Clinical trial NCT02422446
Conditions: Type 2 Diabetes Coronary Artery Disease
Keywords: Endothelial function Eicosapentaenoic acid Triglycerides
Sponsor: Brigham and Women's Hospital
Start date: 2015-04-01; Completion date: 2017-03-01
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This pilot trial seeks to obtain preliminary data on the effects of eicosapentaenoic acid (EPA) (4g/d) on endothelial function measured via endopat2000 after 12 weeks of intervention among adults with elevated triglycerides and type 2 diabetes.

Detailed description:
Thirty adults aged 30-75 y will be randomized to either 4 g/d of eicosapentaenoic acid or no drug for 12 weeks. Endothelial function will be measured at baseline and after 12 weeks. in a secondary aims, we will evaluate effects of eicosapentaenoic acid (EPA) on plasma levels of c-reactive protein, oxidized low-density lipoprotein cholesterol, and endothelin-1.

Arms: arm 1: EPA arm will receive 4 grams per day of EPA (icosapent ethyl) taken twice a day arm 2: Control group will not receive EPA
Interventions: intervention 1: Icosapent ethyl
Intervention descriptions: intervention 1: icosapent ethyl is eicosapentaenoic acid, an omega-3 fatty acid that naturally occurs in fish

Protocol documents:
Prot_SAP_002.pdf: 
 
 
 
 
Title:  
Effects of eicosapentaenoic acid on endothelial function in diabetic 
subjects: a pilot trial 
 
 
 
 
 
 
 
 
 
 
NCT#:  
NCT02422446 
 
 
 
 
 
 
 
 
 
 
 
 
Date:   
February 22, 2016 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Study Protocol and Statistical Analysis Plan 
 
C.1. Study Design 
We will use a randomized single blind controlled trial design to address proposed aims. 
Specifically, the Center for Clinical Investigation (CCI) at Brigham and Women’s Hospital will 
recruit adults aged 30+ years for participation in this study. In order to be eligible, a participant 
must be diagnosed with 1) type 2 diabetes at least one year prior to enrollment, 2) have 
elevated serum triglycerides (150-400 mg/dl), 3) a RHI ≤ 2.0131, and 4) be on statin treatment for 
at least six months at the time of enrollment. Additional eligibility criteria include a) ability to 
travel to the study site at Brigham and Women’s Hospital for three study visits, the last two 
being spaced by 12 weeks, b) ability to provide informed consent, and c) willingness to abstain 
from fish oil and other forms of omega-3 supplements during the study period. Exclusion criteria 
include a) current eating disorders, b) pregnancy (using urine test for all premenopausal women 
of childbearing age without surgical sterilization), c) allergy to EPA or other omega-3 fatty acids, 
d) inability to provide informed consent, e) history or prevalent diagnosis of cancer, asthma, 
kidney insufficiency, stroke, or seizures, f) inability to provide blood specimens, g) current use of 
fish oil, >2 servings of fish per week, or omega-3 fatty acid supplements, and h) intention to 
move out of greater Boston area within one year. Complete list of inclusion and exclusion 
criteria is provided in Table 2. 
 
Table 2. Inclusion and exclusion criteria 
A. Inclusion criteria 
❑ Age 30-75 years  
❑ Hypertriglyceridemia (150-400 mg/dl)  
❑ Statin use for at least six months at the time of screening 
❑ Type 2 diabetes treated with diet and/or oral hypoglycemic agents diagnosed 1+ year 
from first visit 
❑ Ability to provide informed consent and provide blood samples 
❑ Willingness to abstain from fish oil, EPA, over the counter niacin,  and other omega-3 
fatty acid supplements during the study period (12 weeks) 
❑ Ability to travel to the study site at Brigham and Women’s Hospital for 3 study visits  
❑ RHI of ≤ 2.0 
 
B. Exclusion criteria 
❑ Eating disorder or heavy drinkers (>2 standard drinks/d: a drink= 1.5 oz liquor, 4oz wine, 
or 12 oz beer)  
❑ Treatment with chronic prescription pharmacotherapy for metabolic or cardiovascular 
disease management or risk factor modification (e.g., antihypertensive medications) that 
has not been stable for ≥4 weeks prior to screening 
❑ Pregnant or lactating women 
❑ Statin use <6 months at the time of screening 
❑ Allergy to EPA, fish oil, shellfish, or other omega-3 fatty acids 
❑ Current use of insulin, cyclophosphamide, estrogen, fibrates, niacin, hormone 
replacement therapy, testosterone, oral contraceptives, growth hormones, insulin-like 
growth factor-1, and other systemic steroids.  
❑ Inability to provide informed consent or blood samples 
❑ History or prevalent diagnosis of cancer, asthma, kidney insufficiency, stroke, seizures, 
allergic disorders, liver disease, or congestive heart failure 
❑ Diagnosis of diabetes < 1 year prior to enrollment 


