A. Racine-Poon. 2007. “Bayesian Predictive Power for 
Interim Adaptation in Seamless Phase II/III Trials Where the Endpoint Is Survival 
up to Some Specified Timepoint.” Stat Med 26 (27): 4925–38. 
Tsiatis, A. A., G. L. Rosner, and C. R. Mehta. 1984. “Exact Confidence Intervals 
Following a Group Sequential Test.” Biometrics 40 (3): 797–803. 
 


 
 
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9 
APPENDIX 
9.1 
Predictive Probability Calculation 
The PP calculation proposed here involves assuming (nonparametric) priors for the two 
hazard functions corresponding to the two treatment groups. 
Denote the data for the 𝑖-th subject as 𝑦𝑖= (𝑡𝑖, 𝛿𝑖, 𝑧𝑖), where 𝑡𝑖 is the time of the 
occurrence of composite event, 𝛿i is the censoring indicator and 𝑧𝑖 is the set of 
stratification and other covariates including the randomized treatment regimen. At the 
time of the interim analysis, some patients would already have had the primary event of 
interest and some would have completed the planned follow-up (𝑦𝑜𝑜𝑜), while some 
patients enrolled prior to the interim would not have experienced the event of interest and 
would not have completed their follow-up (𝑦𝑚𝑚𝑚𝑚
1
). Data for patients to be enrolled after 
the interim in case the trial continues is denoted as 𝑦𝑚𝑚𝑚𝑚
2
. Also let 𝑦𝑚𝑚𝑚𝑚= (𝑦𝑚𝑚𝑚𝑚
1
, 𝑦𝑚𝑚𝑚𝑚
2
). 
This notation can be generalized to more than one interim analysis. 
The PP will be calculated following the methods outlined in Schmidli, Bretz, and Racine-
Poon (2007). The main difference in our approach is that we base our decision-making 
(𝑅) on the log-rank test where as in Schmidli, Bretz, and Racine-Poon (2007) it is based 
on the test for proportion of events in each treatment arm. 
𝑃𝑃= ∫𝐶𝐶(𝜃 ∣ 𝑦𝑜𝑜𝑜)𝑝(𝜃 ∣ (𝑦𝑜𝑜𝑜, 𝑦𝑚𝑚𝑚𝑚
1
))𝑑𝑑, 
where, 𝜃= (ℎ1, ℎ2) the hazard functions for the two groups, 𝑝(𝜃 ∣ 𝑦𝑜𝑜𝑜, 𝑦𝑚𝑚𝑚𝑚
1
) is the 
posterior distribution of 𝜃 given the interim data and 𝐶𝐶 is the conditional power given 
by 
𝐶𝐶(𝜃 ∣ 𝑦obs) = ∫𝑅(𝑦obs, 𝑦miss)𝑝(𝑦miss  ∣ 𝜃, 𝑦𝑜𝑜𝑜)𝑑𝑦miss, 
where, 𝑅(𝑦) defines a decision function based on the log-rank test with 𝑅(𝑦) = 1 if the 
result based on the data 𝑦 is statistically significant and 0 otherwise. 
9.2 
Simulations to calculate 𝑪𝑪 and 𝑷𝑷 
Extensive simulations to characterize the proposed PP calculation method will be taken 
up prior to the interim analysis. 
Within the current setup, we start by assuming priors for the two hazard functions using 
Gamma processes (Nieto-Barajas [2002]). Using such priors facilitates modeling of the 
hazard function in terms of piece-wise constant hazards, 𝜆k in the time interval 
(𝜏𝑘−1, 𝜏𝑘]. Thus the hazard function is given by 
ℎ(𝑡) = ෍𝜆𝑘
𝐾
𝑘=1
𝐼(𝜏𝑘−1,𝜏𝑘](𝑡). 
Gamma-priors are imposed on each 𝜆k. Further, the dependency between 𝜆k−1 and 𝜆k is 
modeled using a latent-variable which is conditionally independent of {𝜆𝑘} given the 


 
 
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interim data. The dependency consideration results in a smooth estimate of the hazard 
function (Nieto-Barajas [2002]). 
For the REDUCE-IT trial, Gamma-priors can be constructed using data from other recent 
similar trials. 
Once the posterior distributions are obtained for the piece-wise components for the two 
hazard functions, the posterior is sampled several times: 𝜃(1), 𝜃(2), … , 𝜃(𝑀). For each 
𝜃(k), several samples 𝑦𝑚𝑚𝑚𝑚(1), 𝑦𝑚𝑚𝑚𝑚(2), … , 𝑦𝑚𝑚𝑚𝑚(𝑁) are drawn from the likelihood 
𝑝(𝑦𝑚𝑚𝑚𝑚 ∣ 𝜃(𝑘)). Then the CP is calculated at 𝜃(k) as 
𝐶𝐶(𝜃(𝑘) ∣ 𝑦𝑜𝑜𝑜) = 1
𝑁෍𝑅
𝑁
𝑗=1
(𝑦𝑜𝑜𝑜, 𝑦𝑚𝑚𝑚𝑚(𝑗)). 
Next the Predictive Power is calculated as 
𝑃𝑃= 1
𝑀෍𝐶
𝑀
𝑖=1
𝑃(𝜃(𝑖) ∣ 𝑦𝑜𝑜𝑜). 
 


 
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6.2 
Appendix B: Potential Genetic and Non-Genetic Bioassays 
Potential bioassays for archived blood samples are as follows: 
a. Potential non-genetic bioassays (this list may not be all-inclusive): 
Apo A1, Apo C3, Apo E, NMR lipid profile (particle size and number), 
oxidized LDL, Lp(a), Lp-PLA2, serum fatty-acid concentrations, gamma-
glutamyltransferase (GGT). 
b. Potential genetic bioassays: Genetic testing may potentially be as broad as a 
GWAS (genome-wide association study) or as specific as a target gene 
approach. Potential target genes may include but may not be limited to Apo 
C3, Apo E, Apo A5, CETP, LPL, PCSK9, TNFα, TNFβ, ALOX5, COX2, IL-
6, FABPs, haptoglobin 1 vs. 2. 
The markers would be analyzed for effects of treatment on change from baseline (for the 
marker), as well as for relationships between baseline biomarker values and outcome response 
to treatment (primary and key secondary endpoints). 


