Clinical trial NCT02740699
Conditions: Cardiovascular Disease
Keywords: Cholesterol Heart Disease CT Scan Crestor Lipitor
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Start date: 2016-04-11; Completion date: 2022-03-11
Enrollment: 79 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

Coronary artery disease causes plaque in arteries. This can cause stroke or heart disease. Drugs called statins might shrink plaque. Researchers want to study how CT scanning can determine if an individuals arterial plaque has decreased while taking statins.

Objectives:

To measure the change in coronary artery plaque volume in people treated with high-intensity statin therapy using CT and MRI scans. To study the metabolic activity of plaque in arteries. To determine how well plaque measurements from heart CT scans can be replicated.

Eligibility:

Men ages 40-75 and women ages 40-75 who are good candidates for statin treatment

Design:

Visit 1: participants will be screened with:

* Medical history
* Blood tests
* Heart MRI and CT scan: An IV inserted into an arm or hand vein removes blood and injects contrast, and medicine if needed. Participants lie on a table that slides into a machine that takes pictures of the body. For the CT scan, if their heart rate is too high, they get medicine to lower it. They breathe in a special way, holding their breath for 5 seconds.

Participants will begin high-intensity statin treatment.

Participants will have 7 more visits over 3 years. All visits include blood tests and medication review. Some may also include:

* Statin treatment adjustment
* CT scan
* MRI scan
* Physical exam

Participants may join the PET Substudy. This includes 5 more visits during the study. These include:

* Getting an IV in an arm vein
* Blood tests
* PET scans: They fast 12 hours before.

Participants may join the Reproducibility Substudy if they had a slow heart rate during their first CT scan. This includes 1 additional heart CT scan 4 weeks later.

Detailed description:
In high risk patients undergoing invasive angiography, intravascular ultrasound (IVUS) has shown reduction of plaque for patients treated with HMG-CoA reductase inhibitors (statins). However, there is no accepted noninvasive method to determine if treatment for atherosclerosis results in reduction of coronary artery plaque.

Coronary artery CT angiography (CCTA) is noninvasive and can accurately determine the degree of coronary artery stenosis. In addition, the extent of calcified and noncalcified plaque may be directly measured using this technology at low radiation dose using state-of-the-art CT scanners. Several retrospective studies have previously suggested that CCTA may be able to show plaque regression in the coronary arteries due to statin therapy.

The primary aim of this proposal is to determine the change in coronary artery plaque volume in individuals treated with high intensity statin therapy as defined by 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults.

Men and women who meet the inclusion and exclusion criteria will undergo CCTA examination for the presence or absence of coronary artery plaque. Individuals with evidence of noncalcified coronary plaque by CCTA and who meet criteria for HMG-CoA reductase (statin) therapy will be evaluated for a total of 36 months. The change of coronary artery plaque (progression or no change, or regression) in individuals with noncalcified plaque at baseline will be measured by CCTA at yearly intervals.

Arms: arm 1: Participants with coronary artery plaque will receive moderate to high statin treatment at either 20-40 mg once daily Rosuvastatin or 40-80 mg once daily of Atorvastatin.
Interventions: intervention 1: Rosuvastatin intervention 2: Atorvastatin intervention 3: Cardiac Computed Tomography (CT) intervention 4: Cardiac Magnetic Resonance Image (MRI)
Intervention descriptions: intervention 1: Participants will receive 20-40 mg once daily intervention 2: Participants will receive 40-80 mg once daily. intervention 3: Cardiac CT angiography (CCTA) provides a non-invasive method of evaluating both calcified and noncalcified plaque volume. Performed at baseline, 12 months 24 months, and 36 months. intervention 4: Provides a non-invasive method of evaluating both calcified and noncalcified plaque volume. Cardiac MRI may be performed at baseline, and 24 months (optional).

Protocol documents:
Prot_SAP_000.pdf: 
 
Protocol with Statistical Analysis Plan Cover Page:  
 
Official Title: 
 
CT COMPARE:  CT COronary angiography to Measure PlAque REduction 
NCT number: 
 
NCT02740699 
Document Type:  
Protocol with Statistical Analysis Plan   
Document Date: 
August 14, 2020 


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Short Title: CTA Plaque regression 
Protocol #: 16-H-0089 
 
PROTOCOL TITLE: CT COMPARE:  CT COronary angiography to Measure PlAque 
REduction   
 
Principal Investigator: 
 
 
 
 
Nehal Mehta, M.D.  
E-mail: nehal.mehta@nih.gov 
 
 
 
 
 
 
 
 
 
 
 
Accrual number:  190 
Sponsor:  No 
 
Project uses Ionizing Radiation: Yes  
IND/IDE: No 
Project uses Durable Power of Attorney: No 
Off-site study:  No 
 
Multi-institutional protocol:  No 


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Table of contents: 
1 
Introduction .......................................................................................................................................... 5 
Study AIMS: ............................................................................................................................................... 5 
Background and Rationale ......................................................................................................................... 6 
Design ...................................................................................................................................................... 13 
2. 
Eligibility Assessment and Enrollment ................................................................................................ 18 
2.1. 
Inclusion Criteria ......................................................................................................................... 18 
2.2. 
Exclusion Criteria ......................................................................................................................... 18 
2.3. 
Screening Evaluation ................................................................................................................... 19 
2.4. 
Registration Procedures .............................................................................................................. 21 
3. 
Subject Implementation ..................................................................................................................... 21 
3.1 
Study Design ............................................................................................................................... 21 
3.2 
Protocol Evaluation/Study Calendar ........................................................................................... 21 
3.3 
Concurrent Therapies ................................................................................................................. 22 
3.4 
Criteria for removal from Treatment/Protocol ........................................................................... 22 
4. 
Supportive Care .................................................................................................................................. 23 
5. 
Data Collection and Evaluation ........................................................................................................... 23 
5.1. 
HUMAN SPECIMEN USE, DISPOSITION, TRACKING AND STORAGE OF SAMPLES AND Data ....... 23 
5.2. 
Response criteria......................................................................................................................... 26 
6. 
Statistical considerations .................................................................................................................... 26 
7. 
Human Subject Protection .................................................................................................................. 30 
7.1. 
Rationale for Subject Selection ................................................................................................... 30 
7.2. 
Participation of Children: ............................................................................................................ 31 
7.3. 
Exclusion of Pregnant Women: ................................................................................................... 31 
7.4. 
EXCLUSION OF PERSONS UNABLE TO GIVE CONSENT ................................................................ 31 
7.5. 
Evaluation of Benefits and Risks/Discomforts: ........................................................................... 31 


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Statin Therapy .......................................................................................................................................... 32 
7.6. 
Risks/Benefits Analysis ................................................................................................................ 35 
7.7. 
Consent Process and Documentation ......................................................................................... 36 
7.8. 
Data Safety and Monitoring ........................................................................................................ 37 
7.9. 
Compensation ............................................................................................................................. 37 
7.10. 
Conflicts of Interest ..................................................................................................................... 38 
8. 
Safety Reporting Requirements: ......................................................................................................... 38 
8.1. 
Definitions ................................................................................................................................... 38 
8.2. 
IRB Reporting Guidelines ............................................................................................................ 38 
8.3. 
IND/IDE: ...................................................................................................................................... 39 
9 
Pharmaceutical Information ............................................................................................................... 39 
References: ................................................................................................................................................... 49 
Appendices ................................................................................................................................................... 55 
 
 


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Précis 
 
In high risk patients undergoing invasive angiography, intravascular ultrasound (IVUS) 
has shown reduction of plaque for patients treated with HMG-CoA reductase inhibitors 
(statins).  However, there is no accepted noninvasive method to determine if treatment for 
atherosclerosis results in reduction of coronary artery plaque.   
 
Coronary artery CT angiography (CCTA) is noninvasive and can accurately determine 
the degree of coronary artery stenosis.  In addition, the extent of calcified and 
noncalcified plaque may be directly measured using this technology at low radiation dose 
using state-of-the-art CT scanners.  Several retrospective studies have previously 
suggested that CCTA may be able to show plaque regression in the coronary arteries due 
to statin therapy.  
 
The primary aim of this proposal is to determine the change in coronary artery plaque 
volume in individuals treated with high intensity statin therapy as defined by 2013 
ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic 
Cardiovascular Risk in Adults. 
 
Men and women who meet the inclusion and exclusion criteria will undergo CCTA 
examination for the presence or absence of coronary artery plaque.  Individuals with 
evidence of noncalcified coronary plaque by CCTA and who meet criteria for HMG-CoA 
reductase (statin) therapy will be evaluated for a total of 36 months.   The change of 
coronary artery plaque (progression or no change, or regression) in individuals with 
noncalcified plaque at baseline will be measured by CCTA at yearly intervals.    
 