❑ Intention to move out of greater Boston area within one year 
❑ Current use of omega-3 supplements, fish oil, or >2 servings of fish per week 
❑ Bleeding disorder or uncontrolled endocrine (i.e., thyroid) or metabolic disorders  
❑ Treatment with blood thinning drugs (i.e. warfarin and clopidogrel)  
❑ Major surgical operation 3 months before or after screening 
❑ Organ transplantation 
❑ Current participation in another trial or plan to do so during the study 
❑ Inability to give informed consent or to travel to the study center at Brigham and 
Women’s Hospital 
❑ RHI of >2.0 
❑ Triglycerides <150 mg/dl or >400 mg/dl 
❑ Body mass index of 40+ kg/m2 
 
 
C.2. Recruitment of Study Subjects 
Upon receiving IRB approval from Brigham and Women’s Hospital (BWH), potential 
participants will be recruited via usual advertisement techniques, including flyers posted on 
campus, media advertisement, and use of Partners Biobank (a letter co-signed by Partners 
Biobank PI and Dr. Djousse with a card and a prepaid return address will be used). Each flyer 
will contain pertinent information summarizing the study protocol and objectives and contact 
information for study staff. Interested participants will contact the study coordinator, who will 
conduct a telephone screening for eligibility. Once a potential study subject has been 
determined to be eligible via telephone, he/she will be provided with detailed information about 
the study by the PI/study coordinator. The potential participant will then review the study 
materials before determining if he/she will voluntarily participate in the study. If yes, he/she will 
call the investigative team for an appointment for the first visit (screening) at the CCI, Brigham 
and Women’s Hospital, Boston, MA. The goal would be to recruit and enroll 30 people with 
prevalent DM, triglycerides between 150 and 400 mg/dl, and current statin use. We will build in 
margin for 10% attrition and recruit 33 subjects overall. Details on inclusion and exclusion 
criteria are provided in Table 2. 
 
C.3. Randomization Scheme 
Randomization will occur during the second study visit at the CCI for those who meet 
eligibility criteria. In this pilot study, 30 subjects will be randomized with equal probability to EPA 
intervention (n=15) or no EPA (no drug) (n=15) stratified according to gender. Permuted blocks 
(block size of 2) will be used to achieve groups of equal size132.  We will create blocks within 
each gender and each ethnicity (Caucasian, African- American, and others) to assure balance 
distribution of gender and ethnicity between the two groups. 
 
C.4. Study Visits 
Visit # 1: During this visit, the PI will explain the study objectives, study protocol, and 
sequences of events and answer any remaining questions that the subject may have about the 
study. If after such conversation with the PI, the subject is still willing to freely participate in the 
study, then he/she will sign the informed consent  prior to the beginning of the screening 
process. Specifically, subjects will obtain overview of the study and the PI will complete 
endothelial function assessment using EndoPat2000 device. Subjects with RHI of 2.0 or less will 
be eligible and will be asked to provide blood sample for triglyceride measurement. First visit will 
end with the collection of blood specimen and subjects will be told that the coordinator will notify 
them via telephone of the results for further eligibility. Only subjects with triglycerides between 
150 and 400 mg/dl will be eligible to be invited to the second study visit. 


Visit # 2:  Eligible subjects identified during visit # 1 will be asked to the CCI fasting but will be 
allowed to take their usual morning medications. Subjects will be instructed to start fasting at 
8PM of the night before the study visit. Pregnancy test will be done to rule out pregnancy among 
pre-menopausal women without history of surgical sterilization. For subjects randomized to 
Vascepa, women who can become pregnant during the study will be asked to use a 
contraceptive method (i.e., hormone, intrauterine device, barrier, or abstinence) during the study 
and six months after the final visit.During the second visit, we will collect baseline blood samples 
(20 ml) for measurement of biomarkers (hsCRP, ET-1, and oxLDL); other relevant biomarkers 
(i.e., TNFα, NTproBNP, apoC3, apoA5, galectin 3, free fatty acids, relevant single nucleotide 
polymorphisms, and fatty acids will be measured at a later time upon securing new funding on 
stored blood specimens). Resting blood pressure and pulse will be measured (2x) after 15 
minutes of rest and information on age, sex, race, education, height, weight will be collected. 
Subjects will also complete a Willett food frequency questionnaire to assess their baseline diet. 
Digital pulse amplitude measurements (see C.6. below) will be done. A dedicated research 
assistant (RA) will discuss the randomization scheme provided by the statistician with the 
subjects. The RA will not be blinded to the treatment assignment. Otherwise, PI, study 
coordinator, statistician, and other staff at the lab measuring biomarkers will all be blinded. 
Subjects randomized to Vascepa will know that they are taking the drug containing omega-3, 
since the drug is not disguised and there is no placebo (open label trial). The RA will advise 
subjects not randomized to Vascepa (control subjects) to continue their usual habits. Each 
subject randomized to EPA will receive a 12-week supply of study EPA from the BWH 
pharmacy with the instructions to take 4 g/d. Each subject will receive a study diary to record 
potential adverse effects during the next 12 weeks. Enrolled subjects will be contacted by 
telephone once a month by the coordinator to query about potential adverse effects and remind 
them of the upcoming final visit. 
 
Visit # 3: Subjects will be invited to come to the CCI fasting (starting from 8PM of the 
night before the visit) during the last visit, which will be 12 weeks after the second visit. Subjects 
will be allowed to take their morning medications prior to the visit. During the last visit, we will 
also complete count of any leftover pills among subjects randomized to EPA and repeat all 
study procedures conducted during the second visit. 
 