 
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6.3 
Appendix C: Criteria for the Diagnosis of Metabolic Syndrome 
The diagnosis of metabolic syndrome requires the presence of three out of the following five 
specific components using the following criteria (Alberti 2009) with cut points of parameters 
as defined in Table 1 of Alberti et. al.  and listed below, and waist circumference cut points 
further guided by the Table 2 below (adapted from Table 2 within Alberti et. al.): 
 A waist circumference ≥35 inches (88 cm) for all women, and Asian, Hispanic, or 
Latino men, and waist circumference ≥40 inches (102 cm) for all other men; 
 Elevated TG (TG ≥150 mg/dL); 
 Reduced HDL-C (HDL-C <40 mg/dL if male; HDL-C <50 mg/dL if female); 
 Elevated blood pressure (systolic ≥130 mmHg and/or diastolic ≥85 mmHg, OR an 
antihypertensive therapy with medical history of hypertension; 
 Elevated fasting glucose (fasting glucose ≥100 mg/dL, OR on drug therapy for 
elevated glucose. 
 


 
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Table 2.  Current Recommended Waist Circumference Thresholds for Abdominal 
Obesity by Organization and Population (adapted from Alberti et. al. Table 
2) 
Organization 
Population 
(Reference) 
Waist Circumference Threshold 
Men 
(cm) 
Women 
(cm) 
IDF (4) 
Europid 
≥94 
≥80 
WHO (7) 
Caucasian 
≥94 
(increased risk) 
≥80 
≥102 
(still higher risk) 
≥88 
AHA/NHLBI (ATP III)* (5) 
US 
≥102 
≥88 
Health Canada (8,9) 
Canada 
≥102 
≥88 
European Cardiovascular 
Societies (10) 
European 
≥102 
≥88 
IDF (4) 
Asian 
(including Japanese) 
≥90 
≥80 
WHO (11) 
Asian 
≥90 
≥80 
Japanese Obesity Society 
Japanese 
≥85 
≥90 
Cooperative Task Force (13) 
China 
≥85 
≥80 
IDF (4) 
Middle East, 
Mediterranean 
≥94 
≥80 
IDF (4) 
Sub-Saharan 
African 
≥94 
≥80 
IDF (4) 
Ethnic Central & 
South American 
≥90 
≥80 
IDF=International Diabetes Federation; WHO=World Health Organization; AHA/NHLBI (ATP III)=American Heart 
Association/National 
Heart, 
Lung, 
and 
Blood 
Institute 
Adult 
Treatment 
Panel 
III; 
*Recent AHA/NHLBI guidelines for metabolic syndrome recognize an increased risk for cardiovascular disease and 
diabetes at waist-circumference thresholds of ≥94 cm in men and ≥80 cm in women and identify these as optional cut 
points for individuals or populations with increased insulin resistance. 
 


™
 
 
STATISTICAL ANALYSIS PLAN (SAP) ADDENDUM 
REDUCE-IT STUDY 
A Multi-Center, Prospective, Randomized, Double-Blind, 
Placebo-Controlled, Parallel-Group Study to Evaluate the Effect of AMR101 
on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients 
with Cardiovascular Disease or at High Risk for Cardiovascular Disease: 
REDUCE-IT (Reduction of Cardiovascular Events with EPA – Intervention Trial) 
 
Investigational Product: AMR101 (icosapent ethyl [ethyl-EPA]) 
Protocol Number: AMR-01-01-0019 
 
Sponsor: 
Amarin Pharma Inc. 
1430 Route 206 
Bedminster, New Jersey 07921, USA 
Telephone: +1-908-719-1315 
Facsimile: +1-908-719-3012 
 
Date: 15 August 2018 
Version Number: Final 1.0 
 
  
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Amarin Pharma Inc., except to the extent that disclosure would be required by law 
and for the purpose of evaluating and/or conducting a clinical trial for Amarin Pharma Inc. You 
are allowed to disclose the contents of this document only to your Institutional Review Board 
or Independent Ethics Committee and study personnel directly involved with conducting this 
study. Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to Amarin Pharma Inc. and that it may not be further disclosed to 
third parties. 


 
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Amarin Pharma Inc. 
 AMR-01-01-0019 
Confidential and Proprietary 
15 August 2018 
Page 2 of 13  
SIGNATURE PAGE 
TRIAL TITLE: A Multi-Center, Prospective, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group Study to Evaluate the Effect of AMR101 on Cardiovascular 
Health and Mortality in Hypertriglyceridemic Patients with Cardiovascular Disease or at High 
Risk for Cardiovascular Disease: REDUCE-IT (Reduction of Cardiovascular Events with 
EPA – Intervention Trial) 
 
We, the undersigned, have reviewed and approved this SAP Addendum for Protocol AMR-
01-01-0019. 
 
Signature 
 Date 
 
[Name / signature redacted]                   
[Signed (15 August 2018]   
Executive Director, Biostatistics and Data Management 
Amarin Pharma Inc. 
 
[Name / signature redacted]                   
 [Signed (15 August 2018]  
Executive Director, Clinical Development 
Amarin Pharma Inc.  
 
[Name / signature redacted]                   
 [Signed (15 August 2018]  
VP, Clinical Research and Development  
Amarin Pharma Inc. 
 
[Name / signature redacted]                   
 [Signed (15 August 2018]  
Chief Medical Officer, SVP 
Amarin Pharma Inc. 
 
[Name / signature redacted]                   
 [Signed (15 August 2018]  
President of R&D and Chief Scientific Officer, SVP 
Amarin Pharma Inc. 
 