 


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1 
INTRODUCTION 
STUDY AIMS: 
At present, approximately 50% of the U.S. population age 40-75 years are eligible for HMG-CoA reductase 
(statin) therapy (Vogel 2014).  Statin therapy is the primary medical therapy that has shown definitive 
evidence for reduction of cardiovascular events in the population due to coronary artery disease (Stone, 
Robinson et al. 2014).  The benefit of statin therapy is presumed to be the reduction and/or stabilization 
of coronary artery plaque.  However, an accepted method that can reproducibly and noninvasively detect 
reduction of coronary artery plaque is not currently available.   
Data in the literature and our own preliminary data indicate that, on average, atherosclerotic plaque 
decreases due to statin therapy.  However, the atherosclerotic response to statin therapy is variable; 
although the average extent of plaque decreases in a study population, some individuals show plaque 
progression despite “appropriate” statin therapy. 
Coronary computed tomography angiography (CCTA) is accurate for documenting the presence or 
absence of coronary artery stenosis.  However little information is available about the use of CCTA to 
document change in coronary plaque over time during statin therapy.  Thus, the primary aim of this study 
is to determine the mean change of non-calcified plaque over the study period (24 months) in adults 
treated with high intensity statin therapy (as defined by the 2013 ACC/AHA Guidelines to Reduce 
Cardiovascular Risk (GRCR).  We will also examine cardiovascular risk factors associated with coronary 
plaque increase or decrease over the study period. 
Study subjects will have target plaque lesions quantitatively analyzed for volume change over time. Using 
anatomical landmarks, a target plaque volume will be defined at baseline and follow up examinations. 
Semiautomatic software will be used to trace lumen and outer vessel boundaries to determine non-
calcified plaque volume.   
In addition to CCTA coronary artery analysis, novel preliminary studies suggest that some coronary artery 
plaques have abnormal cardiac magnetic resonance (CMR) T1 signal and increased uptake of sodium 
fluoride hypothesized to indicate intraplaque hemorrhage and active microscopic calcification, 
respectively.  We will correlate CMR T1 and sodium fluoride signal with CCTA determined change in 
plaque during statin therapy.      
Primary Aim:  Determine the mean change in noncalcified plaque volume in study subjects treated with 
high intensity statin therapy over a 24 month interval. 
In addition to the 24 months follow-up period specified for the primary endpoint, we plan to follow the 
patients for an extended period of 12 months to study the long-term effects of the statin therapy. As a 
result, the patients will be followed for a total of 36 months with the first 24 months for the primary 
endpoint and the additional 12 months for the secondary endpoints.  The secondary endpoints include: 
1) Change in noncalcified plaque volume assessed by CCTA at the end of 36 months;  
2) Effects of covariates including age, sex, race, body mass index and baseline plaque volume on the 
change of plaque volume measured by CCTA at 24 and 36 months. 


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3) (Pilot study): The relationship of CMR T1 high signal intensity plaque and change in T1 signal by 
CMR over time to CCTA plaque characteristics.   
4) (Pilot study):  the relationship of coronary artery plaque by CCTA to sodium fluoride (F18-NaF) 
uptake using positron emission tomography (PET) scanning:  
a. Determine if F18-NaF signal correlates with CCTA defined plaque volume and CAC score. 
b. Determine the change in F18-NaF signal in relationship to statin therapy 
a. Determine the change in F18-NaF signal in relationship to statin therapy. 
BACKGROUND AND RATIONALE 
CCTA is currently used to document the presence and degree of coronary artery stenosis.  However, very 
little information is available to determine if CCTA can document change in the extent coronary plaque 
over time.   Individuals who have elevated cholesterol levels are prescribed HMG-CoA reductase inhibitor 
(“statin”) therapy; such therapy may be for the duration of an individual’s life.  Although the 
cardiovascular benefits of statin therapy have been documented in population-based studies, the benefit 
for an individual in terms of reduction of coronary artery plaque is much less well known.   The use of 
CCTA has not been previously evaluated in this regard. 
In this study, we will determine the change in CCTA defined noncalcified plaque over a 36-month interval 
during the course of statin therapy.  We will identify a group of subjects with moderate or greater 
cardiovascular risk (as defined by the 2013 ACC/ AHA GRCR guidelines and 2018 ACC/AHA guidelines).  
Study subjects will undergo so-called “high-intensity” statin therapy according to the GRCR guidelines.  A 
high intensity therapy will be chosen because changes in soft plaque are expected to be small; high 
intensity therapies are more likely to result in CCTA detected change in plaque volume.  Eligible subjects 
will not previously have received high intensity statin therapy for more than 90 days prior to enrollment.  
Our underlying hypothesis is that CCTA will detect a decrease in soft plaque volume; we will also correlate 
decrease in plaque volume with other cardiovascular risk factors.   
Study subjects will be treated with high-intensity statin therapy as defined by the 2013 ACC/AHA GRCR 
guidelines and 2018 ACC/AHA guidelines:  rosuvastatin 20-40 mg or atorvastatin 40-80 mg.  The maximum 
statin dose will be administered that is tolerated by the patient and that maintains LDL-C ≥ 25 mg/dl.  
High-intensity statin therapy is defined in the GRCR guidelines as lowering LDL-C on average by 
approximately ≥ 50%. 
Study subjects will undergo state of the art cardiac imaging for 36 months at 12 month intervals using 
coronary computed tomography angiography for determination of plaque volume.   
 


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CORONARY PLAQUE EVALUATION IN ASYMPTOMATIC SUBJECTS 
Background for Primary Aim.   
Coronary artery disease is the most common cause of morbidity and mortality not only in the United 
States but also world-wide (Lozano, Naghavi et al. 2012).  Assuming attainment of 40 years of age, 
symptomatic coronary heart disease occurs in 49% of men and 32% of women over their lifetime (Stone, 
Robinson et al. 2014).   Accounting for both stroke plus heart disease, Vogel has estimated that ideally 
61% of men and 48% of women age 40-75 years should be considered for statin therapy (Vogel 2014).   
Statin therapy is the primary medical therapy that has shown definitive evidence for reduction of 
cardiovascular events due to coronary artery disease (Stone, Robinson et al. 2014).  Coronary artery 
disease (CAD) results in formation of atherosclerotic plaques that may result in stable angina or acute 
coronary syndrome due plaque rupture or ulceration.  Atherosclerotic plaques that are prone to rupture 
have a large lipid core, thin fibrous cap and inflammation (Kern and Meier 2001).  Therefore medications 
that promote plaque regression, stability and/ or reduce inflammation may reduce occurrence of 
coronary syndrome and/ or stroke may also reduce the rate of major cardiovascular events (MACE).  
Studies that use MACE as an endpoint are very costly, involve thousands of patients and require lengthy 
time course.  Therefore, plaque regression using imaging as a surrogate endpoint for MACE has been 
investigated.    
IVUS and plaque regression.  Intravascular ultrasound (IVUS) of the coronary arteries has been the 
primary modality by which plaque regression has been investigated, although the modality is only 
relevant to high risk patients since it involves an invasive angiogram.  A recent meta-analysis evaluated 11 
studies and 7864 patients that used IVUS to quantify plaque atheroma change due to targeted statin 
therapy at baseline and a median follow up of 18 months (D'Ascenzo, Agostoni et al. 2013).  Nine statin 
treatment studies evaluated patients with stable angina, while 2 evaluated patients with acute coronary 
syndrome.  The mean change in plaque volume was 0.5% (-0.25-1.0, 95% CI).  The rate of plaque 
regression was significantly related to incidence of MI or revascularization.   
MRI and plaque regression.  MRI scanning and computed tomography coronary angiography (CCTA) are 
minimally invasive technology (using intravenous peripheral injections) and are capable of imaging plaque 
as well as plaque components.  Studies that have evaluated MRI of plaque and plaque components have 
focused mostly on the carotid artery due its larger size.  Recently, our group demonstrated that plaque 
composition in the carotid artery by MRI is associated with cardiovascular events in the MESA study 
(Zavodni, Wasserman et al. 2014). Two prospective MRI studies have shown reduction of carotid artery 
plaque secondary to statin therapy (Lima, Desai et al. 2004, Corti, Fuster et al. 2005, Sibley, Vavere et al. 
2013).  However, two years of rosuvastatin did not decrease carotid artery plaque volume by MRI in a 
different study (Underhill, Yuan et al. 2008).  No studies have shown regression of coronary plaque with 
MRI; low spatial resolution (~1 mm or more) of the technique makes this very challenging for coronary 
artery disease. Subjects may be co-enrolled in Protocol 18-H-0118 MRI results may be shared across both 
Protocols.  This collaboration may improve the understanding of cardiovascular disease and its 
relationship to other disease states, translating the newer technology to improve diagnosis and 
management of cardiovascular disease and to carefully characterize cardiovascular disease using updated, 
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CT calcium score and plaque regression.  Non-contrast CT scanning is used to detect calcified coronary 
artery plaque.  A comprehensive review of the natural history of CAC score in patients at low, 
intermediate and high cardiovascular risk shows the CAC score increases at an annualized rate CAC from 
21% to 51% (mean, about 20% increase/ year) (Priester and Litwin 2009).  Further, nearly all intervention 
trials (predominately statin therapy) show increased CAC score despite therapy, most commonly with no 
significant change between statin and control groups (Priester and Litwin 2009).  Maturation of unstable 
or noncalcified plaque as a result of statin therapy has been suggested on various IVUS studies (Nicholls, 
Tuzcu et al. 2007).  Thus, CAC score is not appropriate for assessing plaque regression.   
CT angiography of noncalcified plaque.  CCTA has matured to a routine clinical tool with excellent 
sensitivity (>= 80%) and specificity (99%) for coronary artery stenosis (Budoff, Dowe et al. 2008, Mowatt, 
Cummins et al. 2008).  Although CCTA is clinically used to determine coronary stenosis, our group (Kwan, 
May et al. 2014) and others have developed approaches to quantify nonstenotic plaque and/ or total 
plaque burden.  One such measure is the plaque volume index (PVI), which is the total coronary plaque 
volume (Figure 1) normalized by the coronary artery length.  In our study of 224 patients with type 2 
diabetes, greater PVI was associated with age, gender, duration of diabetes and obesity.  In addition, the 
segmental plaque score, segmental stenosis score and segmental involvement score are methods that can 
quantify the regional presence of soft plaque (Johnson, Dowe et al. 2009, Johnson and Dowe 2014). 
Figure 1.  Derivation of plaque 
volume index (PVI) from CCTA.  
After identifying the coronary tree 
(left), the coronary artery wall 
boundaries are contoured for the 
entire coronary tree (right) in a 
manner analogous to IVUS.  The 
amount of plaque (in mm3) divided 
by the total coronary length is the 
PVI. From (Kwan, May et al. 2014) 
Several studies to date have 
evaluated the natural history of 
increase in plaque volume 
detected by CCTA (Table 2) and 
the potential of CCTA to track plaque progression.  Schmid et al. all found a 25% change in noncalcified 
plaque volume in 50 patients in the left main and left anterior descending artery in 12 months (Schmid, 
Achenbach et al. 2008).  Lehman et al. evaluated 69 patients with acute coronary syndrome and optimal 
medical therapy.   Limitations include retrospective studies, small sample size and   older CT scan 
technology.  
Table 2.  Natural history of atheroma growth by CCTA. ACS acute coronary syndrome; CAD coronary artery disease 
Authors 
N (patients) 
Indication for 
CTA 
Study type 
Time  
Results 
Annualized 
plaque 
growth 
Schmid et al. 
(Schmid, 
Achenbach et 
al. 2008) 
50 (86% 
men, mean 
age 58) 
Suspected 
CAD 
Prospective 
17 months 
25% increase in 
noncalcified 
plaque volume 
18%/ year 
 