C.5. Phlebotomy and Blood Processing at the CCI 
Standard methods for phlebotomy and blood processing will be used. Red blood cells 
and plasma will be stored in 1 ml container at -170 degree freezer until assay measurements. 
All assays will be performed by a qualified laboratory selected based on quality of their work and 
competitive pricing bids (i.e., Dr. Tsai’s laboratory at the University of Minnesota or Dr. 
Lichtenstein lab at Tufts University, Boston).  
 
C.6. Assessment of Digital Pulse Amplitude  
   
Study subjects will be asked to refrain from caffeine-containing beverages or tobacco 
consumption 12 hours prior to the measurement of endothelial function. Digital pulse amplitude 
will be measured in the fasting state (as outlined above) with a fingertip peripheral arterial 
tonometry (PAT) device (Endo-PAT2000, Itamar Medical, Caesarea, Israel) in a supine position 
after a minimum of 20 minute rest in a quiet room with controlled temperature (20-23 degree 
Celsius). Details on digital pulse amplitude measurements have been published 
elsewhere131,133,134. Briefly, the PAT device contains a pneumatic plethysmograph, which applies 
a uniform pressure to the surface of the distal index finger, thereby allowing measurement of 
pulse volume changes in the finger. Baseline pulse amplitude will be measured from each finger 
tip for about 5 minutes. The arterial flow will then be interrupted for 5 minutes with a cuff placed 


on a proximal forearm with an occlusion pressure equal to the highest value of 200 mm Hg or 
the subject’s systolic blood pressure plus 60 mm Hg. The contralateral arm (dominant arm) will 
serve as control. Lack of residual pulsatility will be monitored throughout the occlusion period. 
Pulse amplitude will be recorded electronically in the test and control fingers and analyzed by a 
computerized and automated algorithm that provides the average pulse amplitude for each 30-
second interval after forearm cuff deflation up to 4 minutes (Itamar Medical). The change from 
the baseline measurement will be expressed as the reactive hyperemia index (RHI), which in 
part reflects vasodilator function of the digital microcirculation135. Previous studies have 
demonstrated that RHI is to a large part dependent on nitric oxide bioavailability136.  
For statistical analysis, we will calculate the pulse amplitude response to hyperemia for 
each 30-second interval as a ratio of the post-deflation pulse amplitude to the baseline pulse 
amplitude as described previously133. The RHI will be computed by dividing the ratio obtained on 
the test side (side with blood pressure cuff) over the ratio obtained on the control finger. Since 
the peak of the RHI has been shown to occur between 90 and 120 seconds after the cuff 
release133, we will use the average of RHIs obtained at 90 and 120 seconds post deflation for 
analysis. The reproducibility of this technique has been described previously134,137-139. RHI is 
correlated with traditional brachial ultrasound and CVD risk factors133,140. Low RHI has been 
associated with CAD events141-143 and improve CAD prediction beyond traditional risk factors143. 
 
In order to preserve blinding of key personnel, the PI will complete the assessment of 
endothelial function and an independent research assistant will share the assignment group with 
the study subject once all activities of study visit # 2 have been completed and PI and other staff 
have left the CCI. The RA will instruct the subjects assigned to Vascepa on how to obtain the 
study drug at the BWH research pharmacy. Furthermore, during the third visit, the RA will see 
all study subjects before any blinded staff and collect Vascepa bottle with remaining capsules 
when applicable. This way, the possibility that the PI or study staff inadvertently sees the 
Vascepa bottle is minimized. Subjects will be reminded not to disclose their group status to 
study staff other than the RA assigning the group.  
 
 
C.7. Laboratory Assays 
In a random sample of 5 subjects in each arm, we will measure fatty acid profile at visit # 
2 and visit # 3 to assess compliance with EPA intervention. The fatty acid profile will be 
measured in plasma using the method previously described by Cao et al144. For the extraction of 
plasma phospholipid fatty acids, 0.3 mL of plasma is mixed with 0.7 volume of 0.9% saline. 
Then, 50 uL of 2 g/L 17:0 standard (diheptadecanoyl phosphatidylcholine) is added to monitor 
the extraction efficiency. Lipids are extracted from plasma with a mixture of chloroform:methanol 
(2:1, v/v), and cholesterol, triglycerides and phospholipid subclasses are separated on a silica 
thin-layer chromatography plate in a solvent mixture of petroleum ether, diethyl ether, and 
glacial acetic acid (80:20:1, v/v/v). The band of phospholipids is harvested for the formation of 
methyl esters. Fatty acid methyl esters are prepared with 1.5 mL of 14% boron trifluoride in 
methanol, incubated at 80ºC for 90 minutes, and extracted with petroleum ether. The final 
product is dissolved in heptane and injected onto a capillary Varian CP7420 100-m column with 
a Hewlett Packard 5890 gas chromatograph (GC) equipped with a HP6890A autosampler. The 
GC is configured for a single capillary column with a flame ionization detector and interfaced 
with HP chemstation software. Fatty acid methyl esters from 12:0 through 24:1n9 are separated, 
identified and expressed as percent of total fatty acids. The following coefficients of variation 
were obtained on 20 blind duplicates: linoleic acid = 2.6%; ALA= 2.4%; arachidonic acid = 2.4%; 
EPA= 3.3%; docosapentaenoic acid (DPA) = 2.9% and DHA= 2.7% at Dr. Tsai’s laboratory at 
the University of Minnesota (one of our collaborative laboratories).  


