Conditions: Hypertriglyceridemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 80
Healthy volunteers: no

Brief summary:
Effect of Vascepa on Progression of Coronary Atherosclerosis in Persons with Elevated Triglycerides (200-499) on Statin Therapy. The study is to determine progression rates of low attenuation plaque under influence of Vascepa as compared to placebo.

Detailed description:
Residual cardiovascular (CV) risk remains in dyslipidemic patients despite intensive statin therapy, underscoring the need for additional intervention. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, is incorporated into membrane phospholipids and atherosclerotic plaques and exerts beneficial effects on the pathophysiologic cascade from onset of plaque formation through rupture. EPA also improves atherogenic dyslipidemia characterized by reduction of triglycerides without raising low-density lipoprotein cholesterol. All of this data supports the biologic plausibility of EPA as an anti-atherosclerotic agent. The goal of this study is to evaluate whether treatment with Vascepa (4 grams) results in a greater change from baseline in low attenuation plaque than placebo in subjects with elevated triglycerides (200-499 mg/dl).

Arms:
arm 1: Vascepa (4 gm/day), oral dose arm 2: oral dose of placebo

Interventions: intervention 1: Vascepa intervention 2: placebo
Intervention descriptions: intervention 1: Vascepa is a an Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid. intervention 2: placebo

Protocol document:
Prot_SAP_001.pdf: 
1 
 
Effect of Vascepa on Progression of Coronary Atherosclerosis in Persons with Elevated 
Triglycerides on Statin Therapy 
 
 
 
Investigators 
Matthew Budoff, MD 
 
Co-Investigators  
J. Brent Muhlestein, MD 
Viet Le, PA 
Heidi T. May, PhD, MSPH 
John R. Nelson, MD  
Sion Roy, MD 
 
Corresponding Investigator: 
Matthew Budoff, MD 
 
1124 W Carson Street 
 
Torrance, CA 90502 
 
(310) 222-4107 
 
Budoff@ucla.edu 
 
Sponsoring Institutions 
Los Angeles Biomedical Research Institute 
Intermountain Heart Institute, Intermountain Medical Center 
California Cardiovascular Institute 
 
Research funding  
Amarin 
 
Protocol: Version 3, February 13, 2017 
 
ClinicalTrials.gov Identifier: NCT02926027 
 


2 
 
BACKGROUND 
Residual cardiovascular (CV) risk remains in dyslipidemic patients despite intensive statin therapy, 
underscoring the need for additional intervention.  Eicosapentaenoic acid (EPA), an omega-3 
polyunsaturated fatty acid, is incorporated into membrane phospholipids and atherosclerotic 
plaques and exerts beneficial effects on the pathophysiologic cascade from onset of plaque 
formation through rupture. Specific salutary actions have been reported relating to endothelial 
function, oxidative stress, foam cell formation, inflammation, plaque formation/progression, platelet 
aggregation, thrombus formation, and plaque rupture. EPA also improves atherogenic dyslipidemia 
characterized by reduction of triglycerides without raising low-density lipoprotein cholesterol. All 
of this data supports the biologic plausibility of EPA as an anti-atherosclerotic agent (1).  In the 
Study on Prevention of Coronary Atherosclerosis Intervention with Marine Omega-3 Fatty Acids 
(SCIMO) data has shown that omega-3 PUFA (both DHA and EPA) slow progression of 
atherosclerosis in coronary arteries [2].  However, this data used invasive angiography. There is 
only limited data regarding the effects of EPA without DHA added to statin versus statin alone 
therapy in reducing coronary plaque volume. Utilizing integrated backscatter intravascular 
ultrasound (IB-IVUS), 1.8 grams/day of EPA added to standard  statin therapy, unlike statin therapy 
alone, reduced plaque volume and inflammatory cytokines over 6 months of follow-up (3). 
Recently, a second study using IB-IVUS showed reduction in both plaque and lipid volume over 6 
to 8 months in patients who were treated with 1.8 grams/day of EPA and high dose pitavastatin 
(4mg/day) unlike high dose pitavastatin alone (4). Data regarding the effects of EPA on plaque as 
measured by multidetector computed tomography (MDCT) are even more limited, with an abstract 
reporting that MDCT showed that patients randomly assigned to EPA, unlike ezetimibe, reduced 
plaque lipid content at 1 year (5).Furthermore, a case report described a patient with plaque 
regression under the influence of EPA (6).   
 
