Clinical trial NCT00759291
Conditions: Metabolic Syndrome
Keywords: free fatty acids insulin-mediated endothelium-dependent vasodilation metabolic syndrome
Sponsor: Brigham and Women's Hospital
Start date: 2006-04-01; Completion date: 2017-12-30
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will test the hypothesis that reducing the release of free fatty acids (FFA) from fat cells will restore insulin-mediated, endothelium-dependent vasodilation in people with the metabolic syndrome.

Detailed description:
We hypothesize that acipimox, by decreasing plasma FFA concentrations, will augment endothelium-dependent vasodilation in conduit vessels and insulin-mediated vasodilation in forearm resistance arterioles in vivo, whole-body insulin sensitivity, and AKT (also known as Protein Kinase B) and endothelial nitric oxide synthase (eNOS) phosphorylation in skin biopsy specimens ex vivo, when compared with placebo.

Arms: arm 1: Acipimox treatment QID for 7 days arm 2: Placebo treatment QID for 7 days
Interventions: intervention 1: acipimox intervention 2: Placebo
Intervention descriptions: intervention 1: 250 mg tablet orally every 6 hours for 7 days, with a dose at 7 am on the morning of the study visit intervention 2: 1 tablet orally every 6 hours for 7 days, with a dose at 7 am on the morning of the study visit

Protocol documents:
Prot_SAP_ICF_000.pdf: 
Title:  The Impact of Free Fatty Acid Reduction on Vascular Function in the Metabolic 
Syndrome    
 
NCT00759291 
 
 
Document Date: February 28, 2008 


STUDY PROCEDURES AND PROTOCOL 
 
This study uses a randomized, placebo-controlled crossover design.  
 
After providing informed consent, both groups will undergo an initial screening visit in the Vascular 
Medicine Research Center.  This visit will include a comprehensive health history and physical exam 
and anthropomorphic data collection (height, weight, body mass index (BMI) and waist-hip ratio).  
Screening blood tests will be drawn to assess fasting glucose, blood count, lipid profile, glycosylated 
hemoglobin, and assessment of renal and hepatic function.  Baseline serum insulin and nonesterified free 
fatty acid levels will also be drawn at this visit.  An ECG will be performed. 
 
We hypothesize that acipimox, by decreasing plasma FFA concentrations, will augment endothelium-
dependent vasodilation in conduit vessels and insulin-mediated vasodilation in forearm resistance 
arterioles in vivo, whole-body insulin sensitivity, and AKT and eNOS phosphorylation in skin biopsy 
specimens ex vivo, when compared with placebo. 
 
Subjects will be studied at 2 separate visits, 4 weeks apart, in a randomized, double-blind crossover 
design.  Subjects will receive either acipimox 250 mg tablets orally every 6 hours, or matching placebo, 
for 7 days prior to and at 7 am on the morning of the study visit.   Each visit will include vascular 
function testing and a forearm skin biopsy.  Forearm blood flow will be measured in the basal state, and 
with insulin infusion.   
 
Evaluation of vascular function in conduit vessels:  
 
Vascular function of the brachial artery will be measured in all subjects as reported previously by the 
applicants and recommended by a recent task force (56-58) (also see Preliminary Results Section).  To 
assess endothelium-dependent vasodilation, measurements of brachial artery diameter will be made 
under basal conditions and during reactive hyperemia following five minutes of an ischemic stimulus.  
Forearm ischemia will be induced by inflating a blood pressure cuff on the upper part of the arm to 
suprasystolic pressures for 5 minutes.  This results in vasodilation of the downstream resistance 
vessels.  Following release of the cuff, there is a 6 to 10-fold increase in flow through the brachial 
artery, i.e., reactive hyperemia.  Flow is a physiologic stimulus that releases nitric oxide from the 
endothelium.  We have found that the maximal increase in brachial artery diameter occurs at one 
minute of reactive hyperemia and that this dilation is mediated by nitric oxide (56, 57).  Endothelium-
independent vasodilation will be assessed by measuring brachial artery diameter under basal 
conditions and 3 minutes following the administration of sublingual nitroglycerin (0.4 mg) (58).  
Maximal brachial artery dilation occurs 3 to 4 minutes after the administration of sublingual 
nitroglycerin.  
 