Plasma hsCRP will be measured by Sandwich enzyme linked immunosorbent assay 
(ELISA)145. Plasma oxidized LDL and plasma ET-1 will be measured using a commercially 
available sandwich-enzyme immunoassay kit (R & D); 
All samples will be labeled with the date of collection, subject ID, and visit #. Since blood 
samples will be processed and stored in subzero freezer by the CCI lab personnel, PI and study 
staff as well as lab personnel measuring assays will be blinded from the drug assignment. 
 
A summary of major steps of the study is provided below (Table 3). 
 
Table 3. Time points for activities during the study period 
 
  Study Week 
Activities 
-4 to -1 
0 
12 
Prescreening via telephone 
x 
 
 
Measurement of triglycerides  
x 
 
 
Final screening visit  
x 
 
 
Random allocation to EPA or no EPA and study diary 
 
x 
 
PAT measurements (endothelial function) and phlebotomy 
x 
x 
x 
Demographics, height, weight, medical history, food 
questionnaire 
 
x 
x 
Blood pressure and biomarkers (OxLDL, ET-1, and hsCRP)  
 
x 
x 
 
C.8. Data Management 
Our team has developed a sophisticated computer system to create and maintain data 
sets. Out-of-range, internally inconsistent, and unclear data will be reviewed and corrected as 
necessary. Data collected during each visit will be double-entered into the database system. All 
data will undergo additional within-form and across-time checks to verify accuracy. This 
database will be maintained on a UNIX server that is backed up nightly, ensuring at least two 
current copies at all times. Data entry is performed by two different study staff with many years 
of experience in data processing. The two generated files will be compared. Any errors in 
coding or keying will be corrected promptly. Access to the network is password-protected to 
assure confidentiality. 
 
D. Approach to Achieve Proposed Aims  
 
D.1. Main Aim:  
Effects of EPA on endothelial function in adults with diabetes 
and hypertriglyceridemia  
 
Initially, descriptive statistics such as the minimum, maximum, median, mean and standard 
deviation for each continuous variable and frequency table for each categorical variable will be 
used to summarize the data as well as detect outliers, data entry mistakes, and missing values. 
Exploratory graphical techniques such as Boxplots, Histograms, Quantile-Quantile plots, and Stem 
and Leaf plots will be used to further examine these data. The normality of the distribution of 
primary outcome of interest will be examined with a normal probability plot. The differences of 
baseline characteristics between EPA and placebo groups will be assessed using two sample t-
tests, Chi-square tests or other non-parametric tests as appropriate. The primary analysis will 
be a comparison of the change in RHI from baseline to post-intervention between the 2 groups 
of subjects randomized to either 4g/d of EPA or no drug using a two sample t test or Wilcoxon 
rank-sum test. Analyses will follow the intention-to-treat principle although compliance adjusted 
analysis will be explored where applicable. 
           In addition, we will develop a general linear model including treatment and gender as 
the main effects, and the interaction term between treatment and gender.  We will also examine 


confounding by age, gender, blood pressure, smoking, exercise, body mass index, and alcohol 
consumption. However, due to limited sample size of this pilot study, we will evaluate each 
covariate separately, and the final adjusted model will include no more than 5 predictors. 
We expect an increase in RHI in the EPA group compared with the control group. The 
main goal is to estimate this effect size in order to properly design the future confirmatory trial. A 
lack of statistical significance in this pilot study could be due to several possibilities: 1) four 
grams per day of EPA do not influence endothelial function in this population; 2) unbalanced 
distribution of other determinants of digital pulse amplitude that we were unable to control in this 
pilot study biased the findings; a future larger study would address this issue; 3) lack of effect 
may be attributable to inadequate power to detect a smaller improvement in endothelial 
function; such concern will not be an issue in the main trial with adequate statistical power. We 
will calculate nutrients and energy intake from food questionnaires and assess any change in 
dietary patterns during the study period (by comparing post- and pre-nutrients). All analyses will 
be completed by blinded staff and unblinding will only occur when primary and secondary 
analyses are completed. 
 
D.2. Secondary Aim:  
Effects of EPA on CVD biomarkers in subjects with DM 
and hypertriglyceridemia  
 
 
 Same approach as in the primary aim will be used for the secondary aim. Briefly, the 
distribution of each outcome variable will be examined and Box-Cox transformations may be 
applied. A two sample t-test or Willcoxon rank sum test will be used to compare each outcome 
between treatment and control groups. A multiple linear regression model will be used for 
adjusted analysis. Due to the small sample size, potential confounding factors will be assessed 
separately and may be included in the final model when applicable.  
  
D.3. Statistical Power  
This is a pilot trial in which we will generate preliminary data to test the effects of EPA on 
endothelial function in DM subjects. The purpose of this study is to generate exploratory and 
hypothesis generating data, and most importantly, to estimate the effect size with standard error 
in order to determine the appropriate sample size with sufficient power for the future 
confirmatory trial. Assuming a standard deviation of 0.4 and 15 subjects per arm, we will have 
80% power to detect an effect size of 1.05. 
 