MDCT allows for a robust study of atherosclerosis at a nominal cost compared to intravascular 
ultrasound or invasive angiography to demonstrate that Vascepa has a positive effect on 
atherosclerosis, to complement the outcome study ongoing.  This becomes a critical question 
among cardiologists, endocrinologists and primary care physicians, who will want to see event 
reduction and plaque reduction to feel compelled to use this important intervention on their high 
triglyceride patients. MDCT is now used in numerous ongoing studies evaluating such therapies as 
testosterone, statins, hormone replacement, garlic, anti-inflammatories and anti-diabetic agents. The 
ease of use, low cost and minimal invasiveness makes this much more practical and desirable as a 
study tool for atherosclerosis than either intravascular ultrasound or carotid intimal media thickness. 
A small multicenter study can determine with high confidence the ability of Vascepa to modify 
plaque in persons with high triglycerides. 
 
Multiple studies have been published regarding the use of MDCT angiography on plaque over time. 
Initial study sample size is estimated based on MDCTA data showing 24±13% reduction in 
coronary artery plaque volume with statin therapy (6). Other CCTA studies performed by our group 
also demonstrate rapid plaque changes over time, and significant differences between groups. In a 6 
month follow-up study of patients with ACS treated with a 5 lipo-oxygenase inhibitor or placebo, 
cardiac computed tomography angiography (CCTA) demonstrated a 21% increase in plaque in the 
placebo treated population (including statins) (7).  In a second placebo controlled randomized 
study, placebo patients (on statins), exhibited an 8.1% change in plaque, significantly greater than 
those randomized to a garlic preparation (5). In a third study of patients with diabetes, the plaque 


3 
 
progression by CCTA in the entire cohort was 24% per year, a 2.5 fold the rate of change seen in 
non-diabetic patients (8). We have also demonstrated significant differences in 1 year time between 
statin treated and non-statin treated cohorts (10).      
 
While clinical utility of Vascepa is well established in the >500 mg/dl triglyceride level group, there 
remains questions about use in lower TG values. The ability to retard progression or induce 
regression of atherosclerosis would dramatically drive utilization and clinical confidence in the 
therapies. Patients and physicians alike are looking for therapies, in addition to statins, to address 
this very high clinical need. The number of therapies available for triglycerides are plentiful, so 
differentiating Vascepa in this crowded field will be met with great enthusiasm. More evidence of 
benefit, along multiple lines, is clearly a mechanism to improve confidence for physicians and 
patients alike.    
 
The goal of this study is to evaluate whether treatment with Vascepa (4 grams) results in a greater 
change from baseline in low attenuation plaque than placebo in subjects with elevated triglycerides 
(200-499 mg/dl). 
 
HYPOTHESIS  
Primary Hypothesis: Vascepa (4 grams/day) and statin therapy will reduce progression of low 
attenuation plaque volume over 9-18 months as measured by serial coronary CT angiography 
(CTA) as compared to statin alone in patients with triglycerides 200-499 gm/dl.  The mechanisms 
underlying the coronary effect of EPA will include a) reduction in non-calcified coronary 
atherosclerotic plaque, b) reduction in vulnerability features of non-calcified coronary 
atherosclerotic plaque.  
 
Secondary Hypothesis:  1) Vascepa will significantly reduce non-calcified coronary plaque and total 
plaque volume progression as compared to placebo. 2) Decreases in plasma levels of triglycerides, 
remnant lipoproteins (VLDL3-C + IDL-C), Arachadonic acid (AA), an improvement in critical 
indices of inflammation, and an increase in the apoA1 to remnant ratio (apolipoprotein A1/[VLDL3-
C + IDL-C]), EPA, EPA/AA ratio associated with EPA therapy will be predictive of improvement 
in non-calcified coronary atherosclerotic plaque burden and/or vulnerability features.  
 