[Name / signature redacted]                   
 [Signed (20 August 2018] 
Principal Investigator 


 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................ 4 
 
INTRODUCTION ......................................................................................................... 5 
 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ................................ 5 
 
OTHER SENSITIVITY, SUPPORTIVE AND EXPLORATORY 
ANALYSES FOR THE PRIMARY EFFICACY ENDPOINT ................................. 6 
 
ANALYSIS OF SECONDARY EFFICACY ENDPOINTS ..................................... 7 
 
ANALYSIS OF TERTIARY ENDPOINTS ............................................................... 7 
 
EXPLORATORY ANALYSIS OF SUBGROUPS ................................................... 7 
 
ADVERSE EVENTS ................................................................................................... 8 
 
CLINICAL LABORATORY EVALUATION ............................................................. 8 
 
VITAL SIGNS AND PATIENT MEASUREMENTS ................................................ 9 
 
12-LEAD ELECTROCARDIOGRAMS (ECGS) ..................................................... 9 
 
REFERENCES ........................................................................................................... 10 
 
APPENDICES ............................................................................................................ 11 
 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Definition 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
CEC 
Clinical Endpoint Committee 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
CSR 
Clinical Study Report 
CV 
Cardiovascular 
DILI 
Drug-Induced Liver Injury 
ECG 
Electrocardiogram 
EPA 
Eicosapentaenoic Acid 
FDA 
Food and Drug Administration 
HbA1c 
Hemoglobin A1c 
HDL-C 
High-Density Lipoprotein Cholesterol 
HLGT 
High Level Group Term 
HLT 
High Level Term 
HMG CoA 
β-hydroxy β-methylglutaryl coenzyme A 
HR 
Hazard Ratio 
hsCRP 
High-Sensitivity C-Reactive Protein 
ITT 
Intent-to-Treat 
KM 
Kaplan-Meier 
MACE 
Major Adverse Cardiovascular Events 
MI 
Myocardial Infarction 
PAD 
Peripheral Artery Disease 
PCS 
Potentially Clinically Significant 
PLAA 
Pre-specified List of Additional Analyses 
PT 
Preferred Term 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TBL 
Total Bilirubin 
TEAE 
Treatment-Emergent Adverse Event 
TG 
Triglycerides 


 
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INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) Addendum is to describe and document 
additional pre-specified statistical analyses and specifications beyond those that were pre-
specified in the approved SAP version dated 08 July 2016, which will be included in the final 
analysis and reporting of clinical data collected during the conduct of Protocol AMR-01-01-
0019. As discussed and agreed with the Food and Drug Administration (FDA) in relation to a 
pre-sNDA meeting on 07 March 2018, this SAP Addendum has been developed and will be 
finalized and submitted to the AMR101 investigational new drug application prior to database 
lock and unblinding.  Importantly, the additional efficacy endpoints and analyses outlined 
below in this SAP Addendum are exploratory in nature and will not be included in the formal 
SAP testing scheme. Results from the exploratory analyses described herein will be included in 
the AMR-01-01-0019 clinical study report (CSR). Analyses associated with a separate 
document, entitled “pre-specified list of additional analyses (PLAA)”, that will be approved by 
the sponsor prior to database lock and unblinding but that may or may not be performed and 
the results of which may or may not appear in the CSR. 
For each section below, the relevant section of the SAP will be identified. 
 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
This section relates to Section 4.6.3 of version 1 of the SAP dated 08 July 2016. 
For the statin-related analyses, the following medications will be classified as statins: 
Monotherapies: 
C10AA β-hydroxy β-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors 
• C10AA01 simvastatin 
• C10AA02 lovastatin 
• C10AA03 pravastatin 
• C10AA04 fluvastatin 
• C10AA05 atorvastatin 
• C10AA06 cerivastatin 
• C10AA07 rosuvastatin 
• C10AA08 pitavastatin 
Combinations 
C10BA HMG CoA reductase inhibitors in combination with other lipid-modifying 
agents 
• C10BA01 lovastatin and nicotinic acid 
• C10BA02 simvastatin and ezetimibe 
• C10BA03 pravastatin and fenofibrate 
• C10BA04 simvastatin and fenofibrate 
• C10BA05 atorvastatin and ezetimibe 
• C10BA06 rosuvastatin and ezetimibe 


 
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C10BX HMG CoA reductase inhibitors, other combinations 
• C10BX01 simvastatin and acetylsalicylic acid 
• C10BX02 pravastatin and acetylsalicylic acid 
• C10BX03 atorvastatin and amlodipine 
• C10BX04 simvastatin, acetylsalicylic acid, and ramipril 
• C10BX05 rosuvastatin and acetylsalicylic acid 
• C10BX06 atorvastatin, acetylsalicylic acid, and ramipril 
• C10BX07 rosuvastatin, amlodipine, and lisinopril 
• C10BX08 atorvastatin and acetylsalicylic acid 
• C10BX09 rosuvastatin and amlodipine 
• C10BX10 rosuvastatin and valsartan 
• C10BX11 atorvastatin, amlodipine, and perindopril 
• C10BX12 atorvastatin, acetylsalicylic acid, and perindopril 
• C10BX13 rosuvastatin, perindopril, and indapamide 
• C10BX14 rosuvastatin, amlodipine, and perindopril 
• C10BX15 atorvastatin and perindopril 
 
OTHER SENSITIVITY, SUPPORTIVE AND EXPLORATORY ANALYSES 
FOR THE PRIMARY EFFICACY ENDPOINT 
This section relates to Section 4.7.1.2 of version 1 of the SAP dated 08 July 2016. 
Time-to-event analyses as done for the primary analysis will be carried out at 1-year and 2-year 
landmarks for the intent-to-treat (ITT) Population. For each landmark, the log-rank test, 
stratified by stratification variables at randomization (cardiovascular [CV] risk category, use of 
ezetimibe, and geographical region [Westernized, Eastern European, and Asia Pacific 
countries]), will be used to compare the time-to-event between treatment groups. Similarly, 
hazard ratios and 95% confidence intervals will be determined using Cox proportional hazards 
modelling. Patients without events prior to the landmark time will be censored. 
 