ICF_003.pdf: 
 
 
 
 
 
 
Title:  
Effects of eicosapentaenoic acid on endothelial function in diabetic 
subjects: a pilot trial 
 
 
 
 
 
 
 
 
 
 
NCT#:  
NCT02422446 
 
 
 
 
 
 
 
 
 
 
 
 
Date:   
May 28, 2015 
  
 
 
 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  October 2014 
 
Page 1 of 13 
 
 
Subject Identification 
Protocol Title: Effects of eicosapentaenoic acid on endothelial function in 
diabetic subjects: a pilot trial
 
Principal Investigator: Luc Djousse, MD, ScD 
 
Site Principal Investigator:       
 
Description of Subject Population: Adults aged 30-75 with a diagnosis of type 2 
diabetes and elevated triglycerides
About this consent form 
 
Please read this form carefully.  It tells you important information about a research study.  A 
member of our research team will also talk to you about taking part in this research study.  
People who agree to take part in research studies are called “subjects.”  This term will be used 
throughout this consent form. 
 
Partners HealthCare System is made up of Partners hospitals, health care providers, and 
researchers.  In the rest of this consent form, we refer to the Partners system simply as 
“Partners.” 
 
If you have any questions about the research or about this form, please ask us.  Taking part in 
this research study is up to you.  If you decide to take part in this research study, you must sign 
this form to show that you want to take part.  We will give you a signed copy of this form to 
keep. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you.  At most, the Web 
site will include a summary of the results.  You can search this Web site at any time. 
 
Why is this research study being done? 
 
This is a pilot study. Pilot studies are done on a small group of subjects to learn if a larger study 
would be useful.  
 
We are doing this research study to find out if Vascepa (icosapent ethyl), which is an omega-3 
that occurs naturally in fish can improve the health of the blood vessels and other markers of 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  October 2014 
 
 
 
 
Page 2 of 13 
 
 
Subject Identification 
heart disease among people with type 2 diabetes and elevated triglycerides.  We also want to find 
out if Vascepa is safe to take without causing too many side effects.  
 
We are asking you to take part in this research study because you have been diagnosed with type 
2 diabetes and have high levels of triglycerides. Abnormal changes in blood vessels are 
frequently seen in people with diabetes. Elevated triglycerides can increase the risk of heart 
disease, especially among people with diabetes who are already at higher risk of heart disease. 
 
A total of 33 people enrolled at Brigham and Women’s Hospital (BWH), will take part in this 
research study. The Amarin Pharma Inc is providing the drug and paying for this research study 
to be done. 
 
 
Vascepa is approved by the U.S. Food and Drug Administration (FDA) to treat elevated 
triglycerides.  
 
This research study will compare Vascepa to no Vascepa (control). 
 
Amarin Pharma, Inc. is paying for this study to be done. 
 
How long will I take part in this research study? 
 
It will take you about 16 weeks to complete this research study.  During this time, we will ask 
you to make 3 study visits to BWH. We will also call you once a month during the study. 
 
 
What will happen in this research study? 
 
If you choose to take part in this study, we will ask you to sign this consent form before we do 
any study procedures. 
 
Screening Visit (Visit 1) 
 
The Screening Visit will take about 1 hour.  At this visit, we will first obtain your consent to 
participate in this study. Then we will do some tests to see if you qualify to take part in this 
research study.  The study doctor will review the results of these tests and procedures (results for 
blood levels of triglycerides will take few days to arrive). If you don’t qualify, the study doctor 
will tell you why.   
 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  October 2014 
 
 
 
 
Page 3 of 13 
 
 
Subject Identification 
We will ask you to fast and refrain from caffeine-containing beverages or tobacco consumption 
for 12 hours prior to this visit.  Only clear liquids are permitted. You may take your morning 
medications before coming to this visit. 
 
During this visit, we will also: 
 Ask you about your medical history 
 Draw a blood sample (1 tablespoon) 
 Perform endothelial function testing to measure the health of your blood vessel 
using a digital pulse amplitude device with 2 rubber probes on the surface of your 
index fingers on both hands while you are lying down. This test will take about 20 
minutes. We ask that you come to the visit with short nails on your fingers for this 
test because long finger nails could tear the rubber probe that we use for this test. 
 Ask you about your current medications including any supplements you may be 
taking 
 
 
Baseline Visit (Visit 2) – Assignment to a Study Group 
 
We will ask you to fast and refrain from caffeine-containing beverages or tobacco consumption 
for 12 hours prior to this visit.  Only clear liquids are permitted. You may take your morning 
medications before coming to this visit. 
 