STUDY OBJECTIVES 
Primary Objective: Determine progression rates of low attenuation plaque under influence of 
Vascepa as compared to placebo. 
  
Secondary Objectives: a) To determine the effects of Vascepa on the morphology and composition 
of non-calcified coronary atherosclerotic plaque (NCP), including the progression of total plaque 
volume and whether these effects are modulated by lipid changes and markers of inflammation; b) 
To determine the effects of Vascepa on detailed markers of inflammation (Lp-PLA2, hsCRP, IL-6), 
lipids and lipoproteins (ox-LDL, remnants (VLDL3-C + IDL-C), apoliprotein A1 to remnant ratio, 
EPA, AA, EPA/AA ratio), and traditional CVD risk indices.  
 
 
 
 


4 
 
METHODS 
A randomized double blind trial that compares Vascepa 4 gm/day with placebo among patients with 
elevated triglycerides (200-499mg/dl). Patients will be educated to maintain a low cholesterol diet 
through education to patients as well as statin medication compliance. 
 
Study Design 
Patients will be randomized 1:1 to Vascepa or placebo to evaluate progression rates of low 
attenuation plaque volume. At multiple centers, a total of 80 eligible subjects will be enrolled, with 
a goal of 70 completing the study.  Patients will be evaluated for efficacy at an interim evaluation at 
9 months by statistician and DSMB and if efficacy is not achieved then patients will be followed for 
additional 9 months to determine lack of progression of low attenuation plaque volume at 18 
months.   
 
Randomization and Stratification 
Subjects who meet the eligibility criteria will be randomly assigned to receive Vascepa or matching 
placebo. 
 
Inclusion and Exclusion Criteria 
Inclusion Criteria 
*    Age 30-85 years 
*    Elevated triglycerides (fasting value between 200-499 mg/dl) at qualifying or baseline visit 
*    Subjects must provide written informed consent after the scope and nature of the investigation 
has been explained to them 
*    LDL-C ≤115 mg/dL on appropriate statin therapy 
*    LDL-C >40 mg/dL 
*    Stable diet and exercise, as defined as the same pattern for the previous 4 weeks  
*    Stable treatment with a statin+/- ezetimibe for at least 4 weeks  
*    Patients with at least 1 angiographic stenosis with at least 20% narrowing by coronary 
      computed tomography angiography (CTA). 
*    Willingness to be on birth control for women of childbearing age or established post-
menopausal 
 
Exclusion Criteria 
*    A contraindication to fish or fish oils including: known hypersensitivity to drug or fish 
*    Any unstable medical, psychiatric or substance abuse disorder that in the opinion of the      
      investigator or principal investigator is likely to affect the subject's ability to complete the 
      study or precludes the subject's participation in the study 
*    Non-study lipid altering medications or supplements (ie – Niacin, PCSK9, fibrates, bile acid  
      Sequestrants, dietary fish oil supplement capsules, orlistat [OTC (Alli®) as well as Rx 
(Xenical®)] or other drugs used for weight loss) 
*    Stable (same daily dose for the last 4 weeks) on medications that can affect lipids (retinoids, 
hormones, steroids, HIV medications, 
      chemotherapy, thyroid medications) 
*    BMI > 40  
*    Bleeding disorder 


5 
 
*    Uncontrolled hypertension (SBP≥ 180 mmHg or DBP≥100 mmHg) 
*    History of known myocardial infarction, stroke or life-threatening arrhythmia within the prior 
      six months 
*    NYHA Class III- IV heart failure 
*    History of malignancy within the last 5 years (other than skin cancer) or evidence of active 
      cancer which would require concomitant cancer chemotherapy 
*    Serum creatinine > 1.4 mg/dl 
*    Drug or alcohol abuse, or current intake of more than 14 ounces of alcohol per week for men 
      and 10 ounces for women 
*    Concurrent enrollment in another placebo-controlled trial or within 30 days of finishing 
      another trial 
*    Partial ileal bypass or known gastrointestinal disease limiting drug absorption 
*    History of hypertensive encephalopathy or cerebrovascular accident 
*    Hematological or biochemical values at screening outside the reference ranges considered as 
      clinically significant in the opinion of the investigator or PI 
*    Pregnancy 
*    Genetic mutations/polymorphisms having an effect on blood lipids 
*    History of coronary artery bypass surgery 
*    Allergy to contrast material  
*    Allergy to beta-blocker in subjects with resting heart rate >70 bpm 
Endpoints 
Primary: Rate of change in low attenuation plaque volume as measured by MDCT angiography. 
 