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CCTA of coronary plaque during statin therapy. Several studies have shown the potential of CCTA to 
detect coronary plaque regression.   A case report by Johnson et al. showed an example of a patient 
receiving atorvastatin 40 mg qd with a plaque area that decreased over 26 months from 20 mm2 to 
11mm2 (Figure 2).  In our ongoing NIH RIGHT study, we have observed reduction of coronary plaque in 
certain patients (Figure 3).  Papadopoulou et al. evaluated 32 patients with acute coronary syndrome over 
39 months with moderate statin therapy.  They found a slight increase in total atheroma volume increase 
over this period of 6.7%.  Unfortunately they used different types of CT scanners over this study period (as 
did the study by Hoffman et al. (Hoffmann, Frieler et al. 2010)).  Thus technical scan factors could have 
played a role in changes in plaque measurements.     
A summary of clinical trials showing the results of CCTA measurement of plaque during the course of anti-
hyperlipidemic therapy is shown in the table below (Sandfort, Lima et al. 2015).  Overall, 3/5 studies show 
a very low rate of plaque growth or actual regression of plaque in 3 of 5 studies. Two of these studies 
were retrospective, and only 1 was an intervention trial in patients without acute coronary syndrome (n= 
12 subjects).  Limitations of these studies include small sample size and outdated CT scan technology.  
Thus, no prospective study has been conducted of plaque regression in statin treated subjects without 
acute coronary syndrome with adequate sample size that would allow for adjustment of cardiovascular 
risk factors likely to affect the success of statin therapy. 
Lehman et al. 
(Lehman, 
Schlett et al. 
2009)  
69 (59% 
male, mean 
age 55) 
Ruled out ACS 
Prospective 
24 months 
25% increase in 
plaque volume 
12%/ year 
Zeb et al. (Zeb, 
Li et al. 2013) 
40 (83% 
male, mean 
age 64 
Asymptomatic 
CAD 
Retrospective 
13.3 
months 
10% increase in 
noncalcified 
plaque volume 
9%/ year 
Lo et al. (Lo, Lu 
et al. 2015)  
37 (HIV+, 
80% male) 
Asymptomatic 
CAD 
Prospective 
Randomized 
12 month 
Non-calcified 
Placebo: +20% 
Atorva.: -19 % 
20%/ year 
Figure 2.  Regression of plaque after statin therapy, case report study 
from (Johnson, Dowe et al. 2006) 
Figure 3. Regression of total plaque by 22% and 
concomitant increase of calcification during statin therapy 
for two years (atorvastatin 20 mg, NIH data).  


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Table 3.  CCTA assessment of atheroma in response to therapy 
Authors 
N (patients) 
Indication for 
CTA 
Study type 
Time 
Results 
Annualized 
plaque 
growth 
Hoffman et al. 
(Hoffmann, 
Frieler et al. 
2010) 
63 (71% 
male, mean 
age 63) 
Suspected 
CAD 
Retrospective 
observational, 
statin treatment, 
varied dose not 
reported 
25 months 
16 slice CT 
@baseline, 
64 slice CT 
@follow-up 
NCP 
increased 
from 21 mm3 
to 29 mm3 
(38%) 
18%/ year 
Tardif et al. 
(Tardif, L'allier 
et al. 2010) 
28 (90% 
male, mean 
age 57) 
ACS 
Prospective, 
interventional, 
VIA-2291 
treatment 
6 months 
Placebo, 6% 
increase 
VIA-2291, -
4.9% 
decrease 
-10%/ year 
for 
treatment 
arm 
Burgstahler et 
al. (Burgstahler, 
Reimann et al. 
2007) 
12 (100% 
male, mean 
age 61) 
Elevated CV 
risk, PROCAM 
score>3rd 
quintile 
(Agatston 
mean 257) 
Prospective, 
atorvastatin 20 
mg 
16 months 
NCP 
decreased by 
24% 
-18%/ year 
Papadopoulou 
et al. 
(Papadopoulou, 
Neefjes et al. 
2012) 
32 (81%, 
mean age 
53) 
ACS 
Prospective, 
observational, 
atorvastatin 40 
mg (n=29), 
simvastatin 40 
mg, 1 patient 
rosuvastatin 10 
mg, 2 patients 
39 months 
Normalized 
atheroma 
volume 
increased by 
47mm3 
(6.7%) 
+1.7%/ year 
Zeb et al. (Zeb, 
Li et al. 2013) 
60 (83% 
male, mean 
age 64 
Asymptomatic 
CAD 
Retrospective 
13.3 
months 
28% 
decrease in 
noncalcified 
plaque 
volume 
-25%/ year 
Preliminary Data related to the Primary Aim 
a) Plaque reduction intervention, preliminary data.  In an ongoing study (10-CC-0214, The RIGHT Study: 
Risk Stratification With Image Guidance of HMG Coa Reductase Inhibitor Therapy” (NCT01212900), 
Bluemke PI), we are evaluating the effect of statin therapy on carotid artery atherosclerosis using cardiac 
magnetic resonance imaging in adult, asymptomatic study subjects.  High resolution 3 tesla carotid 
magnetic resonance imaging (MRI) was performed on 106 asymptomatic subjects at baseline and 12 
months after therapy.  The median age was 65 years and 64% of subjects were male. Carotid wall area of 
the internal carotid artery was measured and the mean volume change of the arterial wall was calculated. 
Univariate and multivariable models incorporating cardiovascular risk factors were used for analysis 
(Sandfort, Sibley et al. 2014). 
Statin treatment was monitored and serum LDL was measured at 6 months and one year. The on-
treatment LDL was 76 mg/dL; there was significant reduction of LDL during the study (50% of the 
untreated LDL level).   The average decrease in carotid atherosclerosis over 12 months was -0.3 ± 2.4 
mm2.  There was progression of carotid plaque in 46 subjects (43 %) and regression of plaque in 60 
subjects (57 %)   


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In univariate analysis, obesity and hypertension were associated with progression of carotid plaque while 
statin dose was associated with regression (obesity: odds ratio for progression 4.6, CI 1.8-12.4, p < 0.01; 
hypertension: odds ratio 2.4, CI 1.1-5.3, p < 0.05; statin dose: odds ratio for progression 0.4, CI 0.18-0.87, 
p < 0.05).  In a multivariable logistic regression model, obesity remained significantly associated with 
progression (odds ratio 4.2, CI 1.6-12.1, p <0.01) while statin use remained associated with regression 
(odds ratio for progression 0.38, CI 0.16-0.88, p <0.05). The median percent change in atheroma volume 
in obese subjects was +3.4 % vs. -3.0 % in nonobese subjects (p<0.05).   
Progression was not associated with change in LDL levels (p>0.05). 
a) Experience of the investigators in measuring coronary plaque, preliminary data.  In a collaboration with 
investigators at the University of Utah, Intermountain Healthcare and Johns Hopkins, we analyzed CT 
scans of diabetic patients undergoing CCTA as an adjunct to their diabetes care in the FACTOR-64 study 
published in JAMA (Muhlestein, Lappe et al. 2014).  In that study, CCTA screening for coronary stenosis 
was investigated to determine if the cardiovascular events were reduced in diabetic patients.  Over 1.7 
years, cardiovascular event rates in 448 diabetic patients were similar in the group with CCTA compared 
to the group without imaging intervention.  Although the follow-up period was relatively short, the study 
demonstrated that an outcome of detection of coronary stenosis is not sufficient to define at diabetic 
patients who are at higher risk for cardiovascular disease.  However, we also analyzed total plaque 
volume by CCTA in 128 diabetic patients in the FACTOR-64 study.  Risk factors that were associated with a 
greater degree of total coronary artery plaque volume were age, gender and body mass index (Kwan, May 
et al. 2014).  Greater calcium score was associated with lower amounts of noncalcified plaque. 
We applied similar methodology in our NIH cohort (10-CC-0214, The RIGHT Study: Risk Stratification With 
Image Guidance of HMG Coa Reductase Inhibitor Therapy” (NCT01212900)).  We evaluated 202 study 
subjects with low to moderate cardiovascular risk (Kwan, May et al. 2014).The average age of study 
subjects was 65.5±6.9 years (36% women) with median coronary artery calcium score was 73 (IQR 1-434). 
Total coronary plaque index was greater in men than women (42.1±9.2 vs. 34.3±8.3 mm2, p<0.001). In 
Figure 4: Upper part: Univariate 
comparison of continuous carotid 
wall change measurements. A: 
Change for subjects with low BMI 
(light grey) vs. high BMI (dark grey). 
B: Change in subjects with (dark 
grey) and without hypertension 
(light grey). C: Change in subjects 
with a AHA risk ≤ 7.5 % (light grey) 
or AHA risk > 7.5 % (dark grey).  
Lower part: Corresponding 
percentage of subjects 
experiencing progression of carotid 
wall area measurements 
(change>0).  Obese subjects and 
hypertensive subjects have a 
higher median wall area change 
and more frequently show carotid 
artery disease progression (* 
p<0.05). 