Visit 2 will take about two hours.  At this visit, we will: 
 Ask you about your medical history 
 Draw a blood sample (3 tablespoons) 
 Test your urine for pregnancy, if you are a women and able to become pregnant.  
Pregnant women cannot take part in this research study; if you had a surgical 
sterilization or are a menopausal woman and have not had a menstrual period for 
the past 12 months or more, you will not need to have a pregnancy test 
 Perform endothelial function testing using a device to measure the health of your 
blood vessel using a digital pulse amplitude device with 2 rubber probes on the 
surface of your index fingers on both hands while you are lying down. This test 
will take about 20 minutes; We ask that you come to the visit will short nails on 
your fingers for this test because long finger nails could tear the rubber probe that 
we use for this test. 
 Ask you about your current medications including any supplements you may be 
taking 
 Measure your weight, height, blood pressure, and pulse 
 Ask questions about your diet and ask you to complete a questionnaire about your 
diet 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  October 2014 
 
 
 
 
Page 4 of 13 
 
 
Subject Identification 
 We will give you a study diary to complete during the next 12 weeks 
 
 
If you still qualify for the study, we will assign you by chance (like a coin toss) to the Vascepa 
group or the control group.  You and the study doctor cannot choose your study group.  You will 
have an equal chance of being assigned to the Vascepa group and control group. 
 
Your study doctor won’t know which study group you are in, but s/he can find out if necessary. 
 
Taking the Study Drug 
If you are assigned to Vascepa group, we will give you a supply of Vascepa to take home with 
you. You will take the study drug by mouth, two capsules in the morning with foods and two 
capsules in the evening with foods for 12 weeks.  Use enough water to take the capsules. It is 
important for you to follow our instructions about how to take the study drug.  Bring any unused 
study drug with you to your next study visit.  
 
If you are assigned to the control group, we will ask you to continue your usual habits and 
complete all of the study procedures.  
 
Your Study Drug Diary 
We will give you a study diary to fill out at home each day. You will write down the date and 
time you take the 2 capsules of Vascepa, and any side effects you may have after taking those 
capsules.  Bring this diary with you to each study visit, so we can track your progress. 
If you are not assigned to Vascepa, we still ask you to write down the date and time of any side 
effect that you may have. Example: March 2, 2015 at 9 AM: stomach pain. 
 
We will ask you to fill out the diary even if you are assigned to the control group. 
 
We will call you once a month to find out if you are experiencing any side effects or health 
problems, and to remind you about your final study visit.  
 
Final study visit (Visit 3) 
Twelve weeks after the second study visit, you will come back to BWH for a final visit. If you 
were assigned to Vascepa, you will take the study drug for the entire 12 weeks. The third study 
visit will take about 2 hours.  
 
We will ask you to fast and refrain from caffeine-containing beverages or tobacco consumption 
for 12 hours prior to this visit.  Only clear liquids are permitted. You may take your morning 
medications before coming to this visit. 
 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  October 2014 
 
 
 
 
Page 5 of 13 
 
 
Subject Identification 
During this final study visit, we will:  
 Draw a blood sample (3 tablespoons) 
 Perform endothelial function testing using a device to measure the health of your 
blood vessel using a digital pulse amplitude device with 2 rubber probes on the 
surface of your index fingers on both hands while you are lying down. This test 
will take about 20 minutes; We ask that you come to the visit will short nails on 
your fingers for this test because long finger nails could tear the rubber probe that 
we use for this test. 
 Ask you about your current medications including any supplements you may be 
taking 
 Measure your weight, height, blood pressure, and pulse 
 Ask questions about your diet and ask you to complete a questionnaire about your 
diet 
 Ask you about any side effects or health problems since your last visit 
 Collect any unused capsules of Vascepa if you were assigned to the Vascepa 
group 
 Collect your study diary  
 
After You Complete the Study 
After you complete the study, we will refer you back to your own doctor for your ongoing 
medical care.  
 
Study Information Included in Your Electronic Medical Record 
A notation that you are taking part in this research study may be made in your electronic medical 
record.  Information from the research that relates to your general medical care may be included 
in the record (for example: list of allergies, results of standard blood tests done at the hospital 
labs). 
 
 
What are the risks and possible discomforts from being in this research 
study? 
 
Risks of Taking Vascepa 
 
Taking Vascepa may cause you to have one or more of the side effects listed below. 
 
Common side effects: 
 Joint pain (2 out of 100 people reported this side effect) 
 
Less common side effects: 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  October 2014 
 
 
 
 
Page 6 of 13 
 
 
Subject Identification 
 Nausea (3 out of 1000 people reported this side effect) 
 Diarrhea (5 out of 1000 people reported this side effect) 
 Pain (3 out of 1000 people reported this side effect) 
 
There may be other risks of Vascepa that are currently unknown. 
 
As with any drug, an allergic reaction can occur.  Allergic reactions can be mild or more serious, 
and can even result in death. Common symptoms of an allergic reaction are rash, itching, skin 
problems, swelling of the face and throat, or trouble breathing.  If you think you are having an 
allergic reaction, call the study doctor right away.  If you are having trouble breathing, call 911 
immediately.  
 
 
Risks to an Embryo or Fetus, or to a Breastfeeding Infant 
 
The effect of Vascepa on an embryo or fetus (developing baby still in the womb), or on a 
breastfeeding infant, is unknown and may be harmful.  Because of these unknown risks, women 
cannot take part in this study if they are: 
 Pregnant 
 Trying to become pregnant  
 Breastfeeding 
 
If you are a menopausal woman and have not had a menstrual period for the past 12 months or 
more, you will not need to have a pregnancy test. Also, if you have had any well-documented 
method of surgical sterilization, you will not need to have a pregnancy test.  Methods of surgical 
sterilization include having had a hysterectomy (removal of the uterus), bilateral oophorectomy 
(removal of both ovaries), a tubal ligation (having your tubes tied), and transvaginal occlusion 
(plugging the opening of the tubes with a coil).  All other female subjects must have a negative 
pregnancy test before starting the study. 
 