Secondary Endpoints 
1. To assess incident plaque rates and quantitative changes in different plaque types among patients 
randomized to placebo and Vascepa using CTA. 
2. To determine the effects of Vascepa on detailed markers of inflammation (Lp-PLA2, hsCRP, IL-
6). 
3. To determine the effects of Vascepa on lipids and lipoproteins (ox-LDL, remnants [VLDL3-C + 
IDL-C], apoliprotein A1 to remnant ratio, EPA, AA, EPA/AA ratio) 
 
Power Calculation 
Assuming 80% and an alpha of 0.05, a total of 70 (35 per arm) patients are needed to evaluate the 
primary outcome of the study (EAST, version 6.3; Cambridge, MA). The primary outcome is the 
progression rate of low attenuation plaque volume at final assessment compared to baseline 
assessment. Initial study sample size was estimated based on MDCTA data showing 24±13% 
reduction in coronary artery plaque volume with moderate dose statin therapy (7).  We assume an 
8% reduction in plaque volume (1/3 that seen with statin therapy), would be the minimal important 
change in non-calcified plaque volume.  Multiple studies have shown similar progression rates 
under the influence of different therapies (8-11).  Furthermore, ample data has been obtained using 
low attenuation plaque (LAP) volume in both MDCT and IVUS Studies.  In the Niki study (3) 
Statin +EPA vs Statin alone at 6 months), at lipid volume decreased from 18.5 to 15.0(18.9%); 
control 17.8 to 19.8-increased 11.2% (difference 30.1%).  The CHERRY study, (Pitavastatin +EPA 
vs Pitavastatin alone for 6-8 months), lipid volume decreased from 39.2 to 34.8 (11%); control 42.7 


6 
 
to 39.3 (8%).  Thus, plaque decreased between 11 and 18.9% in two studies in the EPA arms.  
Furthermore, in the Shintani study of EPA vs ezetimibe, there was a change of 29.2-25.1 (decreased 
14%), using the same range of HU that we are using to represent LAP. Based on these 3 trials, an 
8% improvement in LAP in the EPA arm of the trial being proposed in this protocol is reasonable. 
Assuming an average of 1.7 measurable plaques per study subject, with intra-subject plaque 
correlation of 0.24 (12) (providing variance inflation factor of 1.06 to account for lack of statistical 
independence of plaques within same study subject) (13), 70 patients would provide power of 0.80 
and a one-sided type I error of 0.05 to detect a 8% difference in plaque volume between the active 
compared to placebo group. Overall change for each plaque type from baseline will be calculated 
for each patient.  Assuming a 15% dropout rate, a total of 80 (40 per arm) patients would need to be 
enrolled.  
 
Interim Analysis 
Using the Lan-DeMets version of the O’Brien-Fleming group sequential boundaries for a 2-look 
sequential design (1 interim at 9 months + final analysis), the statistical power to test the primary 
study endpoint is 80% based on a sample size of 70 patients randomized in a 1:1 allocation ratio 
and an overall experimental type I error equal to 0.05 using a 1-sided hypothesis test. If a p-value of 
<0.006 is achieved at 9 months then the study will terminate because the efficacy boundary will 
have been achieved.  
 