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multivariable analysis controlling for all risk factors, total plaque index was remained greater in men than 
women (by 5.01 mm2; p=0.03), and in those with higher simvastatin dose (by 0.44 mm2/10 mg eq.; 
p=0.02). Noncalcified plaque index was positively correlated with systolic blood pressure (beta = 0.80 
mm2/10 mmHg, p=0.03), diabetes (beta = 4.47 mm2, p=0.03), and LDL –C level (beta = 0.04 mm2/mg/dl, 
p =0.02); the association with LDL-C remained significant (p=0.02) after additional adjustment for CAC 
score. 
In summary, the above studies demonstrate a) ability to recruit patient cohorts relevant to the present 
study; b) technical expertise in assessing total coronary artery plaque as well as plaque volume 
components and c) certain risk factors such as obesity are associated with noncalcified plaque.  The 
proposed study is a logical extension to our prior published work in this area.  Importantly, in an NIH study 
population with favorable LDL response to statin therapy, slightly less than half of study subjects showed 
atheroma progression in the carotid arteries.  We have identified cardiovascular risk factors, especially 
obesity and hypertension, related to atheroma progression despite optimal guideline oriented statin 
therapy.  A gap in our knowledge is the effect of statin therapy for plaque reduction in asymptomatic 
subjects in the coronary arteries.   
Background for Secondary Aims of Comparison of Cardiac CT to Cardiac MRI.   
Magnetic resonance imaging of intraplaque hemorrhage.   In the carotid arteries, there is now strong 
evidence that high T1 signal within an atheromatous plaque is due to intraplaque hemorrhage (McNally, 
Kim et al. 2012).  In the Rotterdam study, intraplaque hemorrhage was considered an indicator of 
unstable plaque and was more prevalent in men compared with women.  Hypertension and current 
smoking were risk factors for the presence of intraplaque hemorrhage (van den Bouwhuijsen, Vernooij et 
al. 2012).  Intraplaque hemorrhage was more frequently found on the ipsilateral side of subcortical brain 
infarction and was associated with disruption of the surface of plaque (Truijman, de Rotte et al. 2014, de 
Rotte, Truijman et al. 2015, van den Bouwhuijsen, Bos et al. 2015, van Dijk, Truijman et al. 2015).  These 
observations strongly support the role of intraplaque hemorrhage as a contributor to unstable 
atheromatous plaque. 
For the coronary arteries, the challenges of demonstrating intraplaque hemorrhage are greater due to 
small plaque size.  However, recent studies have demonstrated abnormal T1 signal related to coronary 
artery plaques on non contrast CMR imaging (Kawasaki, Koga et al. 2009).  Increased T1 signal is present 
on MRI in the presence of hemorrhage or protein and is postulated to represent regions of unstable 
plaque.  T1 signal has been shown to change over time following myocardial infarction (Ibrahim, 
Makowski et al. 2009) and has proven to be a strong predictor of subsequent coronary artery events in 
individuals with high cardiovascular risk (Noguchi, Yamada et al. 2011, Noguchi, Kawasaki et al. 2014).  In 
the current study, we propose that T1 high signal intensity plaques may be characterized in relationship to 
CCTA features of low density plaque and irregular plaque signal.  We propose to assess change in T1 
plaque signal in comparison to NaF activity in the coronary arteries (see next section). 
18F-Sodium Fluoride (NaF) for evaluation of coronary artery plaque:  PET sub study.  18F-Sodium Fluoride 
(NaF) is a 510k FDA approved agent for positron emission tomography (PET).  The agent has recently been 
investigated to identify high-risk coronary plaque as well as carotid plaque.  In 37/40 patients, the highest 
coronary NaF signal was seen in the culprit plaque in patients with myocardial infarction (Joshi, Vesey et 
al. 2014).  In the carotid artery, NaF signal was present in all carotid plaque ruptures in symptomatic 


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patients. NaF is thought to target active microcalcification in atherosclerotic plaques (Chen and Dilsizian 
2013).  Currently, little is known about the initiation and progression of plaque, partly because of lack of a 
noninvasive imaging modality targeting molecular calcification.  Inter-observer repeatability of coronary 
NaF uptake measurements (maximum tissue/background ratio) was excellent (intra-class coefficient 0.99) 
(Dweck, Chow et al. 2012). Activity was higher in patients with coronary atherosclerosis (n = 106) versus 
control subjects (1.64 ± 0.49 vs. 1.23 ± 0.24; p = 0.003) and correlated with the calcium score (r = 0.652, p 
< 0.001), although 40% of those with scores >1,000 displayed normal uptake. Patients with increased 
coronary 18F-NaF activity (n = 40) had higher rates of prior cardiovascular events (p = 0.016) and angina (p 
= 0.023) and higher Framingham risk scores (p = 0.011).   
Thus NaF has been proposed as a promising new approach for the assessment of coronary artery plaque 
biology. Prospective studies are needed to assess whether coronary NaF uptake represents a novel 
marker of plaque vulnerability and future cardiovascular risk.  By comparison, CAC score by CT is a risk 
marker which cannot be modified.  Thus, an unresolved issue is if NaF uptake can be modified by statin 
therapy, which would be expected if NaF relates to cardiovascular risk. 
Summary.  Cardiac CT angiography (CCTA) provides a non-invasive method of evaluating both calcified 
and noncalcified plaque volume.  Plaque regression has been demonstrated by coronary artery IVUS and 
carotid artery MRI.  The potential for tracking plaque progression/ regression is suggested in high risk 
patients using CCTA.  Several retrospective and small prospective studies suggest that CCTA may be useful 
to track plaque reduction.  Comparison to CMR is useful to fully phenotype plaque characteristics due to 
novel studies of T1-weighted high signal plaque.  NaF PET appears as a novel agent that may also be 
useful to explore the relationship between treatment and PET signal with regards to CCTA plaque 
characteristics and CMR T1 signal.  No prior studies have evaluated the change in plaque volume in 
patients evaluated under 2013 AHA/ACC GRCR guidelines for high intensity statin therapy. 
DESIGN 
Primary Endpoint: The primary endpoint of this study is the change in noncalcified plaque volume after 
24 months.  
Secondary Endpoints: In addition to the 24 months follow-up period specified for the primary endpoint, 
we plan to follow the patients for an extended period of 12 months to study the long-term effects of the 
statin therapy. As a result, the patients will be followed for a total of 36 months with the first 24 months 
for the primary endpoint and the additional 12 months for the secondary endpoints.  The secondary 
endpoints include:  
1) Change in noncalcified plaque volume assessed by CCTA at the end of 36 months;  
2) Effects of covariates including age, sex, race, body mass index and baseline plaque volume on the 
change of plaque volume measured by CCTA at 24 and 36 months. 
3) The relationship of CMR T1 high signal intensity plaque and change in T1 signal by CMR over time 
to CCTA plaque characteristics.   
4) (Pilot study):  the relationship of coronary artery plaque by CCTA to sodium fluoride (F18-NaF) 
uptake using positron emission tomography (PET) scanning:  
a. Determine if F18-NaF signal correlates with CCTA defined plaque volume and CAC score. 
b. Determine the change in F18-NaF signal in relationship to statin therapy. 


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In order to achieve the primary aim, we will evaluate men (age 40-75) and women (age 40-75) with a 
screening/ baseline CT scan of the coronary arteries.  Study subjects will be followed over time if they a) 
have noncalcified coronary artery plaque, b) have not been treated with GRCR defined high intensity 
statin treatment for more than 90 days prior to enrollment and c) agree to receive high intensity statin 
treatment.  The study duration will be 36 months.  Subjects eligible based off their screening/baseline CT 
scan of the coronary arteries will receive Rosuvastatin or another high intensity statin treatment.  Study 
subjects will also undergo CMR scan to detect T1 high signal intensity plaque and for comprehensive 
cardiovascular phenotyping.  Correlation of NaF signal on PET scanning will also be performed. 
For the primary aim, subjects fulfilling basic inclusion/exclusion criteria and giving informed consent to 
the study will be examined using CT angiography (3rd generation CT scanner, advanced dose reduction 
techniques). If noncalcified plaque is present, the subject will have follow-up CCTA at 12, 24 and 36 
months.  Additional correlative testing is detailed in the study calendar.  The primary outcome parameter 
is change in noncalcified plaque volume.  Noncalcified plaque volume will be assessed based on the 
largest noncalcified atheroma at baseline CCTA.     
 
OVERVIEW OF ENROLLMENT 
All participants will be screened for their willingness/ability to participate in the various study procedures 
(see Appendix for MRI screening questionnaire) and those unwilling/unable to participate in a specific 
procedure will be excluded from that study. Prior to enrollment onto the study, potential research 
subjects will be sent a Study Questionnaire form to assist the research team in confirming diagnosis and 
determining which tests will be appropriate for the subject (see appendix E). The questionnaire will also 
guide medical record gathering prior to the visit to aid consultants. The initial screening visit will consist of 
laboratory evaluation initial laboratory assays in addition to a focused clinical exam and history. The 
objectives of the screening visit are a) exclude any contraindication for CCTA, nitrates or beta blockers 
(e.g. history of hyperthyroidism, aortic stenosis or prior use of sildenafil); b) determine lipid levels and c) 
determine if noncalcified plaque is present.  Study subjects already receiving high intensity therapy for 
more than 90 days prior to enrollment will not be considered.  Study subjects will be eligible for at least 
moderate statin therapy according to ACC/AHA 2013GRCR criterion and 2018 ACC/AHA guidelines.  Note 
that study subjects at low GCRC cardiovascular risk (using traditional risk factors) but with CAC score > 
75th percentile for age, gender and ethnicity will be classified to be moderate risk.  Specific inclusion/ 
exclusion criteria are indicated in Sections 2.1 and 2.2 below. 