The diameter of the brachial artery will be measured using high resolution B-mode ultrasonography.  
An ultrasound scanner (Toshiba model Powervision 8000) equipped with a high resolution linear array 
transducer (7.5 mHz) is used to image the artery and thus enable measurement of its diameter and 
cross-sectional area.  A longitudinal image (parallel to the artery) is acquired just proximal to the 
antecubital fossa.  The transducer is then positioned at 90 degrees to the vessel to acquire an image 
through the center of the vessel so that the near and far wall interfaces will be clearly discernible.  A 
simultaneous electrocardiographic signal is recorded.  The video output and electrocardiographic 


signal of the ultrasound machine is connected to a computer equipped with a Data Translation frame 
grabber videocard.  The R wave on the electrocardiogram is used as a trigger to acquire (digitize) 
frames.  Digitized images at baseline and after intervention (e.g., reactive hyperemia, nitroglycerin) 
are stored on the hard drive and backed up on removable media.  Acquisition and analysis of the 
stored images is performed using software designed for this purpose by Medical Imaging 
Applications.  The vessel wall lumen interface is determined by derivative based edge detection 
following identification of the region of the anterior and posterior walls by the investigator.  The 
maximum diameter of the vessel is then determined (59).  We have found that this technique yields an 
interobserver variability of 0.05±0.16% and intraobserver variability of 0.01±0.15%. 
 
Evaluation of vascular function in forearm resistance vessels: 
 
Each subject will be studied in the post-absorptive state, in a quiet, temperature-controlled (23°C) 
room.  Alcohol and caffeine will be withheld for 12 hours prior to the study.  In order to evaluate 
insulin-mediated vasodilator function in forearm resistance vessels, resistance arteriole flow will be 
determined before and during euglycemic, hyperinsulinemic clamp.  Measurement of insulin-mediated 
vasodilation will be made in each study condition (placebo & drug) before and during 
hyperinsulinemic clamp.  Forearm blood flow will be determined by venous-occlusion strain-gauge 
plethysmography, as described previously by this laboratory (60, 61).  Forearm blood flow (FBF) will 
be derived from the rate of change in forearm circumference during venous occlusion and will be 
expressed at ml/100 ml tissue/minute.  Each determination of forearm blood flow will comprise at 
least five separate measurements.  FBF measurements will be recorded on a Hokanson AI6 
physiologic recorder.   
 
Hyperinsulinemic Clamp 
 
A whole-body hyperinsulinemic- euglycemic clamp will be created via an intravenous infusion of 
insulin.  A primed constant insulin infusion of 80mU/m2/min is started and continued for 120 minutes.  
This dose has been demonstrated to attain typical postprandial insulin concentrations, facilitating 
evaluation of both initial-phase and steady-state insulin-mediated vasodilation (65).  Contralateral 
cubital vein glucose will be measured every 5 minutes to ensure a constant glucose concentration of 
5.1 mmol (90 mg/dL).  Adjusted dextrose 20% solution will be infused intravenously to maintain this 
concentration.  Systemic glucose and insulin concentrations will be determined from the control arm 
cubital vein.  Whole body insulin sensitivity will be quantified by determining M, (metabolized 
glucose) during the final 5 steady-state measurements.  M will be calculated as the glucose infusion 
rate, adjusted according the method described by DeFronzo and colleagues (66). 
 
Tissue Acquisition 
 
Abnormalities in endothelium-dependent vasodilation have been demonstrated in humans in 
peripheral and coronary conduit arteries, peripheral and coronary resistance arterioles, and in skin 
microvessels of patients with diabetes (67-70).  Therefore, we will biopsy easily accessible arm skin 
microvessels to determine the effects of each intervention on endothelial insulin signaling.  The skin 
will be cleansed with betadyne and draped to create a sterile field.  Lidocaine 2% will be used to 
anesthetize a 1.2 cm ring in the arm around the biopsy site.  A 6 mm bioptome will be used to obtain a 


skin sample.  The skin biopsy is marked for orientation and immediately frozen in liquid nitrogen and 
stored at –80 C for subsequent protein extraction for Western blot.   
 
Tissue Analysis 
The analyses of biopsy specimens will be performed in the laboratory of Dr. Thomas Michel. 
 