Statistical Analysis  
Baseline examination of the subjects will include the results of their demographics, coronary risk 
factor, laboratory tests, coronary calcium, as well as coronary plaque volume/composition. These 
baseline characteristics will be compared between the arms. Baseline information regarding risk 
factors for atherosclerotic cardiovascular disease (cigarette smoking status, systemic hypertension, 
family history of premature atherosclerosis, menopausal and hormone replacement status in 
women, sedentary lifestyle, current medications, chest pain questionnaire and measures of obesity, 
diabetes medication use) will also be determined.  After randomization, participants will evaluated 
at 3, 9 and 12 months, and if needed 15 months (by phone-only) and 18 months, to assess 
compliance with medication, and receive an additional supply of medicine. At 9 and 18 (if needed) 
months, coronary plaque volume/composition will be measured at MDCT by readers blinded to the 
randomization and clinical activities, who are not aware of study-group assignments. The primary 
analysis will utilize intention-to-treat principles, with study subjects analyzed by treatment group 
assigned regardless of study drug adherence. A sensitivity analysis will be performed for those 
adhering to interventions for over 80% of the duration of the study. Differences in baseline 
characteristics between groups will use analysis of variance for normally distributed continuous 
traits and chi-square or Fisher’s exact test for categorical variables. For normally distributed 
continuous outcomes, including percent change in low attenuation plaque, we estimate mean 
percent group differences using linear mixed models with baseline value, time and treatment group 
as fixed effects. Least squares means will be estimated from the models. Models evaluating per 
patient outcomes will include fixed effects. Natural log-transformations will be used for variables 
with log-normal distributions. For the analyses of the primary, secondary, and exploratory efficacy 
variables, the statistical modeling assumptions should be examined. If significant departures from 
normality (p-value <0.01 for the Shapiro-Wilk test) and/or homogeneity of variance are observed, 
the non-parametric analysis approach will be considered. When parametric and non-parametric 
results do not corroborate each other, the results from the non-parametric analysis will be used. 


7 
 
Otherwise, the parametric analysis will be reported.  Baseline characteristics will be provided as 
mean and standard deviation or median and interquartile range, changes from baseline are provided 
with 95% confidence limits. All statistical tests report 1-sided p-values for the outcomes. A p-value 
less than 0.048 will be considered significant for the outcomes. All analyses will be performed 
using SAS for Windows, version 9.3 (SAS Institute, Cary, North Carolina). 
 
CCTA EVALUATIONS 
CCTA 
As successfully performed in previous NHLBI-funded investigations by the PI, CCTA scans will be 
read in a blinded fashion at the MESA CT Reading Center (RC). CCTA will be performed using 
state of the art 64+ MDCT technology. At Intermountain Health, a 64-slice coronary computed 
tomography (CT) scanner (Aquilion 64, Toshiba America Medical Systems) will be used.  At Los 
Angeles Biomedical research Center, a Revolution 256-detector scanner (GE Medical, Milwaukee, 
WI). Both sites will pass quality control training under RC supervision and have extensive expertise 
in performing CCTA. All participants will be hydrated pre and post scan. Nonionic contrast 
material will be used. The CCTA study will incorporate all dose reduction strategies available, 
including prospective ECG-triggering and iterative reconstruction. Participant burden for the CCTA 
is anticipated to be 1 hour.  
 
CCTA Protocol 
1.  Renal function will be measured within 3 months of the scan to determine eligibility for contrast 
injection.  
2.  Preprocedural Medications [beta blockade (only when needed for increased heart rate)] 
a. Metoprolol: If the heart rate is >70 beats per minute (BPM), 50 mg of metroprolol will be given 
orally and if HR remains >70 BPM at the scan acquisition then, intravenous metoprolol 2.5-5 mg 
every 5 minutes administered to achieve a heart rate between 50-70 BPM as blood pressure 
tolerates under physician supervision.  Participants may receive intravenous diltiazem 10-25 mg IV 
if contraindicated for β-blockade (reactive airway disease).   
b. Nitroglycerin: Unless systolic blood pressure is less than 90 mm Hg supine or known nitrate 
intolerance, participants will receive 0.4 mg of sublingual NTG one minute before contrast scan 
initiation to improve epicardial vasodilation, unless the participant took Viagra, Cialis or LeVitra 
within 24 hours of the study. 
 