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If a) noncalcified coronary plaque is identified on 
CCTA, and b) the study subject qualifies for at 
least moderate statin therapy, the study subject 
will be enrolled for statin therapy and follow-up.  
Only study subjects with a noncalcified plaque 
component extending over 4 mm will be 
considered for further follow-up in the study.    
IMAGING - OVERVIEW 
Imaging consists of CCTA for plaque evaluation 
at baseline, 12 months 24 months, and 36 
months.  Cardiac MRI may be performed at 
baseline, and 24 months (optional).  A clinical 
report of imaging and lab results will be offered 
to all subjects and – if requested by the subject – 
can be sent to a physician.   
A study of F18 NaF PET imaging will be 
conducted; participation in the PET study will be 
considered to be optional for participants.  Lack 
of participation will not exclude subjects from 
the study cohort.   
 
 


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CT IMAGING 
CT Imaging protocol 
1. Coronary calcium scan  
2. Coronary computed tomography angiography (CCTA) 
3. Cardiac cine CT 
If a subject has had eGFR measured within the prior 6 weeks and is not on diuretics, ACE inhibitors 
(angiotensin converting enzyme inhibitors), ARBs (angiotensin receptor blockers), and has had no major 
change in clinical status, then the eGFR does not need to be rechecked. Otherwise, the eGFR will be 
measured. 
CCTA will be performed during an intravenous iodinated contrast infusion. A test bolus of iodinated 
contrast (approximately 20 ml) will be used to judge contrast bolus arrival time and optimize image 
quality.  CCTA examination is performed with 60-80 ml iodinated contrast according to Clinical Center 
guidelines. 
4. Radiation and iodine contrast dose 
The estimated average radiation dose for the entire cardiac computed protocol will be less than or equal 
to 2.1 rem per year.  Iodinated contrast dose will be in accordance with current CT Clinical Center 
guidelines.  
Medication to facilitate imaging 
Beta Blockade 
In order to optimize image quality by reducing cardiac motion, participants may receive beta blockade on 
the day of the scan if the expected heart rate is > 60/min.  Participants will have heart rate and blood 
pressure measured, and will be assessed for contraindications to beta blockade (bradycardia, active 
wheezing and history of adverse reaction).   
Beta blockade will proceed according to NHLBI and CC clinical standards:  a net dose of metoprolol 25-200 
mg or atenolol 50-100 mg or diltiazem 90-360 mg will be administered orally potentially in divided doses 
over a period of approximately 1-2 hours titrated to achieve a heart rate less than 60 beats per minute.  In 
addition, metoprolol or diltiazem 5-20 mg intravenously may be administered in divided doses at the 
judgment of the supervising physician if heart rate is not adequately controlled and the subject appears 
capable of tolerating the additional medication.  Vital signs (blood pressure, Heart rate) will be obtained 
and documented following metoprolol administration.  If at any time the heart rate is <50 bpm and/or the 
systolic BP is <100, and the subject becomes symptomatic the supervising physician will be notified.  All 
participants who receive beta blockers will be assessed for symptoms of bradycardia, hypotension and 
orthostasis after scan completion.  
Nitrates 
The use of short acting nitrates (i.e. sublingual nitroglycerine) will be used according to NHLBI and CC 
standards for CCTA for study subjects with systolic blood pressure >100mmHg to allow for accurate 
assessment of the degree of coronary artery stenosis, reduce vasospasm and to standardize vasomotor 
tone.  Potential contraindications to nitroglycerine use should be reviewed prior to administration (known 


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allergy or severe intolerance, critical aortic stenosis, pre-existing hypotension, prior PDE5 (e.g. sildenafil) 
use.  If the patient cannot receive nitroglycerine (due to intolerance, borderline blood pressure, 
investigator judgment, contraindication), the patient may still proceed with the study. Known risks of 
nitroglycerine use include headache, reduction in blood pressure, hypotension.  
CT image analysis 
CT angiogram images will be reconstructed and post-processed on a separate workstation using dedicated 
CCTA software.  Readers will be blinded as to subject and date of the CT angiogram examination. 
Coronary calcification 
Coronary calcification will be measured by the Agatston (Agatston, Janowitz et al. 1990) method.  The 
volume, calcium mass and a voxel based calcium density analysis will also be performed. Total coronary 
artery calcium scores will be generated by summing the values from the left main, left anterior 
descending, left circumflex and right coronary arteries.    
Total plaque quantification 
Raw data will be reconstructed at approximately 0.5 mm slice-thickness. The baseline axial MDCT images 
with adequate reconstruction phase will be post processed and analyzed by commercial software (e.g. 
Medis QAngioCT). Lumen and wall boundaries of target vessels will be semi-automatically detected on 
cross sectional images. Under the guide of multiplanar reconstructed images, experienced readers will 
review and edit lumen and outer wall contours of coronary segments of the left anterior descending 
coronary artery (LAD), left circumflex coronary artery (LCX) and right coronary artery (RCA) from ostium to 
vessel diameter < 2.0mm from cross sectional image. Segments with artifact or blur will be excluded. 
Volume estimates of plaque extent are obtained by multiplying cross sectional area of plaque by slice 
thickness. Plaque wall volume is computed by subtracting lumen volume from vessel volume.  
In order to assess target plaque lesions, the inner and outer contours of the vessel will be determined 
independently and blinded for the time of the exam (i.e., dates of scans will be masked for analysis and 
order of performance mixed). For comparison an index lesion will be selected (based on largest non-
calcified plaque component and sufficient image quality on both exams). Using proprietary software 
developed in conjunction with the software manufacturer, both vessels will be visually aligned based on 
anatomical landmarks and the lesion will be selected on both exams (baseline and follow up). The 
software provides the volume measurements for each lesion. 
An improved tool for the co-registration step (fully automatic co-registration) is under development and 
may also be used. 
CARDIAC MRI (CMR) (OPTIONAL) 
CMR will be performed using a high field (1.5 or 3T) scanner.  The aim of the cardiac study is to a) identify 
high signal intensity T1 coronary artery plaque.  The CMR protocol will include localization images with 
coronary CMR to localize plaque volume. Myocardial structure, function and tissue composition will be 
performed per NIH Clinical Center standard protocol for comprehensive phenotyping to characterize 
subclinical disease that may be present.  In a population of middle and older adults in the U.S.,  


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approximately 9% of study subjects have evidence of myocardial damage defined by myocardial scar or 
abnormalities in cardiac wall motion (Turkbey et al, JAMA 2015, 314(18));  of myocardial scars, 
approximately 80% are undetected by clinical correlation/ ECG (Barbier, Bjerner et al. 2006, Schelbert, Cao 
et al. 2012). 
18F NAF PET IMAGING 
For 18F-NaF uptake, the coronary arteries are visually identified, and regions of interest will be drawn 
around areas of maximal uptake in the left main stem, left anterior descending artery, circumflex artery, 
and the right coronary artery. The maximum standard uptake value (SUV) is recorded from these regions. 
The SUV is the decay-corrected tissue concentration of 18F-NaF divided by the injected dose/body weight. 
However, SUV measurements in vascular structures are influenced by variability in 18F-FDG and 18F-NaF 
activity in the blood. Therefore, SUV measurements are divided by an averaged mean SUV value in the 
blood pool, derived from 5 circular regions of interest drawn in the center of the superior vena cava. This 
provides maximum tissue/background ratios (TBRs) as a measure of arterial tracer uptake. 
2. 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1. 
INCLUSION CRITERIA  
A. Men ≥ 40 and ≤ 75 years of age;  women  ≥ 40 and ≤ 75 years of age 
B. Willing to travel to the NIH for follow-up visits. 
C. Willing to start or modify statin therapy. 
D. Able to understand and sign informed consent. 
E. Serum Creatinine  ≤ 1.5 mg/dL within 30 days in accordance with the NIH Clinical Center Radiology 
and Imaging Sciences SOP. (http://intranet.cc.nih.gov/radiology/policies/ct_iv_contrast_sop.html) 
F. 
Eligible for primary prevention statin therapy 
1) Eligible for at least moderate intensity statin according to 2013 ACC/AHA GRCR  (i.e., ≥5%  10 year 
cardiovascular risk,   https://my.americanheart.org/professional/StatementsGuidelines/Prevention-
Guidelines_UCM_457698_SubHomePage.jsp)  OR  
2) low (<5%) 10 year cardiovascular risk per 2013 ACC/ AHA and with coronary artery calcium score 
≥300 Agatston units or ≥75 percentile for age, sex, and ethnicity determined per MESA study 
(http://www.mesa-nhlbi.org/calcium/input.aspx). 
2.2. 
EXCLUSION CRITERIA 
A. Allergy or prior clinically relevant adverse reaction to Rosuvastatin (does not include minor muscle 
pain).  
B. High intensity statin treatment for more than 90 days prior to enrollment 
C. LDL ≥ 190 mg/ml 
D. Physician-diagnosed heart attack 
E. Physician-diagnosed stroke or TIA 
F. 
Physician-diagnosed heart failure 
G. Having undergone procedures related to cardiovascular disease (CABG, angioplasty, valve 
replacement, pacemaker or defibrillator implantation, any surgery on the heart or arteries) 