Western blotting:  The analyses of the skin and muscle biopsy specimens will be performed under the 
direction of Dr. Thomas Michel (consultant). Skin biopsy specimens are immediately frozen in liquid 
nitrogen.  Frozen tissues are homogenized using a Polytron homogenizer in lysis buffer (71).  After 30 
min of incubation on ice, samples are centrifuged for 20 min at 14,000 g at 4°C to yield a solubilized 
preparation.  Protein concentration is measured by using a protein assay (Bio-Rad; Richmond, CA).  
Equal quantities of protein from each sample (10 μg) are resolved by SDS-PAGE on 9% gels and 
electroblotted onto nitrocellulose.  After incubation overnight with 5% bovine albumin -Tris-buffered 
saline with 0.1% Tween 20 (TBST), membranes are incubated for 1 h with the specified primary 
antibody [(monoclonal anti-eNOS or anti-Akt antibodies at 1:10,000 dilution, Transduction 
Laboratories) or (polyclonal phospho-eNOS Ser1179 or phospho-Akt antibodies at 1:5,000 dilution; 
Cell Signaling)].  After several washes, the membranes are incubated for 1 h with a horseradish 
peroxidase-labeled goat anti-rabbit (for phospho-Akt or phospho-eNOS Ser1179) or anti-mouse (for 
total Akt or total eNOS) immunoglobulin secondary antibody (Pierce Chemical).  After being washed 
10–15 additional times, the membranes are incubated with a chemiluminescent reagent according to 
the manufacturer’s protocols (SuperSignal West Femto; Pierce Chemical) and exposed to X-ray film. 
 
Immunodetection:  Serial 4 uM sections of skin biopsy sections are deparaffinized, hydrated, and 
serially incubated in citrate buffer, H2O2, blocking solution, primary antibody, and appropriate 
secondary antibody, with intervening washes.  The ABC biotin/avidin method with Nova Red 
substrate is utilized for immunodetection (Vector Labs).  Primary antibodies include:  total Akt (Cell 
Signaling), phospho-specific Akt (Ser 473, Cell Signaling), total eNOS (Transduction Labs), and 
phospho-specific eNOS (Ser 1177, Cell Signaling).  When available, blocking peptide is incubated 
with primary antibody in a separate section to ensure specificity of staining.  If blocking peptide is not 
available, additional sections are incubated without primary antibody.  To ensure localization of 
identified signal in vascular cells, additional sections will be processed for immunofluorescence and 
colocalization with primary antibodies directed against the endothelium-specific von Willebrand 
factor (Santa Cruz Biotechnology).  Images will be viewed using an AX70 Olympus Microscope with 
Phase 3 Imaging System (Image Pro 4.0 software) or the Zeiss LSM-410 Invert Laser Scan confocal 
microscope with imaging software (Matrox Image-Series Utilities).   
 
Assays for markers of inflammation, insulin, free fatty acids 
 
Plasma samples from insulin resistant and healthy subjects will be assayed for high sensitivity CRP 
(hsCRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) using the respective ELISA kits 
(Sigma; Endogen, Woburn, MA; BenderMedSystems; Vienna, Austria).  Plasma insulin concentration 
will be measured using an Immunoenzymatic Sandwich Assay (Beckman Coulter, Inc.). Acrylodan-
labeled Intestinal Fatty Acid Binding Protein (ADIFAB), a fluorescent molecule, will be used to assay 
the concentration of free fatty acids.  The assay is accurate to about 1nM (72).  All assays will be 
performed in duplicate by investigators blinded to the status of the subject (metabolic syndrome or 
control) and treatment. 