If you are sexually active and able to become pregnant, you must agree to use one of the birth 
control methods listed below.  You must use birth control for the entire study period and six 
months after your final visit.  
 
Acceptable birth control methods for use in this study are: 
 hormonal methods, such as birth control pills, patches, injections, vaginal 
rings, or implants 
 barrier methods (such as a condom or diaphragm) used with a spermicide (a 
foam, cream, or gel that kills sperm) 
 intrauterine device (IUD) 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  October 2014 
 
 
 
 
Page 7 of 13 
 
 
Subject Identification 
 abstinence (no sex) 
 
If you miss a period, or think you might be pregnant during the study, you must tell the study 
doctor immediately.  If you become pregnant, you must stop taking the study drug and stop 
taking part in the study.  The study doctor may ask for your permission to collect information 
about the outcome of your pregnancy and the condition of your newborn.  
 
 
Risks of Taking Vascepa with Other Medications 
 
Taking Vascepa with blood thinners together may increase the risk of bleeding and may cause 
serious side effects. You must stop Vascepa before starting your treatment with any blood 
thinners. 
 
For your safety during this study, call your study doctor BEFORE you take any: 
 new medications prescribed by your own doctor 
 other medications sold over-the-counter without a prescription 
 dietary or herbal supplements 
 
 
Risks of Blood Draws 
 
You may have a bruise (a black and blue mark) or pain where we take the blood samples.  There 
is also a small risk of infection, lightheadedness, and/or fainting.  
 
Pain during the test assessing the health of your blood vessels: 
You may have pain on the testing upper arm during this test when the air is put into the blood 
pressure cuff (as if we were measuring your blood pressure). However, such pain usually goes 
away few minutes once the blood pressure cuff is released. You may have bruise where the 
blood pressure cuff was placed.  
 
 
What are the possible benefits from being in this research study? 
 
You may not benefit from taking part in this research study.  If you receive Vascepa, it is 
possible that your elevated triglycerides may improve while you are taking it.   
Others with heart disease may benefit in the future from what we learn in this study.  
 
 
What other treatments or procedures are available for my condition? 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  October 2014 
 
 
 
 
Page 8 of 13 
 
 
Subject Identification 
 
You do not have to take part in this research study to be treated for elevated triglycerides.  Other 
treatments or procedures that are available to treat elevated triglycerides include: statins 
(rosuvastatin, artovastatin, fluvastatin, or pravastatin) and other drugs that lower lipids. 
 
Talk with the study doctor if you have questions about any of these treatments or procedures. 
 
 
Can I still get medical care within Partners if I don’t take part in this 
research study, or if I stop taking part?  
 
Yes.  Your decision won’t change the medical care you get within Partners now or in the future.  
There will be no penalty, and you won’t lose any benefits you receive now or have a right to 
receive. 
 
Taking part in this research study is up to you.  You can decide not to take part.  If you decide to 
take part now, you can change your mind and drop out later.  We will tell you if we learn new 
information that could make you change your mind about taking part in this research study. 
 
 
What should I do if I want to stop taking part in the study? 
 
If you take part in this research study, and want to drop out, you should tell us.  We will make 
sure that you stop the study safely.  We will also talk to you about follow-up care, if needed. 
 
Also, it is possible that we will have to ask you to drop out of the study before you finish it.  If 
this happens, we will tell you why.  We will also help arrange other care for you, if needed. 
 
 
Will I be paid to take part in this research study? 
 
We will pay you $200 if you complete all three study visits.  If you do not complete the study, 
you will not receive any payment. 
 
 
We will pay for parking in the hospital garage during study visits. 
We will pay for the cost of your parking up to $8 for each visit. 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  October 2014 
 
 
 
 
Page 9 of 13 
 
 
Subject Identification 
We may use your samples and information to develop a new product or medical test to be sold.   
The Sponsor, hospital, and researchers may benefit if this happens.  There are no plans to pay 
you if your samples are used for this purpose.   
 
What will I have to pay for if I take part in this research study? 
 
Amarin Pharma Inc is providing the study drug at no cost. 
 
Study funds will pay for study-related procedures (for example: test to examine the health of 
your vessel, blood levels of triglycerides, diet and health questionnaires), and blood pressure, 
weight, and height measured during the study visits that are done only for research. 
 
Study funds will pay for certain study-related items and services.  We may bill your health 
insurer for, among other things, routine items and services you would have received even if you 
did not take part in the research.  You will be responsible for payment of any deductibles and co-
payments required by your insurer for this routine care or other billed care.  If you have any 
questions about costs to you that may result from taking part in the research, please speak with 
the study doctors and study staff.  If necessary, we will arrange for you to speak with someone in 
Patient Financial Services about these costs. 
 
 
What happens if I am injured as a result of taking part in this research 
study?
 
We will offer you the care needed to treat any injury that directly results from taking part in this 
research study.  We reserve the right to bill your insurance company or other third parties, if 
appropriate, for the care you get for the injury.  We will try to have these costs paid for, but you 
may be responsible for some of them.  For example, if the care is billed to your insurer, you will 
be responsible for payment of any deductibles and co-payments required by your insurer. 
 