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H. Active treatment for cancer 
I. 
Prior hypersensitivity reaction to iodinated contrast injection 
J. 
Known hyperthyroidism.  
K. Acute renal failure, renal transplant, dialysis and renal failure clinically diagnosed. 
L. 
History of liver transplant or severe liver disease or unexplained elevation of baseline ALT>3x upper 
limit of normal 
M. Pregnancy and nursing 
N. Mental, neurologic or social condition preventing understanding of the rationale, procedures, risks 
and potential benefits associated with the trial. 
O. Any other conditions that precludes safety for MRI and/or CT imaging per the researcher’s evaluation. 
P. Individuals with hemoglobinopathies or severe asthma. 
Q. Severe renal excretory dysfunction, estimated glomerular filtration (eGFR) rate < 30 mL/min/1.73m2 
body surface area according to the Modification of Diet in Renal Disease criteria  
Glomerular filtration rate will be estimated using the MDRD 2005 revised study formula:  
eGFR (mL/min/1.73m2) = 175 x (standardized serum creatinine)-1.154 x (age)-0.203 x 0.742 (if the 
subject is female) or x 1.212 (if the subject is black) 
2.3. SCREENING EVALUATION 
On-Study Assessments:   
Study activities below (see Appendix A for overview) specify the required study tests and procedures for 
participants.  A Telehealth platform visit may be utilized to review subject eligibility at baseline visit in 
accordance with the NIH-approved telehealth policy. 
Baseline visit tests and procedures will be completed within 4 weeks before the first dose of study 
medication, unless otherwise noted. Results from procedures and laboratory tests from other NIH IRB 
approved protocols that subjects may have participated in within 4 weeks of enrollment in this study may 
be used as part of the screening evaluation for this study.  At the baseline visit, the Investigator and/or 
study staff will:  
A. Review the study procedures and determine that the eligible patient is willing to comply with all 
protocol requirements;  
B. Review the inclusion and exclusion criteria with the patient and determine if the patient can be a 
participant in the study;  
C. Record previous and concomitant medications, including vitamin and herbal supplements for the 4 
weeks before study start.  
Special consideration of drug interaction is necessary in the following context: In regard to interaction 
with CT associated medications (beta blocker, calcium antagonists, Nitroglycerin): Phosphodiesterase 
inhibitors (e.g. Viagra), antiarrhythmic drugs. 
Special consideration of drug interaction with Rosuvastatin: Coumadin, Niacin, Fenofibrate, Colchicine. 
D. Record known diagnoses. Relevant in the context of study associated medications: Asthma 
(contraindication for beta blocker use) 
E. Record vital signs, height and weight (at Baseline visit) 


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F. 
Collect blood and complete laboratory screening and or clinical evaluations that may include the 
following: 
• 
Fasting lipid panel 
• 
Whole blood serum creatinine 
• 
Complete blood count (CBC),  
• 
Chemistry Labs: Electrolyte Panel, Creatinine, eGFR, Aspartate Amino-Transferase (AST), Alanine 
Aminotransferase (ALT), Creatine kinase (CK), hsCRP 
• 
HbA1c, fasting glucose 
• 
C-reactive protein (CRP) 
• 
Lipoprotein profile 
• 
Urine pregnancy test (for women of childbearing age) 
• 
Other laboratory measures available in CRIS that may be required to ensure participant safety 
• 
Research blood (10 mL) 
G. Baseline CT is performed.  
H. Review baseline CT study for regarding continuation of study (presence of CAD): 
• 
Noncalcified plaque component extending over 4 mm 
• 
Study subject must be either 1) at least moderate 10 year cardiovascular risk according to 
ACC/AHA 2013 criteria OR  2) low risk ACC/AHA risk and CAC score ≥300 or ≥ 75th percentile for age, 
gender and ethnicity. 
I. 
If accepted into study for follow up:  
• 
Cardiac MRI (optional) 
• 
PET study (optional) 
J. 
Perform follow-up lipid panel, creatine kinase and liver function testing at 3 months. 
Scheduled study visits which are part of the trial expected procedures will be made by one of the 
Investigators including the Nurse Coordinator. Clinical follow up will be made at the time of one of  the 
scheduled clinic visits or in response to notification of any perceived clinical alteration.  
We expect a some subjects will have ongoing statin treatment when screened for eligibility. We will allow 
an estimation for the native LDL based on the following statin efficacy chart by multiplying the measured 
LDL with the correction factor that corresponds to the current statin drug and dosage (source: FDA 
website). 
Atorva 
Fluva 
Pitava 
Lova 
Prava 
Rosuva 
Vytorin† 
Simva 
%↓ LDL-C 
Correction 
Factor 
----- 
40 mg 
1 mg 
20 mg 
20 mg 
----- 
----- 
10 mg 
30% 
1.43 
10 mg 
80 mg 
2 mg 
40 or 80 mg 
40 mg 
----- 
----- 
20 mg 
38% 
1.61 


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20 mg 
----- 
4 mg 
80 mg 
80 mg 
5 mg 
10/10 mg 
40 mg 
41% 
1.69 
40 mg 
----- 
  
----- 
----- 
10 mg 
10/20 mg 
 
47% 
1.89 
80 mg 
----- 
  
----- 
----- 
20 mg 
10/40 mg 
----- 
55% 
2.22 
  
----- 
  
----- 
----- 
40 mg 
 
----- 
63% 
2.70 
 
2.4. 
REGISTRATION PROCEDURES 
Upon completion of the screening process, eligible subjects will be enrolled on the study and will begin 
treatment. 
 
3. 
SUBJECT IMPLEMENTATION 
3.1 
STUDY DESIGN 
This is an interventional trial in which 190 adult men and women will receive high intensity statin 
treatment.   The study duration will be when subjects complete their 36 month visit.     
 
3.2 
PROTOCOL EVALUATION/STUDY CALENDAR 
Treatment: 
 
High intensity statin therapy: 
• 
High intensity lipid lowering therapy: rosuvastatin, target dose 40 mg (Nicholls et al., 2011). 
• 
If the drug is not tolerated by a patient during the study, alternatives are rosuvastatin 20 mg or 
atorvastatin 80 mg.  Statin dose will be reduced if the serum LDL is below 25 mg/dL (Everett, Mora et 
al. 2014) 
Failure to meet target therapies will not result in removal from the study but will instead be assessed on 
an intention-to-treat basis. 
 
Protocol Evaluation: 
 
A. Study Subjects will have a study visits for imaging at baseline, 12, 24 and 36 months, 18 and 30 month 
assessments will be done via telephone, Telehealth platform and or e-mail (Appendix A, Study Calendar). 
Note: After Amendment O Protocol dated 7/02/2020- no longer enrolling in sub-studies:  The PET study 
subjects will have additional visits.   Up to 60 subjects will be accrued to the PET sub study.  30 subjects 
will be asked to return within 30 days for repeat visit to insure CCTA data reproducibility.    Visits will 
follow the Protocol Evaluation schema in Appendix A.  Visits will occur within +/-  12 weeks  due for 
unforeseen events.  
B. Clinical Laboratory Measures will be done before starting study drug at baseline enrollment then as 
clinically indicated per Safety Announcement by the FDA 2.28.2012: 
• 
Serum creatinine kinase, lipid panel and liver function tests will be measured at baseline enrollment 
and at 3 months after start of drug treatment and annually thereafter when clinically indicated.   


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• 
If symptoms indicating possible muscle or liver alterations appear (muscle pain, fatigue, jaundice, 
abdominal pain, anorexia) the study drug will be paused and a timely evaluation including lab testing 
for liver and muscle enzymes will be recommended and offered. Depending on the results of the 
evaluation the drug can be resumed (if association with statin is unlikely), reduced or stopped (based 
on clinical judgment).  
• 
HbA1c will be measured during the course of the study.  
• 
Urine HCG test for women of childbearing age.  Blood glucose measurements also prior to PET 
imaging. 
• 
Review of interim medical history and evaluation for interim adverse events, off treatment or off 
study criteria. Complete review and recording of participant medications including over the counter 
and herbal compounds.   
• 
Prior to CT and MRI scanning:  Obtain MRI Screening Questionnaire (MRI scan days only) Urine HCG 
test for women of childbearing age.   
Response to abnormal results 
All clinically abnormal test results will be relayed to participants and/or their referring providers.  
Participants will be instructed to consult with their physician for follow up and referral to specialists as 
appropriate.  Abnormal lab results may be repeated or reassessed at PI discretion as part of the subject’s 
clinical care. 
If ALT, AST, alkaline phosphatase reaches more than 3 times the upper limit of normal without symptoms 
indicating liver disease or CK is greater than 1000 U/L without muscle symptoms the study drug will be 
paused and results will be repeated within 2 weeks. Other causes of the abnormalities should also be 
considered. Restarting the study drug depends on clinical judgment. 
ALT, AST, alkaline phosphatase reaching more than 3 times the upper limit of normal or CK >1000 U/L 
with muscle symptoms will be reported at the time of Continuing Review (see section 8.1).  
3.3 
CONCURRENT THERAPIES 
N/A 
3.4 
CRITERIA FOR REMOVAL FROM TREATMENT/PROTOCOL 
3.4.1 OFF TREATMENT CRITERIA: 
Subjects who come off treatment will be returned to usual care for cardiac risk factors as directed by their 
primary physician.  If they consent to continue imaging follow up, they will complete imaging as per 
protocol. 