For the recurrent CV events analyses based on 5-component Major Adverse Cardiovascular 
Events (MACE) (CV death, non-fatal myocardial infarction [MI], non-fatal stroke, unstable 
angina requiring hospitalization, or coronary revascularization), in addition to the Anderson 
and Gill and the Li and Lagakos methods specified in the SAP dated 08 July 2016, the total CV 
event counts will be analyzed using a Negative Binomial Model (Rogers 2012, Rogers 2014, 
and Claggett 2018).  It will be implemented using SAS Proc Genmod with a log link function, 
log exposure time as offset, and treatment group and randomization strata as factors. 
 
As additional sensitivity analysis for the primary composite endpoint will be carried out, 
namely, an on-treatment analysis which includes primary event onset up to 0 and 30-days after 
permanent discontinuation of study drug.  
 
All SAP Addendum efficacy analyses are considered exploratory and are not included in the 
formal SAP testing scheme. 
 


 
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ANALYSIS OF SECONDARY EFFICACY ENDPOINTS 
This section relates to Section 4.7.3 of version 1 of the SAP dated 08 July 2016. 
As done for the primary analysis, time-to-event analyses will be carried out at 1-year and 2-
year landmarks for the key secondary endpoints for the ITT Population. 
 
ANALYSIS OF TERTIARY ENDPOINTS 
This section relates to Section 4.7.4 of version 1 of the SAP dated 08 July 2016. 
The following clinical events that are positively adjudicated by the Clinical Endpoint 
Committee (CEC) will be analyzed as tertiary endpoints for the ITT Population: 
• Composite of total mortality, or new congestive heart failure (CHF) 
• Composite of CV death, or new CHF 
• Sudden cardiac death 
• Peripheral artery disease (PAD) 
• Atrial fibrillation, or atrial flutter 
 
These tertiary endpoints will be analysed similarly as for the primary composite endpoint. 
In addition, the following will be analysed as tertiary endpoints for the ITT Population: 
• Relationship between on-treatment high-sensitivity C-reactive protein (hsCRP) and the 
primary and key secondary endpoints 
• Relationship between on-treatment serum eicosapentaenoic acid (EPA) and the primary 
and key secondary endpoints 
 
To assess the relationship between on-treatment hsCRP and the primary and key secondary 
endpoints, subgroup analyses will be carried out as done for the ITT population for patients 
grouped according to values greater or equal to or less than 2 mg/dL at baseline and at 2 years. 
To assess the relationship between on-treatment serum EPA and the primary and key secondary 
endpoints, Kaplan-Meier (KM) curves will be produced for AMR101 treated patients grouped 
into tertiles based on their values at year 1 and will be compared with the placebo-treated 
patients.  
 
EXPLORATORY ANALYSIS OF SUBGROUPS 
This section relates to Section 4.7.5 of version 1 of the SAP dated 08 July 2016. 
The following will be added to the subgroup analyses: 
• Baseline Hemoglobin A1c (HbA1c) value (<6.5%, ≥6.5%) 


 
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• Baseline PAD  
• Baseline triglyceride (TG) levels ≥ 150 mg/dL with high-density lipoprotein cholesterol 
(HDL-C) levels ≤ 40 mg/dL for males and ≤ 50 mg/dL for females 
Subgroup analyses of the primary and key secondary endpoints will be performed as described 
for the primary endpoint. For each subgroup, Kaplan-Meier estimates, the log-rank test 
stratified by stratification factors used at randomization (except where the subgroup is a 
stratification factor), and hazard ratios (HRs) and confidence intervals (CIs) from the Cox 
proportional hazards model as specified for the primary efficacy endpoint, will be summarized 
by treatment group. 
 
ADVERSE EVENTS 
This section relates to Section 4.8.1 of version 1 of the SAP dated 08 July 2016. 
In addition to the treatment-emergent adverse events analyses specified in the SAP dated 08 Jul 
2016, the following analyses will be performed:  
• All adverse events (AEs) (serious and non-serious) 
o Treatment-emergent adverse event (TEAE) by high level group term (HLGT) 
o TEAE by high level term (HLT) 
o TEAE by system organ class (SOC), HLGT, HLT, and preferred term (PT) (4-
level table) 
• All serious AEs (SAEs) 
o Treatment emergent SAE by HLGT 
o Treatment emergent SAE by HLT 
o Treatment emergent SAE by SOC, HLGT, HLT, and PT (4-level table) 
 
CLINICAL LABORATORY EVALUATION 
This section relates to Section 4.8.2 of version 1 of the SAP dated 08 July 2016. 
The criteria for potentially clinically significant (PCS) laboratory values are provided in Table 
1 and Table 2 of Appendix A. A treatment-emergent PCS high value at any time will be defined 
as a change from a value less than or equal to the upper reference limit at baseline to a PCS 
high value at any post-baseline measurement. A treatment-emergent PCS low value at any time 
will be defined as a change from a value greater than or equal to the lower reference limit at 
baseline to a PCS low value at any post-baseline measurement. Number (%) of patients with 
any post-baseline PCS laboratory values will be summarized by treatment group. A listing of 
patients with PCS laboratory values at any time, i.e., baseline or at any post-baseline visit, will 
be included. 
 