 
BIOSTATISTICAL ANALYSIS 
 
Statistical Analysis  
Sample size calculation:  All specified protocols employ a randomized, placebo-control cross-
over design.  Given the paired-design, the sample sizes have been calculated using estimates of the 
difference in flow-mediated, endothelium-dependent vasodilation after placebo and active treatment. 
Based on previous studies, we expect to find 
an absolute difference in flow-mediated, 
endothelium-dependent vasodilation of the brachial 
artery between the test agent and placebo of 3% 
with an estimated standard deviation of 4% (68).  
With a 2-sided alpha error of 0.05 and a power of 
90%, 30 subjects in each group of each protocol 
should find at least this difference in the primary 
endpoint (Table 2).  
Statistical methods:  All descriptive data will 
be expressed as means ± standard deviation.  The 
primary endpoint of change in flow-mediated, 
endothelium-dependent vasodilation (i.e., the change in brachial artery vasodilation) between active 
therapy and placebo, will be assessed using repeated measures ANOVA (73).  All analyses will 
employ the intention-to-treat principle.  The treatment “order effect” will be explored by examining 
the interaction between treatment group (e.g. acipimox vs. placebo) and sequence of treatment 
(placebo first vs. active therapy first).   
Baseline characteristics of treatment and control patients will be compared using Student’s t-test 
or non-parametric tests, depending on the distribution of the data.  To examine whether the active 
therapy has similar effects on flow-mediated vasodilation between healthy subjects and those with the 
metabolic syndrome, we will test the interaction between treatment group and the metabolic syndrome 
(yes/no).  In secondary analyses, we will assess the effects of active therapy on eNOS 
phosphorylation, insulin sensitivity, and plasma inflammatory markers such as CRP, IL-6, and TNF-a.  
We will assess the relationship between the change in eNOS phosphorylation and changes in 
endothelium-dependent vasodilation using linear regression analyses, controlling for age, and gender.  
Likewise, we will examine the relationship between changes in insulin-mediated vasodilation and 
insulin-sensitivity associated with active treatment.  Multiple analysis of variance (MANOVA) will be 
used to examine the main and interaction effects of categorical variables on multiple dependent 
variables, and multiple analysis of covariance (MANCOVA) for continuous independents.  Thus, in 
the analyses, we can include vascular function and other outcomes simultaneously as dependent 
variables in the models.  If the dependent variables are uncorrelated with each other, repeated measure 
ANOVA for each dependent variable will be employed. 
 
Data interpretation:  Vascular function will be determined after each intervention.  Each 
intervention will be studied individually.  If flow-mediated vasodilation is restored after an 
intervention (acipimox) compared with placebo, it will be interpreted that FFA impairs endothelial 
insulin signaling and decreases endothelium-dependent vasodilation.  This interpretation will be 
confirmed by cutaneous tissue testing.  If eNOS serine1177 phosphorylation is increased after an 
intervention compared to placebo, it will be interpreted that improved activation of the PI3-kinase 
.98
.99
1.0
3.5%
.94
.98
.99
3.0%
.84
.91
.97
2.5%
4.5%
4.0%
3.5%
Standard Deviation
Treatment Effect
Table 2: Calculated Power For a Given 
Effect Size and Standard Deviation


pathway increases eNOS phosphorylation and resultant NO production.  This interpretation will be 
supported if multivariate linear regression analysis defines a significant positive relationship between 
changes in eNOS phosphorylation and vascular and/or skeletal muscle metabolic function.  If 
endothelium-dependent (flow-mediated) or insulin-mediated vasodilation remains similar despite an 
intervention (acipimox), it will be interpreted as a lack of effect of the agent on endothelial-insulin 
signaling and vascular function.  If any intervention increases vasodilation to nitroglycerin, it will be 
interpreted that the intervention has improved vascular smooth muscle function.  If the intervention 
improves vascular function in both subjects with the metabolic syndrome and healthy subjects, this 
will be interpreted as a generalized effect, independent of the metabolic syndrome. 
 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
Template Version Date:  June 2005 
Page 1 
 
 
Subject Identification 
Protocol Title:  The Impact of Free Fatty Acid Reduction on Vascular Function 
in the Metabolic Syndrome 
 
Principal Investigator: Joshua A. Beckman, MD 
 
Site Principal Investigator:       
 
Description of Subject Population: Adults with Metabolic Syndrome & Healthy 
Adults 
 
 
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.  If you have any questions about the research or about this form, 
please ask us.  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 copy of this form to keep. 
 
 
Why is this research study being done? 
 
We would like permission to enroll you as a participant in a research study.  The purpose of 
the study is to test the effect reducing the release of free fatty acids from fat cells with 
acipimox.  Free fatty acids are fats in the blood used to provide energy to cells that are not 
attached to other small particles.  We want to see if acipimox improves the ability of cells to 
use blood sugar for energy and improves the way blood vessels expand.  We will be 
comparing acipimox to an inactive medicine (placebo).  You will receive both acipimox and 
placebo at different times during the study. 
 
 
Acipimox is approved for use in humans in Europe, and is used as a cholesterol lowering 
medicine.   Acipimox has not been approved by the U.S. Food and Drug Administration 
(FDA) and is not available in the United States. Therefore, this is considered an 
investigational research study. 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
Template Version Date:  June 2005 
 
 
 
 
Page 2 
 
 
Subject Identification 
Thirty (30) adults with Metabolic Syndrome and 30 healthy adult volunteers will be enrolled 
in this study at Brigham & Women’s Hospital (BWH).  You are being asked to participate 
because you are a non-smoker with Metabolic Syndrome, or you are a non-smoking healthy 
adult.  Studying healthy volunteers helps us to understand whether the results we get are 
different in people with diabetes. 
 