Contrast Administration 
CCTA will be performed during a 4-5 ml/sec intravenous iodinated infusion.  The total contrast 
dose will not exceed 70 ml.  Depending on participant size, 50-70 ml iodinated contrast will be 
used. The automated bolus tracking feature will be used to judge contrast bolus arrival and optimize 
image quality.  Participant breath hold during scanning will be approximately 10-15 seconds.   
 
CCTA Evaluation 
The CT reader will interactively use axial images, multi-planar reconstructions (MPR) and 
maximum intensity projections to assess the degree of luminal narrowing stenosis in all assessable 
coronary segments. Standard display settings will be used for the evaluation of the CCTA scans 
(window width 800 HU; window center 250 HU). Stenotic segments will be defined as minimal (1-
25% diameter narrowing); mild (26%-50%); moderate (51-70%) and severe (>70% stenosis). We 
will specifically report % diameter stenosis (not area), since the spatial resolution of CCTA cannot 


8 
 
achieve quantitative coronary angiography precision. The most narrowed diameter in each segment 
will be reported even if the plaque is eccentric. Segment stenosis score will also be generated based 
on the degree of underlying stenotic disease in each segment (0=none, 1=1-25%, 2=26-50%, 3=51-
70%, 4=>70%). The summed scores of 15 segments will yield a total score from 0-60.   
 
CAC METHODOLOGY 
After arterial trajectories are determined and a phantom-based adjustment applied, candidate 
calcified plaques will be identified by the software with the criteria that each plaque be composed 
of at least 4 contiguous voxels with an attenuation level of 130 HU or greater. The readers review 
each candidate plaque and accept or reject its classification as calcified plaque. To calculate the 
Agatston score, each accepted lesion is assigned a score by multiplying the lesion volume by a 
coefficient based on its maximum HU (coefficient of 1 if maximum=130-199, 2 if 200-299, 3 if 
300-399, 4 if ≥400). The Agatston score is the sum of the scores across all accepted lesions.  We 
will also derive volume scores, and density measures of each plaque.  
 
Plaque quantification 
Plaque volume will be assessed per slice in all affected coronary segments measured by semi-
automated quantification software (QAngio, Medis, Netherlands). First, an automatic tree extraction 
algorithm will be used to obtain all the 3-dimensional centerlines of the coronary tree. Based on 
these centerlines, straightened MPR volumes are created of all vessels. Next, the lumen border 
contours and vessel wall borders are assessed using spatial first- and second-derivative gradient 
filters in longitudinal cross sections. Thereafter lumen and vessel contour are detected in the 
individual transversal cross-sections perpendicular to the centerlines. This method is insensitive to 
differences in attenuation values between data sets and independent of window and level settings. 
Once automated software has completed the vessel trace, an expert reader will manually correct 
areas of misregistration. The volume of each plaque visualized in at least 2 adjacent slices (slice 
thickness 0.6 mm) will be determined. For each lesion, minimal lumen diameter will be summed 
and plaque reported as non-calcified, low attenuation or calcified. The protocol for quantitative 
plaque assessment has been widely used in numerous previous studies by the PI, including active 
NHLBI studies: R01 HL095129 (MACS) and 5U01AG030644 (T Trials, PI- Snyder).  
 
Plaque Composition 
Plaque Composition is based upon predefined fixed intensity cutoff values of CT attenuation. These 
are based upon studies by comparing CCTA with virtual histology by IVUS or histological 
examination in our lab and others. The fixed HU cut-off values that will be used for classifying are: 
-50 to 50 for low attenuation plaque, 51–130 for non-calcified, 131–350 for fibrotic, and >350 for 
dense calcium. These values were initially based on Brodoefel  and empirically optimized using 
three representative training sets.  The inter- and intra-observer variability for the lumen and plaque 
volumes have been previously described.  
 
Image Post-processing and Reconstruction 
For prospective imaging, several phases will be transmitted to the MESA RC.  In case of vessel 
wall calcification, additional images will be reconstructed using sharp-tissue convolution kernel and 
analyzed using a bone window setting to compensate for blooming artifacts. We anticipate the 
number of excluded segments to be <3%, and the number of image-quality excluded participants to 


9 
 
be <1%.  Stented segments will be excluded from baseline and follow-up analysis for plaque and 
CAC measures.   
 