 


 
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Drug-Induced Liver Injury (DILI) 
Potential DILI cases will be investigated through the following analyses: 
• A graph of distribution of peak values of alanine aminotransferase (ALT) versus peak 
values of total bilirubin (TBL) during the treatment period will be presented, using a 
logarithmic scale. In the graph, for each patient, the peak TBL times the Upper Limit of 
Normal (ULN) will be plotted against the peak ALT times the ULN, where the peak 
TBL and peak ALT may or may not happen on the same day of liver testing. The graph 
will be divided into 4 quadrants with a vertical line corresponding to 3x ULN for ALT 
and a horizontal line corresponding to 2x ULN for TBL. The upper right quadrant will 
be referred to as the potential Hy’s Law quadrant, including potentially DILI cases. 
• A similar graph will be plotted with respect to aspartate aminotransferase (AST). 
• The individual patient profile of liver function tests (ALT, AST, alkaline phosphatase 
[ALP] and TBL) over time will be provided through a graph for all patients with peak 
value of ALT >3x ULN and peak value of TBL >2x ULN during the treatment period. 
• Number (%) of patients will be provided for the following:  
o ALT or AST >3x ULN  
o ALT or AST >3x ULN and TBL >2x ULN  
o ALT or AST >3x ULN and TBL >2x ULN, and ALP < 2x ULN. 
 
VITAL SIGNS AND PATIENT MEASUREMENTS 
This section relates to Section 4.8.4 of version 1 of the SAP dated 08 July 2016. 
Shift tables will present baseline value categories and post-baseline endpoint value categories 
as defined in Table 3 of Appendix A. The definitions for potentially clinically significant 
treatment-emergent values are defined in Table 4 of Appendix A. 
Number (%) of patients with any post-baseline PCS vital sign values will be summarized by 
treatment group. A listing of patients who meet the threshold criteria will be provided. 
 
12-LEAD ELECTROCARDIOGRAMS (ECGS)  
This section relates to Section 4.8.5 of version 1 of the SAP dated 08 July 2016. 
A treatment-emergent PCS high value at any time will be defined as a change from a value less 
than or equal to the defined PCS value at baseline to a PCS high value at any post-baseline 
measurement. A treatment-emergent PCS low value at any time will be defined as a change 
from a value greater than or equal to the lower PCS value at baseline to a PCS low value at any 
post-baseline measurement. Table 5 of Appendix A provides the PCS ECG values.  
Number (%) of patients with post-baseline PCS ECG values will be presented by treatment 
group. A listing of subjects with potentially clinically significant changes in ECG values will 
be included. 
 


 
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REFERENCES 
Rogers JK, et al. Eplerenone in Patients With Systolic Heart Failure and Mild Symptoms: 
Analysis of Repeat Hospitalizations. Circulation 2012; 126:2317-2323.  
Rogers JK, et al. Analysing recurrent hospitalisations in heart failure: a review of statistical 
methodology, with application to CHARM-Preserved. Eur J Heart Fail. 2014; 16:33-40. 
Claggett B, et al. Comparison of time-to-first event and recurrent event methods in randomized 
clinical trials. Circulation 2018; 138:570-577. 
 
 


 
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APPENDICES 
13.1 
Appendix A. Potentially Clinically Significant Lab, Vital Signs, and ECG Values 
Table 1:  Potentially Clinically Significant Chemistry Values 
Parameter 
PCS Low 
PCS High 
Albumin 
<3.3 g/dL 
>5.8 g/dL 
Alkaline Phosphatase 
Not Applicable (NA) 
>1x ULN to 2x ULN 
>2x ULN to 3x ULN 
>3x ULN 
ALT 
NA 
>1x ULN to 2x ULN 
>2x ULN to 3x ULN 
>3x ULN 
AST 
NA 
>1x ULN to 2x ULN 
>2x ULN to 3x ULN 
>3x ULN 
Bilirubin 
NA 
>1x ULN to 2x ULN 
>2x ULN to 3x ULN 
>3x ULN 
ALT + Bilirubin 
NA 
>3x ULN (ALT) + 2 x ULN 
(Bilirubin) 
AST + Bilirubin 
NA 
>3x ULN (AST) + 2x ULN 
(Bilirubin) 
Calcium  
<7 mg/dL 
≥11 mg/dL; 
≥12 mg/dL 
Chloride 
<70 mmol/L 
>120mmol/L 
Creatinine 
 
<0.5 mg/dL (Female) 
<0.65 mg/dL (Male) 
 
>1.6 mg/dL (Female) 
>2.0 mg/dL (Male); 
≥ 50% increase from baseline 
 
Creatine Kinase 
 
<30 U/L (Female) 
<0.55 U/L (Male) 
 
>1x ULN to 5x ULN 
>5x ULN to 10x ULN 
>10x ULN 
 
Glucose (fasting) 
<36 mg/dL;                  
≤70 mg/dL                   
>126 mg/dL; 
>130 mg/dL 
Potassium (K) 
<3.0 mEq/L 
>5.5 mEq/L 
Sodium (Na) 
<130 mEq/L 
>150 mEq/L 


 
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Table 1:  
Potentially Clinically Significant Chemistry Values (continued) 
Parameter 
PCS Low 
PCS High 
Total Protein 
<5.0 g/dL 
>9.5 g/dL 
Urea Nitrogen (BUN) 
NA 
>31 mg/dL 
Uric Acid 
<1.9 mg/dL (Female) 
<2.5 mg/dL (Male) 
>7.5 mg/dL (Female) 
>8 mg/dL (Male) 
 
Table 2:  Potentially Clinically Significant Hematology Values 
Parameter 
PCS Low 
PCS High 
Red Blood Cell (RBC) 
 <3.5 x 106/uL (Female) 
<3.8 x 106/uL (Male) 
 >5.5 x 106/uL (Female) 
>6.0 x 106/uL (Male) 
Hemoglobin (Hgb) 
 <10.0 g/dL (Female) 
<10.0 g/dL (Male) 
 >16.5 g/dL(Female) 
>18.0 g/dL (Male) 
Hematocrit (Hct) 
<37% (Female) 
<42% (Male) 
>42% (Female) 
>50% (Male) 
White Blood Cells (WBC) 
<1.5 x 103/uL  
NA 
White Cell Differential 
Segmented neutrophils <50% 
Lymphocytes <30% 
Monocytes NA 
Basophils NA 
Eosinophils NA 
Segmented neutrophils >70% 
Lymphocytes > 45% 
Monocytes > 6 % 
Basophils > 1% 
Eosinophils > 3% 
Platelet count 
<100 x 103/uL 
>500 x 103/uL 
 