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1. Occurrence of a clinical cardiovascular event including myocardial infarction, acute coronary 
syndrome, angina, heart failure, stroke or revascularization.  
2. Inability to continue on study medications (adverse reaction, not wanting to adhere to the study 
medications) 
3. Elevations of liver enzymes more than three times the upper limits of normal that persists in repeat 
testing and cannot be explained by other factors than statin use.  
4. Myopathy defined as muscle pain with serum creatinine kinase concentrations > 1000 U/L. Any other 
relevant clinical or laboratory abnormality which cannot be confidently excluded as a side effect from 
study medications will lead to discontinuation of an individual patient from the trial. 
3.4.2 OFF STUDY CRITERIA 
1. Request of the patient or their personal physician.  
2. Pregnancy or nursing 
3. Subjects who come off study for any reason will be referred back to their personal physician. 
4. Per PI discretion 
4. 
SUPPORTIVE CARE 
Study investigators and support staff will provide further consultation to participants by in-person visits, 
phone or electronic communication (telehealth) as needed to address participant concerns regarding 
study therapy or imaging evaluation.  
5. 
DATA COLLECTION AND EVALUATION 
5.1. 
HUMAN SPECIMEN USE, DISPOSITION, TRACKING AND STORAGE OF 
SAMPLES AND DATA 
During the course of participating on this study, blood, tissue and data may be collected for correlative 
laboratory research studies.  Specimens collected strictly for research purposes will not be read by a 
pathologist.   
Biospecimen management: Specimens and their derivatives (e.g., genomic material, cell lines) will be 
coded and stored in conformity with DIR Policy (e.g., BSI). Coded biospecimens may be sent to 
collaborators outside of the NIH with IRB approval in accordance with applicable NIH and DIR Policy for 
sharing research resources, including an executed material transfer agreement. Biospecimens with 
subject personal identifiers may be sent to associate investigators and collaborators outside of the NIH 
only after approvals of both NHLBI and local IRBs, an executed reliance agreement with NHLBI’s IRB, or an 
extension of the NIH’s FWA through an Individual Investigator Agreement. 
Data Management: The principal investigator, associate investigators, research nurses and/or a data 
manager will assist with the data management efforts. Data will be abstracted from Clinical Center 
progress notes as well as intake forms and the case report forms. Laboratory data from NIH will be 
reviewed using CRIS. The principal investigator, associate investigators/research nurses and/or a 
contracted data manager will assist with the data management efforts to ensure that data are verifiable 


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and evaluable. Data will be abstracted from Clinical Center progress notes as well as from progress notes 
forwarded from the subjects’ home physician. 
The PI will be responsible for overseeing entry of data into an in-house password protected electronic 
system and ensuring data accuracy, consistency and timeliness. Laboratory values from referring home 
physicians will be entered into the system. The principal investigator, associate investigators/research 
nurses and/or a contracted data manager will assist with the data management efforts to ensure that 
data are verifiable and evaluable.   
Research data will be prospectively collected by authorized Investigator personnel and entered into an 
NHLBI, 21 CFR 11 compliant, database which will consist of the study specific set of electronic CRFs (e-
CRFs) used for capturing, managing and reporting clinical research data.  
The database will maintain complete data records on each research subject. Subjective and objective 
patient experiences during the duration of the study will be documented in the patient medical record 
notes. These protocol notes will serve as the primary source material from which data will be collected in 
the database. Any pertinent supplementary information obtained from outside laboratories, outside 
hospitals, radiology reports, laboratory reports, or other patient records will be used as additional sources 
for data collection. 
We will maintain the confidentiality of identifiable private information collected in this Clinical Trial and 
protect the privacy of the individual human subjects. Primary data containing individually identifiable 
information obtained during the conduct of the protocol will be kept in secure network drives or in 
approved alternative sites that comply with NIH information security standards. Neither individual 
personal identifiers nor the key linking coded data to individuals will be released without prior IRB 
approval and an executed confidential disclosure agreement (CDA) or material transfer agreement (MTA). 
Identifiable data will not be sent outside NIH without prior IRB approval or appropriate conditions for 
disclosure outlined in the executed CDA or MTA. 
Standard forms for patient history, labs, imaging results.  Digital source documentation from CTDB 
(Clinical Trials Database) will be used.  CTDB is a password protected secure database at the NIH Clinical 
Center.  Complete records must be maintained on each patient, which will consist of the hospital chart 
with any supplementary information obtained from patient, outside laboratories, progress notes, reports, 
consults or tests.  
The database storing the entire information set will be based on coded identification. The confidentiality 
and security of the data files in the computer will be maintained by ensuring password protection on all 
computer accounts. Protection against loss of data is essential to our data management. Quality control 
procedures will also include:  
1) Assurance or the prevention of possible errors;  
2) Assessment, or the detection of errors after they have occurred and;  
3) Feedback, or the correction of system failures which originated the error and is necessary to avoid errors 
in the future. Detailed checklists are used for data collection and trial procedures.  


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Storage: All samples will be stored in the laboratory of Dr. Mehta. Collected samples will be de-identified 
prior to storage in the laboratory of the principal investigator following current NHLBI DIR BSI Policy. 
Efforts to ensure protection of patient information include; 
 
• 
Each sample is assigned a unique number.  
• 
Vials holding patient samples are labeled with the sequential laboratory accession ID 
number that does not contain any personal identifier information. 
• 
An electronic database is used to store patient information related to the coded samples  
• 
The laboratory is located in a controlled access building and laboratory doors are kept 
locked. Visitors to the laboratory are required to be accompanied by laboratory staff at all 
times.  
 
Hard copy records or electronic copies of documents containing patient information are kept in the locked 
laboratory or other controlled access locations. 
 
Data sharing and future use of data 
Research data may be shared with qualified non-collaborator recipients following publication of the 
primary research results after removal of PII and IRB or OHSRP approval. Future research use of data not 
defined in the research protocol may occur only after IRB review and approval or an exemption from the 
NIH Office of Human Subjects Research Protections (OHSRP). Refusal of a research subject participant to 
permit future use of data--other than required in the protocol or by the FDA--will be honored. Limitations 
in data sharing and future use of data due to contractual obligations (e.g., CRADAs) or intellectual 
property proceedings (such as patent filings) will be honored. 
 
Future use of biospecimens 
Following analyses of biospecimens for primary research purposes as described in the protocol, remaining 
samples suitable for future research must be stored in manner that conforms with DIR policy (such as BSI) 
or in a publicly accessible research biospecimen repository following IRB approval. Biospecimens may be 
destroyed only when permitted by the clinical director and approved by the IRB.  
 
Any future research use of biospecimens not defined in the research protocol in which NHLBI 
investigators are engaged in research (e.g., they are undertaking research activities and hold the key that 
identifies research subjects) requires IRB review and approval. Coded biospecimens (NHLBI investigators 
hold the key that identifies research subjects) to be shared outside of NIH for future research use requires 
IRB review and approval (for research collaborations) or submission of a determination to OHSRP (for 
non-collaborative research), and an executed transfer agreement. Unlinked biospecimens (no key to 
identify research subjects exists) to be shared outside of NIH for future research use requires submission 
of a determination to OHSRP and an executed transfer agreement. There are a few types of biospecimens 
that do not require IRB or OHSRP approval for future research use outside of NIH, such as specimens from 
deceased individuals (refer to OHSRP SOP5, Appendix 1 for complete list); an executed transfer 
agreement is required in these special cases. Refusal of a research subject participant to allow for future 
use of biospecimens-other than required in the protocol or the FDA-will be honored. 
 
Tracking: Samples will be ordered and tracked through CRIS Research Screens. Should a CRIS screen not 
be available, the NIH form 2803-1 will be completed and will accompany the specimen and be filed in the 


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medical record. Samples will not be sent outside NIH without IRB notification and an executed MTA or 
CTA.  
 
End of study procedures: Samples from consenting subjects will be stored until they are no longer of 
scientific value. At the completion of the protocol (termination), samples and data will be maintained in a 
repository for future research. 
 
Loss or destruction of samples:  Should we become aware that a major breech in our plan for tracking and 
storage of samples has occurred, the IRB will be notified. 
 
Loss or destruction of data: Should we become aware that a major breech in the plan to protect patient 
confidentiality and trail data has occurred, the clinical director and IRB will be notified. 
 
Publication Policy: Given the research mandate of the NIH, patient data including the results of testing 
and responses to treatment will be entered into an NIH-authorized and controlled research database. Any 
future research use will occur only after appropriate human subject protection institutional approval such 
as prospective NIH IRB review and approval or an exemption from the NIH Office of Human Subjects 
Research Protection (OHSRP). 
Privacy and Confidentiality:  All efforts, within reason, will be made to keep subjects’ protected health 
information (PHI) and private identifiable information (PII) private.  Using or sharing (“disclosure”) such 
data must follow federal privacy rules.  Under certain circumstances, the United States Office of Human 
Research Protections (OHRP), The US Food and Drug Administration (FDA), and the NIH Intramural 
Institutional Review Board (IRB), will be able to inspect and copy confidential study-related records which 
identify participants by name. Therefore, absolute confidentiality cannot be guaranteed. 
5.2. 
RESPONSE CRITERIA 
Response to high-intensity therapy will be assessed according to GRCR 2013 guidelines and are expected 
to result in LDL levels by 50%.  To be consistent with new clinical practice guidelines for lipid lowering 
therapy, specific lipid targets will not be used as response criteria to guide therapy.   
6. 
STATISTICAL CONSIDERATIONS  
Primary Endpoint: The primary endpoint of this study is the change in noncalcified plaque volume after 
24 months.  
Secondary Endpoints: In addition to the 24 months follow-up period specified for the primary endpoint, 
we plan to follow the patients for an extended period of 12 months to study the long term effects of the 
statin therapy. As a result, the patients will be followed for a total of 36 months with the first 24 months 
for the primary endpoint and the additional 12 months for the secondary endpoints.  The secondary 
endpoints include:  
1) Change in noncalcified plaque volume assessed by CCTA at the end of 36 months;  
2) Effects of covariates including age, sex, race, body mass index and baseline plaque volume on the 
change of plaque volume measured by CCTA at 24 and 36 months. 