How long will I take part in this research study? 
 
It will take you about 6-10 weeks to complete the study. During this time, you will be asked to 
make 5 study visits.  
 
What will happen in this research study? 
 
This study will test blood vessel function during treatment with acipimox and a placebo.  The 
order of medications that you will receive is random and neither you nor the study doctors 
know what you are receiving until the end of the study.  Should your medical condition 
require it, we can find out the name of the medication as needed. 
 
Visit 1:  Screening Visit (about 1 hour) 
 
If you agree to participate in this study, you will be asked to sign this consent form, and a 
copy will be given to you.  At the first study visit, a doctor or nurse will ask you questions 
about your health history.  You will also have a complete physical examination, including an 
electrocardiogram (ECG).  An ECG is a tracing of the electrical activity in your heart.  Your 
height, weight, and waist/hip measurements will also be recorded.  You will also have blood 
drawn (about 3 tablespoons) to test for: 
 
• the number of red and white blood cells 
• liver function 
• kidney function 
• cholesterol 
 
The tests described above are done to be sure it is safe for you to take part in the study. 
 
The levels of insulin (a hormone produced by your pancreas that regulates the level of sugar 
in your blood) and fatty acids will also be measured.   
 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
Template Version Date:  June 2005 
 
 
 
 
Page 3 
 
 
Subject Identification 
If you are a woman of childbearing age, you will also have a urine test to make sure that you 
are not pregnant.  If the test is positive, (pregnant) you will not be able to participate in the 
study.  If the test is negative, you must agree not to try to become pregnant during the study.  
You must use one of the following birth control methods: 
• abstinence from sexual relations (no sexual intercourse)  
• oral contraceptives (birth control pills)    
• IUD or other barrier methods, such as cervical cap, or diaphragm with a gel that kills 
sperm 
• condoms with gels that kill sperm 
 
If you suspect that you have become pregnant while participating in the study, you must 
contact Dr. Beckman at once. You will have to withdraw from the study if you become 
pregnant, since we don’t know if salsalate would harm an unborn child.    
 
 
Visit 2 (about 20 minutes) 
  
If the test results from the screening visit show that you can continue in the study, you will be 
asked to come to the Vascular Medicine Research Center.  This is Visit 2, when we will give 
you the study medicine to take home.  You will be asked to return one week later for Visit 3.   
 
At Visit 2 you will either receive the active study medicine, acipimox, or a placebo.  (You 
will receive both acipimox and placebo during this study.)  The medicine you receive first 
will be determined like the flip of a coin.  Neither you nor the study staff will know which 
medicine you receive first.  You will be asked to take one tablet four times a day for one 
week, and report to the Vascular Laboratory on the morning of Visit 3.  The dose of 
acipimox in this study will be 250 mg tablets every 6 hours.  The acipimox and placebo 
tablets look exactly alike.   
 
Visit  3:  (5 hours) 
 
You should have nothing to eat or drink, other than water, after midnight. You should take the 
study medicine as instructed.  At this visit we will test the function of your blood vessels and 
take a small piece of skin (punch biopsy) from the inside of your forearm. The blood vessel 
testing and the punch biopsy are explained below: 
 
During the blood vessel testing, you will be lying quietly on your back on a portable bed, and 
the lights in the room will be dimmed.  First, a picture of the artery in your forearm, called 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
Template Version Date:  June 2005 
 
 
 
 
Page 4 
 
 
Subject Identification 
the brachial artery, will be taken using an ultrasound machine.  We will put a cool gel on 
your arm and move a probe back and forth over the artery. The probe looks like a 
microphone.  Pictures of the artery will be taken before and after inflating a blood pressure 
cuff on the upper part of your arm.  The cuff will remain inflated for 5 minutes.  Next, you 
will be given a small dose of nitroglycerin under your tongue.  This causes the blood vessels 
in your arm to relax.  Ultrasound pictures of the artery will be taken again to find out the 
effect of the nitroglycerin.  This testing gives us information that future ultrasound tests can 
be compared to. 
 