 


 
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Table 3:  Vital Signs Value Categories 
Vital Sign 
Low 
Normal 
High 
Systolic Blood Pressure 
≤90 mmHg 
>90 mmHg to <160mmHg 
≥160 mmHg 
Diastolic Blood Pressure 
≤50 mmHg 
>50 mmHg to <100mmHg 
≥100 mmHg 
Pulse 
≤50 beats/min 
>50 beats/min to <90 beat/min 
≥90 beats/min 
 
Table 4:  Potentially Clinically Significant Vital Signs Value Definitions 
Vital Sign 
PCS Low 
PCS High 
Systolic Blood Pressure 
≤90 mmHg AND  
decrease of ≥20 mmHg; 
≤90 mmHg; 
decrease of ≥20 mmHg 
≥160 mmHg AND  
increase of ≥20 mmHg; 
≥160 mmHg;  
increase of ≥20 mmHg 
Diastolic Blood Pressure 
≤50 mmHg AND  
decrease of >10 mmHg; 
≤50 mmHg;  
decrease of >10 mmHg 
≥100 mmHg AND  
increase of >10 mmHg; 
≥100 mmHg; 
increase of >10 mmHg 
Pulse 
≤50 beats/min AND  
decrease of ≥15 beats/min; 
≤50 beats/min; 
decrease of ≥15 beats/min 
≥90 beats/min AND  
increase of ≥15 beats/min; 
≥90 beats/min;  
increase of ≥15 beats/min 
 
Table 5:  Potentially Clinically Significant ECG Value Definitions 
ECG Parameter 
PCS Low 
PCS High 
PR Interval 
<120 msec 
>120 msec and increase >20 msec 
from baseline 
QRS Interval 
NA 
>110 msec 
QTc 
NA 
>500 msec 
 
 


™
 
 
PRE-SPECIFIED LIST OF ADDITIONAL ANALYSES 
REDUCE-IT STUDY 
A Multi-Center, Prospective, Randomized, Double-Blind, 
Placebo-Controlled, Parallel-Group Study to Evaluate the Effect of AMR101 
on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients 
with Cardiovascular Disease or at High Risk for Cardiovascular Disease: 
REDUCE-IT (Reduction of Cardiovascular Events with EPA – Intervention Trial) 
 
Investigational Product: AMR101 (icosapent ethyl [ethyl-EPA]) 
Protocol Number: AMR-01-01-0019 
 
Sponsor: 
Amarin Pharma Inc. 
1430 Route 206 
Bedminster, New Jersey 07921, USA 
Telephone: +1-908-719-1315 
Facsimile: +1-908-719-3012 
 
Date: 15 August 2018 
Version Number: Final 1.0 
 
  
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Amarin Pharma Inc., except to the extent that disclosure would be required by law 
and for the purpose of evaluating and/or conducting a clinical trial for Amarin Pharma Inc. You 
are allowed to disclose the contents of this document only to your Institutional Review Board 
or Independent Ethics Committee and study personnel directly involved with conducting this 
study. Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to Amarin Pharma Inc. and that it may not be further disclosed to 
third parties. 


 
 Pre-Specified List of Additional Analyses  
Amarin Pharma, Inc. 
 AMR-01-01-0019 
Confidential and Proprietary 
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Page 2 of 10  
SIGNATURE PAGE 
TRIAL TITLE: A Multi-Center, Prospective, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group Study to Evaluate the Effect of AMR101 on Cardiovascular 
Health and Mortality in Hypertriglyceridemic Patients with Cardiovascular Disease or at High 
Risk for Cardiovascular Disease: REDUCE-IT (Reduction of Cardiovascular Events with 
EPA – Intervention Trial) 
 
We, the undersigned, have reviewed and approved this pre-specified list of additional 
exploratory analyses for Protocol AMR-01-01-0019. 
 
Signature 
Date 
 
[Name / signature redacted]                    
[Signed (15 August 2018)]   
Executive Director, Biostatistics and Data Management 
Amarin Pharma Inc. 
 
[Name / signature redacted]                    
[Signed (15 August 2018)] 
Executive Director, Clinical Development 
Amarin Pharma Inc.  
 
[Name / signature redacted]                    
[Signed (15 August 2018)] 
VP, Clinical Research and Development  
Amarin Pharma Inc. 
 
[Name / signature redacted]                    
[Signed (15 August 2018)] 
Chief Medical Officer, SVP 
Amarin Pharma Inc. 
 
[Name / signature redacted]                    
[Signed (15 August 2018)] 
President of R&D and Chief Scientific Officer, SVP 
Amarin Pharma Inc. 
 
[Name / signature redacted]                    
[Signed (20 August 2018)] 
Principal Investigator 