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
you or give you other compensation for an injury, should one occur.  However, you are not 
giving up any of your legal rights by signing this form. 
 
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of this study as soon as possible.  The 
researcher's name and phone number are listed in the next section of this consent form. 
 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  October 2014 
 
 
 
 
Page 10 of 13 
 
 
Subject Identification 
If I have questions or concerns about this research study, whom can I 
call? 
 
You can call us with your questions or concerns.  Our telephone numbers are listed below.  Ask 
questions as often as you want.
 
Luc Djousse, MD, ScD is the person in charge of this research study.  You can call him at 617-
525-7591, M-F 9-5 with questions about this research study. 
 
If you want to speak with someone not directly involved in this research study, please contact 
the Partners Human Research Committee office.  You can call them at 617-424-4100. 
 
You can talk to them about: 
 Your rights as a research subject 
 Your concerns about the research 
 A complaint about the research 
 
Also, if you feel pressured to take part in this research study, or to continue with it, they want to 
know and can help. 
 
 
If I take part in this research study, how will you protect my privacy? 
 
During this research, identifiable information about your health will be collected.  In the rest of 
this section, we refer to this information simply as “health information.”  In general, under 
federal law, health information is private.  However, there are exceptions to this rule, and you 
should know who may be able to see, use, and share your health information for research and 
why they may need to do so. 
 
In this study, we may collect health information about you from: 
 Past, present, and future medical records 
 Research procedures, including research office visits, tests, interviews, and 
questionnaires 
 
Who may see, use, and share your identifiable health information and why they may 
need to do so: 
 Partners research staff involved in this study 
 The sponsor(s) of this study, and the people or groups it hires to help perform this 
research 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  October 2014 
 
 
 
 
Page 11 of 13 
 
 
Subject Identification 
 Other researchers and medical centers that are part of this study and their ethics boards 
 A group that oversees the data (study information) and safety of this research 
 Non-research staff within Partners who need this information to do their jobs (such as for  
treatment, payment (billing), or health care operations) 
 The Partners ethics board that oversees the research and the Partners research quality 
improvement programs. 
 People from organizations that provide independent accreditation and oversight of 
hospitals and research 
 People or groups that we hire to do work for us, such as data storage companies, insurers, 
and lawyers 
 Federal and state agencies (such as the Food and Drug Administration, the Department of 
Health and Human Services, the National Institutes of Health, and other US or foreign 
government bodies that oversee or review research)  
 Public health and safety authorities (for example, if we learn information that could mean 
harm to you or others, we may need to report this, as required by law) 
 Other:        
 
Some people or groups who get your health information might not have to follow the same 
privacy rules that we follow and might use or share your health information without your 
permission in ways that are not described in this form.  For example, we understand that the 
sponsor of this study may use your health information to perform additional research on various 
products or conditions, to obtain regulatory approval of its products, to propose new products, 
and to oversee and improve its products’ performance.  We share your health information only 
when we must, and we ask anyone who receives it from us to take measures to protect your 
privacy.  The sponsor has agreed that it will not contact you without your permission and will not 
use or share your information for any mailing or marketing list.  However, once your information 
is shared outside Partners, we cannot control all the ways that others use or share it and cannot 
promise that it will remain private. 
 
Because research is an ongoing process, we cannot give you an exact date when we will either 
destroy or stop using or sharing your health information. 
 
The results of this research study may be published in a medical book or journal, or used to teach 
others.  However, your name or other identifying information will not be used for these purposes 
without your specific permission. 
 
Your Privacy Rights 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  October 2014 
 
 
 
 
Page 12 of 13 
 
 
Subject Identification 
You have the right not to sign this form that allows us to use and share your health information 
for research; however, if you don’t sign it, you can’t take part in this research study.    
 
You have the right to withdraw your permission for us to use or share your health information 
for this research study.  If you want to withdraw your permission, you must notify the person in 
charge of this research study in writing.  Once permission is withdrawn, you cannot continue to 
take part in the study. 
 
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others. 
 
You have the right to see and get a copy of your health information that is used or shared for 
treatment or for payment.  To ask for this information, please contact the person in charge of this 
research study.  You may only get such information after the research is finished. 
 
 
Informed Consent and Authorization 
 
Statement of Person Giving Informed Consent and Authorization 
 
 I have read this consent form. 
 This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the study. 
 I have had the opportunity to ask questions. 
 I understand the information given to me. 
 
 
 
Signature of Subject: 
 
I give my consent to take part in this research study and agree to allow my health information to 
be used and shared as described above. 
 
 
 
 
 
 
 
 
 
 
 
Subject 
Date 
Time (optional) 


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  October 2014 
 
 
 
 
Page 13 of 13 
 
 
Subject Identification 
 
 
Signature of Study Doctor or Person Obtaining Consent: 
 
Statement of Study Doctor or Person Obtaining Consent 
 
 I have explained the research to the study subject. 
 I have answered all questions about this research study to the best of my ability. 
 
 
 
 
 
 
 
 
 
 
 
Study Doctor or Person Obtaining Consent 
Date 
Time (optional) 
 
 
 
Consent Form Version:  May 28, 2015