DATA SAFETY AND MONITORING BOARD   
The DSMB will meet via teleconference at six-month intervals during the course of the trial to 
monitor trial progress, safety and efficacy.  The report includes extensive summaries by treatment 
group. Treatment groups will be coded for confidentiality (Group A and Group B) in the event there 
is significant adverse events (p<0.05) or significant benefit (P<0.001); the DSMB will be informed 
of the treatment codes prior to the end of the study. Along with a detailed commentary summarizing 
the results, the following statistical summaries by treatment arm will be provided: 
 
Treatment comparisons of all endpoints  
 
Summary of adverse events by type and level of severity 
 
Summary of study drug discontinuation  
 
Analyses of major endpoints by baseline subgroups 
 
 
Schedule of Assessments 
  
Visit 1 
(baseline) 
Visit 2 (3 
month) 
Visit 3 (9 
month) 
Visit 4-phone only 
(15 month) 
Visit 5 (18 
month) 
Informed Consent 
X  
  
  
  
  
Demographics, Medical History 
X  
  
  
  
  
Concomitant Medications 
X  
X  
X  
  
X  
Blood pressure, height, weight 
X  
X  
X  
  
X  
Blood draw 
X  
  
 X  
  
X  
Physical Exam 
X  
  
X  
  
X  
CCTA 
X  
  
 X  
  
X  
Dispense Study Drug 
 X  
 X  
 X  
  
  
Drug accountability 
  
 X  
X  
  
X  
AE/ SAE assessment 
  
 X  
 X  
 X  
X  
 
 
Visit 1 (baseline):  
The study staff will meet the prospective candidates at the study site.  After study staff presenting 
the study and patient agreeing to participate, s/he will collect the following items: 
1)  Authorization for medical records release and informed consent, 
2)  Address, telephone number, social security number, phone numbers of contacts and 
physicians, 
3)  Demographic information including family history of CAD, smoking history, and 
medical history 


10 
 
4)  Medication usage, including anti-platelets, prior or current use of cholesterol lowering 
medication, beta adrenergic blocking agents and other anti-hypertensives, calcium 
supplementation, hormone replacement and bisphosphonate use.  All medications, 
including dietary supplements, and nutritional assessment will be measured to assess fish-
oil intake. 
5)  Review of all inclusion/exclusion criteria. 
6)  If the patient meets all inclusion/exclusion criteria, will be scheduled for visit CCTA. 
If the patient qualifies for the study and has signed informed consent, patient will undergo the 
following at this visit.  If the patient is fasting and qualifies, the following can be performed on the 
same day, preferably in the morning and will be fasting for a minimum of 12 hours: 
1) Blood pressure and pulse measurements from each arm 
2) Height and weight measures 
3) Laboratories – Phlebotomy (fasting) for markers of inflammation (Lp-PLA2, hsCRP, 
IL-6), lipids and lipoproteins (ox-LDL, remnants [VLDL3-C + IDL-C], apoliprotein A1 
to remnant ratio, EPA, AA, EPA/AA ratio), genetic studies  Additional blood storage 
(samples will be stored at -70 0C) for possible future testing (see Laboratory Analysis 
section below).  Urinalysis and serum pregnancy testing (if appropriate) will be performed 
at this visit.   
4)   
Physical examination 
5)   Coronary plaque volume/composition assessment using CT angiography 
6) Re-Assessment of all medications, including dietary supplements, and nutritional 
assessment (dietary questionnaire), as well as allergies to contrast material and beta-
blockers 
7) Randomization to 1:1 to Vascepa or placebo.   
The participants will then be randomly assigned to one of two treatment categories in a 
double-blind fashion. Randomization will occur according to a computer generated 
randomization code.   Patients will receive a supply of randomized mediations, and be 
instructed to take medication each day.  Group I will receive substance A and group II 
will receive substance B with same markings.  Each bottle will have a 2-panel label 


11 
 
affixed, which will include the following information: study number, visit number, 
directions for use, emergency number.  All analyses will be based upon intention to treat.  
The central laboratory assessment of fasting blood lipids will be determined throughout 
the study, and the central laboratory will be blinded as to patient treatment category.   
 