 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................ 4 
 
INTRODUCTION ......................................................................................................... 6 
 
ADDITIONAL EXPLORATORY EFFICACY ANALYSES .................................... 6 
 
ADDITIONAL EXPLORATORY SAFETY ANALYSES ........................................ 9 
 
REFERENCES ........................................................................................................... 10 
 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Definition 
AA 
Arachidonic acid 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
Apo A-I 
Apolipoprotein A-I 
Apo A-1I 
Apolipoprotein A-II 
Apo A-V 
Apolipoprotein A-V 
Apo B 
Apolipoprotein B 
Apo C-III 
Apolipoprotein C-III 
Apo E 
Apolipoprotein E 
AUC 
Area under the curve 
BP 
Blood Pressure 
CEC 
Clinical Endpoint Committee 
CHF 
Congestive Heart Failure 
CV 
Cardiovascular 
CVD 
Cardiovascular Disease 
DHA 
Docosahexaenoic acid 
DPA 
Docosapentaenoic acid 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
EPA 
Eicosapentaenoic Acid 
HDL2 
High Density Lipoprotein subfraction HDL2 
HDL3 
High Density Lipoprotein subfraction HDL3 
HDL-P 
High Density Lipoprotein Particle Number 
hsCRP 
High-Sensitivity C-Reactive Protein 
hsTNT 
High-sensitivity troponin T 
ICD 
Implantable Cardioverter Defibrillator 
IL-6 
Interleukin 6 
ITT 
Intent-to-Treat 
LDL-C 
Low Density Lipoprotein Cholesterol 
LDL-P 
Low Density Lipoprotein Particle Number 
LDL-TG 
Low Density Lipoprotein Trigyceride 
Lp(a) 
Lipoprotein a 
LPL 
Lipoprotein Lipase 
LpPLA2 
Lipoprotein-associated Phospholipase-A2 


 
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Abbreviation or Term 
Definition 
AA 
Arachidonic acid 
MALE 
Major Adverse Limb Event 
MI 
Myocardial Infarction 
NAFLD 
Nonalcoholic Fatty Liver Disease 
NFS 
NAFLD Fibrosis Score 
NT-proBNP 
N-terminal-pro-brain Natriuretic Peptide 
Ox-LDL 
Oxidized Low Density Lipoprotein 
RLP-C 
Remnant Lipoprotein Cholesterol 
SAP 
Statistical Analysis Plan 
SMI 
Silent Myocardial Infarction 
TG 
Triglycerides 
ULN 
Upper Limit of Normal 
US 
United States 


 
 Pre-Specified List of Additional Analyses  
Amarin Pharma, Inc. 
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INTRODUCTION  
This purpose of this Pre-Specified List of Additional Analyses (PLAA) is to document any 
additional pre-specified exploratory statistical analyses that may be carried out beyond those 
that were pre-specified in the approved statistical analysis plan (SAP) version dated 08 July 
2016 as well as the SAP Addendum dated 15 August 2018. This PLAA identifies pre-specified 
analyses that may or may not be performed and the results of which may or may not appear in 
the CSR depending upon overall results from the trial. This PLAA will be finalized and signed 
off prior to database lock and unblinding. 
 
ADDITIONAL EXPLORATORY EFFICACY ANALYSES 
The following list presents additional pre-specified exploratory efficacy analyses that could be 
of interest to the general clinical and scientific community: 
• Non-fatal myocardial infarction (MI) (including both clinical manifestation and silent MI 
categorizations) – intent-to-treat (ITT) Population 
• Evaluation of effect of time-weighted (or area under the curve [AUC]) eicosapentaenoic 
acid (EPA) data on the primary and key secondary composite endpoints – ITT Population 
• Sensitivity analyses on the primary and key secondary composite endpoints by excluding 
elective coronary artery revascularizations if onset is <3 months post randomization; and 
also excluding peri-procedural MIs – ITT Population 
• Two silent MI (SMI) sensitivity analyses on the primary and key secondary composite 
endpoints – ITT Population: 
 counting all potential SMIs identified by Clinical Endpoint Committee (CEC) 
electrocardiogram (ECG) reviewer, whether confirmed at final ECG or not; and,  
 counting only potential SMIs that have at least one confirmatory ECG showing 
persistence of Q-waves (even if not present at final ECG) 
• Non-alcoholic fatty liver disease (NAFLD) analyses using NAFLD Fibrosis Score (NFS), 
assessing – ITT Population: 
 effect on primary and key secondary composite endpoints by baseline NFS category; 
and, 
 treatment effect on change from baseline in NFS at 1 and 5 years 
• Individual and combined on-treatment goal achievement of triglyceride (TG) ≤ 150 mg/dL 
and hsCRP ≤ 2 mg/L at 2 years, and end of study – ITT Population 
• Additional renal function (eGFR) analyses – ITT Population: 
 primary and key secondary composite endpoints for patients with baseline renal 
dysfunction [eGFR] ≥60 and <90 mL/min/1.73m2 


 
 Pre-Specified List of Additional Analyses  
Amarin Pharma, Inc. 
 AMR-01-01-0019 
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 treatment effect on change from baseline in renal function (eGFR) at 1 and 5 years 
• Sensitivity analyses on the primary and key secondary composite endpoints by excluding 
patients with post-randomization low density lipoprotein cholesterol (LDL-C) values >100 
mg/dL; and another for >70 mg/dL – ITT Population 
• Analyses of hospitalization data (pooled positively adjudicated unstable angina requiring 
hospitalization, congestive heart failure [CHF] requiring hospitalization, and cardiac 
arrhythmia requiring hospitalization) – ITT Population 
 Time from randomization to first hospitalization 
 Recurrent event analysis on hospitalization 
• Additional subgroup analyses (United States [US] versus Non-US) on the primary and key 
secondary composite endpoints; also potentially other endpoints – ITT Population 
• Additional subgroup analyses for patients with very high-risk cardiovascular disease (CVD) 
(defined as recurrent cardiovascular [CV] events or CV events in more than one vascular 
bed, i.e., polyvascular disease) on the primary and key secondary composite endpoints; also 
potentially other endpoints – ITT Population 
• Sensitivity analyses for apolipoprotein B (apo B) to assess whether subgroup(s) with apo B 
reductions from baseline beyond certain threshold(s) have corresponding incremental 
reductions in clinical endpoint events 
• Sensitivity analyses for endpoints comprised of myocardial infarctions which exclude peri-
procedural MIs (Type 4a) 
 Additional analyses factoring for recency and number of prior MIs 
• Sensitivity analyses for stroke, factoring for patients with history of stroke 
• Sensitivity analyses for heart failure, factoring for patients with history of heart failure 
• Sensitivity analyses for endpoints comprised of coronary revascularizations which exclude 
early elective revascularizations (e.g., within 30-90 days post-randomization)  
• Subgroup analyses of primary and potentially key secondary endpoints among the following 
cohorts: 
 High risk patients with “the hypertriglyceridemic waist” (obese patients at high CV 
risk) 
 High risk subgroup defined by baseline high-sensitivity troponin T (hsTNT) level 
(and potentially by N-terminal-pro-brain Natriuretic Peptide [NT-proBNP] from 
archived frozen samples) 
 High TG/low LDL-C phenotypes beyond those currently specified in the SAP and 
SAP Addendum 