After the ultrasound test, the blood flow in your forearm will be measured using a method 
called plethysmography.  Very thin, flexible tubes (catheters-also called an I.V. for 
“intravenous”) will also be inserted into a vein in each forearm.  One of these IV’s will be 
inserted after warming one of your hands in a warming box.  A warming box is a clear plastic 
box that you rest your hand in.  The temperature inside this box is 150 degrees F.  This IV 
will be used to take tiny blood samples (several drops each) for measurement of blood sugar 
every 5-7 minutes during the test.  A constant amount of insulin will be given   through the 
catheter in your other arm for up to two hours.  Also, glucose (sugar solution) will be infused 
(given over time slowly) through the same catheter.  The amount of glucose infused will be 
adjusted to keep blood sugar levels within the normal range.   
 
During the testing of your blood vessels, you will be quietly lying on your back on a stretcher 
and the lights in the room will be dimmed. The blood flow will be measured with an instrument 
that measures the size of a body part based on the amount of blood flow, using thin straps that 
are wrapped around your forearms.  Two blood pressure cuffs will be used during this procedure, 
one on the wrist and one on the upper part of the arm.  The cuffs will be inflated and deflated at 
different times during the study.  You will not feel pressure from the increase in blood flow.   
   
At this visit you will also have a punch biopsy. We will use a special instrument to remove 
(punch) 3/16th inch (5 mm) circular piece of skin from the inner side of one forearm. You may 
choose which arm the sample is taken from. The sample will be about the size of a pencil eraser.  
The area will be washed with betadine, a brown soap that kills germs on the skin.  Xylocaine 
(numbing medicine) is injected through a small needle into the skin surrounding the biopsy site 
to decrease pain.  The wound will be closed with a bandage that you can take off after 3-4 days. 
 
Once all of the tests are finished, you can have something to eat. 
 
Visit 4:  (about 20 minutes) 
 


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Research Consent Form 
 
 
 
 
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Subject Identification 
Four weeks after Visit 3, you will be asked to come to the Vascular Medicine Research 
Center for Visit 4.  At that time, you will be given study medicine again. You will be asked 
to return one week later for Visit 5.  You will be asked to take one tablet of the medicine with 
food or milk at 7:00 p.m. that evening, one tablet with water at 1:00 a.m. on the morning of 
Visit 5 and one tablet with water at 7:00 a.m. on the morning of Visit 5.   
 
Visit 5:  (about 6 hours) 
 
You should have nothing to eat or drink, other than water, after midnight. You should take the 
study medication as instructed before this visit.  All of the procedures explained under Visit 3 
above will be repeated.    
 
Up to 9 tablespoons (a little more than 4 ounces) of blood will be drawn during the entire 
study. 
 
 
What are the risks and possible discomforts from being in this research 
study? 
 
Acipimox, the active drug in this study, has been used by thousands of people and is 
generally well tolerated.  In people who took acipimox  (250 mg 3 times a day) for 1 month 
or longer, the most common side effects were (the most common are listed first):    
 
• flushing, itching, and/or a feeling of heat in the skin. (more common in women than 
men)   
• upset stomach   
• headache    
• vomiting (throwing up) 
• low blood pressure  
• heartburn  
• loose stools (bowel movements) 
• skin blisters    
  
Rarely, (slightly more than 1 in 1000 people) allergic-like reactions have occurred after one 
dose.  You should seek medical attention and contact the study staff immediately if you 
develop allergic reactions after taking the study medicine, such as:   
• hives   


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Subject Identification 
• swelling of the eyelids, lips, tongue or face  
• difficulty breathing  
 
During the ultrasound test, a blood pressure cuff on your upper arm will be inflated to a high 
pressure for 5 minutes.  This may cause temporary discomfort or aching.  There are no 
known risks. The ultrasound test itself is non-invasive, that is, no needles are used and testing 
is done on the surface of the skin only.   
 
Nitroglycerin is taken under the tongue during the vascular function ultrasound tests. 
Nitroglycerin may cause a temporary headache.  Less than 1 in 100 people may develop low 
blood pressure or a fall in heart rate with low blood pressure.  Blood pressure and heart rate 
are checked regularly during the study, and a member of the study staff is with you at all 
times.  If the top number of your blood pressure at rest is lower than 100 mm Hg, you will 
not be given nitroglycerin.  
  