After randomization, participants will return 3 months to assess compliance with 
medication, and receive an additional supply of medicine.  Vital signs, blood samples, 
AE/ SAE/ MACE events will be also be assessed at the 3 month visit.  At the 9 month 
visit, ALL baseline assessments will be repeated, inclusive of the cardiac CT angiography. 
   
Interim evaluation will take place at 9 months and if efficacy is not achieved then 
participants will be followed for an additional 9 months, to determine lack of progression 
of low attenuation plaque volume.  ALL baseline assessments will be repeated at 18 
months, inclusive of the cardiac CT angiography. 
At 15 months, a phone evaluation will take place, to assess AE/ SAE/ MACE events.   
 
Laboratory Analyses 
Upon entering the study, each subject will have blood drawn after a 12 hour fast. In all 
subjects, a blood sample of approximately 30 cc will be drawn from an arm vein by the 
phlebotomist.  The sample(s) will be centrifuged and the serum and plasma separated.  
This will be placed into four tubes and aliquoted into 16 micro-vials for shipping and 
long-term storage. Locally, samples will be stored at -70 0C or below. Analyses will be 
performed to measure chemistry analysis, lipids and lipoproteins, as well as inflammatory 
markers.  Frozen serum for coagulation factors, antioxidant levels, and hormonal levels 


12 
 
will potentially be evaluated for future studies/sub studies, and storage at –700C, will 
allow future studies. In addition to the above variables, biochemical and physiological 
parameters will be measured.  At 9 months, fasting blood parameters, cardiac CT 
angiography and assessments will be made, and will be repeated again at the 18 month 
visit, as applicable.   
 
 
 
Genetic Studies  
If the subject consents to the optional genetic portion of this study, DNA analyses may be 
performed. These optional genetic analyses focus on inherited genetic variations such as 
Statin myopathy SLCO1b1, Clopidogrel Response(CYP2C19), ApoE-Isoform, Factor II, 
Factor V Leiden, MTHFR to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study. 
 


13 
 
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3.Niki T,Wakatsuki T,Yamaguchi K,Taketani Y,Oeduka H,Kusunose K,Ise T,Iwase T,Yamada 
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Appendix 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. 
 
Serious Adverse Event Reporting – Procedure for Investigators 
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 
 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. 
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. 


16 
 
3 Data Safety Monitoring Board (DSMB) 
The adverse events will be monitored by an independent DSMB. A DSMB consisting of 
individuals with expertise in each of the efficacy areas (cardiac computed tomography, 
atherosclerosis) will be established.  Dr Sion Roy will chair the DSMB, and will also be 
represented by Dr Muhlestein (cardiologist at IMH).  DSMB will be independent from all staff 
involved in the day-to-day conduct of the study. The DSMB Chair will prepare interim reports to 
the DSMB on a regular basis, every 6 months or more often as it deems appropriate.  Reports 
that include general study information such as accrual, dropout, and ineligibility rates and other 
performance parameters, will be available to the study leadership and will be discussed with 
them at open sessions.  Data relating to safety and efficacy that are presented by treatment arm 
will be considered highly confidential and will be available only to the DSMB and the 
statistician preparing the reports, and will be discussed at closed sessions of the DSMB. The 
Interim reports to the DSMB will focus on analyses of the safety data -- primarily related to 
cardiac CT and study drug-- but other safety-related outcomes, such as CT related adverse 
effects, will also be reviewed in an unblinded fashion. Formal statistical comparisons on 
incidence of AEs, lab abnormalities, and concomitant medication use likely will lack power 
given the relatively small amount of patients.  Will therefore use descriptive statistics for these 
data.  The DSMB will decide on the basis of these data whether to recommend modifying or 
stopping the trial and will make recommendations to the sponsor and the study leadership.