 
 Pre-Specified List of Additional Analyses  
Amarin Pharma, Inc. 
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 High-risk patients as defined by their atherothrombotic risk score (Bohula 2016) 
• Treatment effect on: 
 Peripheral arterial events (e.g., major adverse limb [MALE] events) 
 Hypertension, using blood pressure (BP) as a continuous variable 
• Using archived frozen serum biosamples, additional analyses of fatty-acid levels (and 
ratios) not currently specified in the SAP Addendum, including baseline and on-treatment 
effects on EPA, docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), arachidonic 
acid (AA) (and associated ratios) and relationships between fatty-acid levels and 
cardiovascular outcomes.  
 Relationship between on-treatment fatty-acid levels and  
▪ baseline fatty-acid levels and 
▪ study medication compliance 
• Using archived frozen biosamples (serum and whole blood); potential analyses of treatment 
effects on biomarkers and genetic markers and associations with outcomes, including but 
not limited to the following: 
 Low density lipoprotein particle number (LDL-P) 
 Remnant lipoprotein cholesterol (RLP-C) (measured) 
 Low density lipoprotein triglyceride (LDL-TG) 
 Oxidized low density lipoprotein (Ox-LDL) 
 Galectin-3 
 Lipoprotein a (Lp(a)) at baseline, as a predictor of CVD benefit 
 Lipoprotein-associated phospholipase-A2 (LpPLA2) 
 High density lipoprotein subfraction 2 (HDL2), high density lipoprotein subfraction 
3 (HDL3), apolipoprotein A-I (apo A-I), apolipoprotein A-II (apo A-II), high 
density lipoprotein particle number (HDL-P), apolipoprotein C-III (apo C-III) (and 
apo C-III in apo-B containing proteins), apolipoprotein A-V (apo A-V), 
apolipoprotein E (Apo E) subtypes (2, 3, 4), interleukin 6 (IL-6), lipoprotein lipase 
(LPL) 
 Analyses may include change (and percent change) from baseline, and on-treatment 
comparisons between treatment groups with testing as predictors of CV risk 
• Exploratory analyses of differential treatment effects for potential benefit (from adverse 
event reports) of: 
 ophthalmologic changes (e.g., incidence of age-related macular degeneration, 
progression of diabetic retinopathy) 


 
 Pre-Specified List of Additional Analyses  
Amarin Pharma, Inc. 
 AMR-01-01-0019 
Confidential and Proprietary 
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 cognitive impairment (Schwarz 2018) 
 erectile dysfunction (Shim 2016) 
 ischemic cardiomyopathy (as indicated by hospitalization for CHF, implantable 
cardioverter defibrillator [ICD] placement etc.) 
• Additional genetic bioassays not included in the REDUCE-IT SAP including genes which 
may relate to triglyceride, lipid metabolism, and CVD  
• Effects of potential mediators identified post hoc on primary/key secondary outcome 
measures (Inzucchi 2018) 
 
ADDITIONAL EXPLORATORY SAFETY ANALYSES 
The following list presents additional pre-specified exploratory safety analyses that could be of 
interest to the general clinical and scientific community: 
• Number and percent of patients with the following liver function abnormalities – Safety 
Population: 
 Alanine aminotransferase (ALT) >/=3x Upper Limit of Normal (ULN) + Total 
Bilirubin >1.5x ULN 
 ALT >/=5x ULN 
 ALT >/=3x ULN with an appearance of rash or worsening hepatitis symptoms 
• Number and percent of patients with treatment-emergent cancer (overall, Lung Cancer, and 
Prostate Cancer) reported as adverse event (AE); each in 2 populations (ITT and hsCRP ≥2 
mg/L) – Safety Population 
• Number and percent of patients with treatment-emergent depression and social dysfunction 
reported as AE – Safety Population 
 
 


 
 Pre-Specified List of Additional Analyses  
Amarin Pharma, Inc. 
 AMR-01-01-0019 
Confidential and Proprietary 
15 August 2018 
Page 10 of 10  
 
REFERENCES 
Bohula EA, Bonaca MP, Braunwald E, Aylward PE, Corbalan R, De Ferrari GM, He P, Lewis 
BS, Merlini PA, Murphy SA, Sabatine MS, Scirica BM, Morrow DA. Atherothrombotic Risk 
Stratification and the Efficacy and Safety of Vorapaxar in Patients With Stable Ischemic Heart 
Disease and Previous Myocardial Infarction. Circulation. 2016;134(4):304-13 
Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, Schumacher M, Schmoor C, 
Ohneberg K, Johansen OE, George JT, Hantel S, Bluhmki E, Lachin JM. How Does 
Empagliflozin Reduce Cardiovascular Mortality? Insights From a Mediation Analysis of the 
EMPA-REG OUTCOME Trial. Diabetes Care. 2018;41(2):356-363. 
Schwarz C, Wirth M, Gerischer L, Grittner U, Witte AV, Köbe T, Flöel A. Effects of Omega-
3 Fatty Acids on Resting Cerebral Perfusion in Patients with Mild Cognitive Impairment: A 
Randomized Controlled Trial. J Prev Alzheimers Dis. 2018;5(1):26-30. 
Shim JS, Kim DH, Bae JH, Moon du G. Effects of Omega-3 Fatty Acids on Erectile 
Dysfunction in a Rat Model of Atherosclerosis-induced Chronic Pelvic Ischemia. J Korean Med 
Sci. 2016;31(4):585-9.