As with all blood drawing or tube insertion, there is usually some pain at the site of the 
needle stick.  Bruising (turning black and blue) may also occur.  Rarely, lightheadedness or 
fainting can occur.  As with any arterial tube, clotting, inflammation (redness, swelling) or 
infection may occur.   
 
Once you leave the hospital after the study, you should contact the study doctor right away if 
you have: 
• bleeding from the needle site(s) that does not stop after putting pressure on the 
area for 10 minutes.     
• redness or swelling in the area of the needle site(s) or develop a fever.    
 
 
You may have an ache or discomfort after the biopsy procedure.  Rarely, there may be some 
bleeding requiring 1-2 stitches, or an infection.  These will be treated if they occur.  You may 
develop a small scar at the site of the biopsy.   
 
What are the possible benefits from being in this research study? 
 
You will not receive any direct health benefit from taking part in this study.  We hope that the 
knowledge we gain from this study will help us better understand how blood vessels work in 
people with atherosclerosis. 
    
 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
Template Version Date:  June 2005 
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Subject Identification 
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. 
 
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. 
 
It is possible that we will have to ask you to drop out before you finish the study.  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? 
 
You will be paid for your time spent in participating, and will receive $100 for each vascular 
function test visit (Visits 3 and 5). You will receive up to $200 for completing the study.  
Payments will be issued within a few weeks of completing the study.  In addition, parking costs 
will be validated at the time of each study visit. Costs for public transportation will be 
reimbursed at the end of the study.    
 
What will I have to pay for if I take part in this research study? 
 
There will be no cost to you or to your health insurer to participate in this study.  All costs 
associated with this study will be paid for by the research funds of the investigator.  Cost for 
routine medical care, not associated with this study, will be charged to you or to your health 
insurer.   
 
 
What happens if I am injured as a result of taking part in this research 
study? 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
Template Version Date:  June 2005 
 
 
 
 
Page 8 
 
 
Subject Identification 
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. 
 
Giving you care does not mean that Partners hospitals or researchers are at fault, or that there 
was any wrongdoing.  There are no plans for Partners to pay you or give you other compensation 
for the injury.  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. 
 
 
If I have questions or concerns about this research study, who 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.  
 
Joshua A. Beckman, MD is the person in charge of this research study.  You can call him/her at 
617-525-7052 Monday-Friday 9-5.   
 
If you have questions about the scheduling of appointments or study visits, call the research 
assistants at 617-732-6320.
 
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? 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
Template Version Date:  June 2005 
 
 
 
 
Page 9 
 
 
Subject Identification 
 
Federal law requires Partners (Partners HealthCare System and its hospitals, health care 
providers and researchers) to protect the privacy of health information that identifies you.  This 
information is called Protected Health Information.  In the rest of this section, we refer to this 
simply as “health information.” 
 
If you decide to take part in this research study, your health information may be used within 
Partners and may be shared with others outside of Partners, as explained below. 
 
We have marked with a 
 how we plan to use and share your health information.  If a box 
is not checked 
, it means that type of use or sharing is not planned for in this research 
study.  
We will also give you the Partners Notice for Use and Sharing of Protected Health 
Information.  The Notice gives more details about how we use and share your health 
information. 
 
§ Health Information About You That Might be Used or Shared During This Research 
 
Information from your hospital or office health records within Partners or 
elsewhere, that may be reasonably related to the conduct and oversight of the 
research study.  If health information is needed from your doctors or hospitals 
outside Partners, you will be asked to give permission for these records to be sent 
to researchers within Partners. 
 
New health information from tests, procedures, visits, interviews, or forms filled 
out as part of this research study 
 
§ Why Health Information About You Might be Used or Shared with Others 
The reasons we might use or share your health information are: 
• 
To do the research described above 
• 
To make sure we do the research according to certain standards - standards set by 
ethics and law, and by quality groups 
• For public health and safety - for example, if we learn new health information that 
could mean harm to you or others, we may need to report this to a public health or 
a public safety authority 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
Template Version Date:  June 2005 
 
 
 
 
Page 10 
 
 
Subject Identification 
• For treatment, payment, or health care operations 
 
§ People and Groups That May Use or Share Your Health Information 
1. People or groups within Partners 
 Researchers and the staff involved in this research study 
 The Partners review board that oversees the research 
 Staff within Partners who need the information to do their jobs (such as billing, or 
for overseeing quality of care or research) 
2. People or groups outside Partners 
 People or groups that we hire to do certain work for us, such as data storage 
companies, our insurers, or our lawyers 
 Federal and state agencies (such as the U.S. Department of Health and Human 
Services, the Food and Drug Administration, the National Institutes of Health, 
and/or the Office for Human Research Protections) and other U.S. or foreign 
government bodies, if required by law or involved in overseeing the research 
 Organizations that make sure hospital standards are met 
 The sponsor(s) of the research study, and people or groups it hires to help perform 
this research study 
 Other researchers and medical centers that are part of this research study 
 A group that oversees the data (study information) and safety of this research study 
 Other:       
Some people or groups who get your health information might not have to follow the 
same privacy rules that we follow.  We share your health information only when we 
must, and we ask anyone who receives it from us to protect your privacy.  However, once 
your information is shared outside Partners, we cannot promise that it will remain private. 
 
§ Time Period During Which Your Health Information Might be Used or Shared With 
Others 
• 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. 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
Template Version Date:  June 2005 
 
 
 
 
Page 11 
 
 
Subject Identification 
§ Your Privacy Rights 
• 
You have the right not to sign this form permitting us to use and share your health 
information for research.  If you don’t sign this form, you can’t take part in this research 
study.  This is because we need to use the health information of everyone who takes 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. 
If you withdraw your permission, we will not be able to take back information that has 
already been used or shared with others.  This includes information used or shared to 
carry out the research study or to be sure the research is safe and of high quality. 
If you withdraw your permission, you cannot continue to take part in this research study. 
• 
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.  
 
In this research study, you may only get such health information after the research is 
finished. 
 
§ 
If Research Results Are Published or Used to Teach Others 
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. 
 
Consent to take part in this research study, and authorization to use or 
share your health information for research 
 
Statement of Subject or Person Giving Consent 
 
§ 
I have read this consent form. 
§ 
This research study has been explained to me, including risks and possible benefits (if 
any), other options for treatments or procedures, and other important things about the 
study. 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
Template Version Date:  June 2005 
 
 
 
 
Page 12 
 
 
Subject Identification 
§ 
I have had the opportunity to ask questions. 
 
If you understand the information we have given you, and would like to take part in this research 
study, and also agree to allow your health information to be used and shared as described above, 
then please sign below: 
 
 
Signature of Subject: 
 
 
 
 
 
 
Subject 
Date/Time 
 
 
OR 
 
If you understand the information we have given you, and would like to give your permission for 
the person you are authorized to represent to take part in this research study, and also agree to 
allow his/her health information to be used and shared as described above, then please sign 
below: 
 
Signature of Parent(s)/Guardian or Authorized Representative: 
 
 
 
 
 
 
Parent(s)/Guardian of Minor 
Date/Time 
 
 
OR 
 
 
 
 
 
 
Court-appointed Guardian or Health Care Proxy 
Date/Time 
 
OR 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
Template Version Date:  June 2005 
 
 
 
 
Page 13 
 
 
Subject Identification 
 
 
 
 
 
Family Member/Next-of-Kin 
Date/Time 
 
 
Relationship to Subject: 
 
 
 
 
 
 
 
 
 
 
 
Signature of a Witness (when required by the PHRC or by the Sponsor): 
 
 
 
 
 
 
Witness (when required) 
 
 
 
 
 
Date/Time 
 
 
Statement of Study Doctor or Person Obtaining Consent 
 
§ 
I have explained the research to the study subject, and 
§ 
I have answered all questions about this research study to the best of my ability. 
 
 
 
 
 
 
Study Doctor or Person Obtaining Consent 
Date/Time 
 
 
In certain situations, the Partners Human Research Committee (PHRC) will require that a subject 
advocate also be involved in the consent process.  The subject advocate is a person who looks 
out for the interests of the study subject.  This person is not directly involved in carrying out the 
research.  By signing below, the subject advocate represents (or “says”) that the subject has 
given meaningful consent to take part in the research study. 
 
Statement of Subject Advocate Witnessing the Consent Process 
 
§ 
I represent that the subject, parent(s), or legally authorized individual signing above has 
given meaningful consent. 
 
 
 
 


Partners HealthCare System 
Research Consent Form 
 
 
 
 
Template Version Date:  June 2005 
 
 
 
 
Page 14 
 
 
Subject Identification 
Subject Advocate 
Date/Time 
(if required by the PHRC or sponsor for this study)  
 
 
Consent Form Version Date:  February 2008