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3) The relationship of CMR T1 high signal intensity plaque and change in T1 signal by CMR over time 
to CCTA plaque characteristics.   
4) (Pilot study):  the relationship of coronary artery plaque by CCTA to sodium fluoride (F18-NaF) 
uptake using positron emission tomography (PET) scanning:  
a.  Determine if F18-NaF signal correlates with CCTA defined plaque volume and CAC score. 
b. Determine the change in F18-NaF signal in relationship to statin therapy 
Preliminary Information: One study in the literature was conducted as a pilot study with similar goals 
(Burgstahler et al. 2007). This pilot study investigated 22 noncalcified plaques in 12 patients before and 
after lipid lower therapy for 18 months. The mean patient age (61) and cardiovascular risk profile was 
similar to that expected in our cohort. The medication used was atorvastatin 20 mg. The mean (±sd) 
volume of all plaques was reduced by statin therapy form 0.042±0.029 mL to 0.030±0.014 mL (P<0.05). 
The mean reduction of plaque volume was 0.012 mL with the standard deviation 0.017 mL.  
Statistical Hypotheses: Because the study of Burgstahler et al. (2007) is based on a small sample size, we 
would like to consider a somewhat conservative assumption on the mean and sd for the plaque volume 
reduction than the preliminary information provided by this study. Specifically, we hypothesize that the 
patients with high intensity statin treatment will have at least 0.008 mL mean reduction of plaque volume 
at the end of the 24 months treatment period. Let  
Δ = mean reduction of plaque volume at 24 months. 
The statistical setting is to test the null hypothesis “H0: Δ=0” versus the two-sided alternative of “H1: Δ≠0” 
at 0.05 significance level with 90% power. The null hypothesis suggests that the mean plaque volume 
reduction is the same at the beginning of the study and the end of 24 months, while the alternative 
suggesting changes of the mean plaque volume at the two time points. Based on the information 
provided in Burgstahler et al. (2007), we believe that it is reasonable to conduct a statistical test to detect 
an effective Δ of at least 0.008 mL under the somewhat conservative assumption that the sd of Δ is 0.03 
mL.   
Sample Size Justification: We plan to conduct a group sequential trial with one interim analysis when 
approximately half of the patients completed the 24 months follow-up. Using the Lan-DeMets O’Brien-
Fleming approximate spending function, our test requires n=151 patients to be followed at the end of the 
24 months to reach the required 0.05 significance level and 90% power.   Assuming approximately 20% 
dropout at the 24 month time point, the number of enrolled subjects will be 190. 
Interim Analysis: The interim analysis will be conducted when n1=76 patients completed the 24 months 
follow-up period. The lower and upper stopping boundaries for the interim analysis are Z1=-2.96 and 2.96, 
respectively, where Z1 is the test statistic for the statistical hypotheses H0 and H1 at the interim look (see 
Figure 1 below). The corresponding nominal p-value at this interim look is 0.0015. The study will be 
considered for stopping due to efficacy if the test statistic Z1 crosses the upper bound, i.e., Z1 > 2.96, 
while, the study will be considered for stopping due to futility if the test statistic Z1 crosses the lower 
bound, i.e. Z1 < -2.96. However, the DSMB will make the decision on whether the study should be stopped 
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Final Analysis: In the most like event the study is proceeded to the final stage, the final analysis for the 
primary endpoint will be determined by the test statistic Z2 with all N=151 patients completed the 24 
months follow-up. The null hypothesis H0 of no difference of the mean plaque volume between the 
baseline and the 24 months will be rejected if |Z2| > 1.97 (see Figure 1 below).  
Software: Sample sizes and stopping boundaries of the group sequential design are computed using the R 
“gsDesign” package, version 3.1.3 (2015-03-09). Details of the statistical methods and theory of the design 
are described in C. Jennison and B. W. Turnbull (2000, “Group Sequential Methods with Applications to 
Clinical Trials”, Chapman and Hall/CRC, Boca Raton, FL).  
 
Figure. Stopping boundaries with one interim 
look based on the Lan-DeMets O’Brien-Fleming 
approximate spending function.  
 
 
 
 
 
Noncompliance and Missing Data: Given our 
past experience in similar clinical trials, we do 
not anticipate noncompliance as a major 
problem.  However, despite the best possible 
effort, there are inevitably noncompliant patients and/or patients with missing data. We categorize the 
noncompliance and missing data into the following three situations:  
1) Noncompliant patients with complete follow-up examinations at baseline and 24 months: The 
primary analysis of these patients, including both the interim analysis and the final analysis of 
the primary endpoint, will be carried out using the intent-to-treat (ITT) principle.  Under the ITT 
principle, the observed plaque volumes at baseline and 24 months from these patients will be 
included in the primary analysis.    
2) Noncompliant patients with missing examinations at 24 months: Since plaque volume normally 
does not decrease without significant intervention, we will apply the ITT principle to these 
patients using the approach of setting their plaque volumes at 24 months to be the same as 
their baseline values.   
3) Compliant patients with missing examination at 24 months: We expect that only a small 
portion of the patents will fall into this category, since our study coordinators will give their best 
efforts to contact and keep track these patients. For the primary analysis, we will include these 
patients using the same approach as 2) by setting their plaque volumes at 24 months to be the 
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4) Secondary analysis of the above patients: In addition to the ITT and missing data approaches 
mentioned in 1)-3), our secondary analysis of the primary endpoint (change of plaque volume 
between baseline and 36 months) will also include: a) non-ITT approach of including only 
treatment compliant patients in the analysis, b) complete data approach of using only patients 
with observed plaque volumes in both baseline and 36 months. As a sensitivity analysis, we will 
compare the results obtained from a) and b) above with the primary analysis of 1)-3). This 
sensitivity analysis will provide useful insights into the characteristics of the patients with 
noncompliance and/or missing plaque volume data at 24 and 36 months.  
Secondary Analysis with Subgroups and Covariates:  Regression models will be considered for the 
analysis of secondary endpoints. 
1) Cross-Sectional Data: Regression models with cross-sectional outcome and covariates, i.e. data 
without repeated measurements over time, will include multivariable linear and nonlinear 
models. Nonparametric smoothing methods, such as splines and local polynomials, will be used 
to explore the relationships between the outcome and covariates. The flexible ANOVA F 
Goodness-of-Fit tests will be used to test the adequacy of the parametric linear and nonlinear 
regression models.  
2) Longitudinal Outcome and Covariate Data: For data including repeatedly measured outcome 
and/or covariates over time, we will consider the commonly used linear and nonlinear mixed 
effects models to explore the time trends of the outcome variables and corresponding covariate 
effects. Similar to the exploratory analysis with cross-sectional data, we will also consider the 
flexible nonparametric longitudinal regression methods, such as the time-varying coefficient 
models and models of functional data analysis, to evaluate the appropriateness of the parametric 
mixed effects models.  
3) For Secondary endpoint 3 (relationship of CCTA plaque to T1 CMR signal):  CMR high signal 
intensity plaque is postulated to represent “unstable” plaque or plaque containing hemorrhage 
and/ or protein. CCTA plaque characteristics that are thought to be associated with unstable 
plaque include spotty calcification and low density plaque.   Since this aim represents an 
exploratory aim with the use of technologically advanced CMR imaging, the incidence of CMR T1 
high signal intensity plaque is unknown. We will therefore use descriptive statistics to relate the 
presence or absence of T1 high signal intensity to the presence or absence of various CCTA 
plaque characteristics. In addition, we will determine if T1 signal changes in various plaques over 
the study period; if T1 signal changes (e.g. due to plaque healing), we would expect that this 
would be more common in the presence of unstable plaque features by CCTA.  For this aim, the 
number of T1 high signal intensity plaques at baseline that do not show high signal at 24 months 
will be determined. The percentage of these plaques that demonstrated unstable CCTA plaque 
characteristics at baseline will be determined. Data for both the 12 and 24 month time points will 
be considered because at present the time course of change of high T1 signal intensity plaques is 
not known 
4) For Secondary endpoint 4 (pilot study, relationship of CCTA plaque to F18-NaF signal).   A 
comparison of the presence or absence of NaF signal by PET will be performed. NaF signal (with 
both TBR and SUVmax) will be compared across different plaque morphology and compositions 
defined by CCTA (for example, presence of a lipid core or calcification) in order to gain an 
understanding of the relationships between these two imaging modalities.  Correlation between 
imaging findings and changes will be made with age, gender, traditional risk factors (height, 


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weight, hypertension, etc.), absolute values and changes in statin dose, total cholesterol, LDL, 
HDL, triglycerides and hematological biomarkers markers of inflammation, thrombosis and 
atheroprotection. 
Safety Monitoring of Adverse Events: Because the statin treatment is known to be safe and involve 
minimal risk, we do not plan a statistical stopping rule. Any adverse events will be reported to the DSMB. 
Continuation or stopping of the study because of the safety reasons will be made following the 
recommendations of the DSMB.    
7. 
HUMAN SUBJECT PROTECTION  
7.1. 
RATIONALE FOR SUBJECT SELECTION  
Individuals age 40-75 (men) and 40-75 (women) from all racial/ethnical groups are eligible to participate.  
NIH employees who meet the eligibility requirements are eligible to be screened and considered for 
protocol participation. Subjects may be referred from other NIH protocols. 
A comprehensive strategy of advertising and recruitment through the NIH clinical center patient 
recruitment and referral center will be utilized including social media and internet PSAs as well as NIH 
Newsletters. Walter Reed National Military Medical Center may also be a recruitment site for referring 
patients for participation on this protocol. 
Recruitment and enrollment of NIH employee subjects will be consistent with NIH HRPP SOP 14 F..  NIH 
employees may voluntarily participate in this protocol.  Neither participation nor refusal to participate as 
a subject in this protocol will have an effect, either beneficial or adverse, on the participant’s employment 
or position at NIH.  Employee subjects’ privacy and confidentiality will be respected by protocol and 
consenting staff the same as for all subjects’ participation in research protocols.  However, all subjects will 
be made aware that there are limits to these protections.  The PI, through the consenting staff members, 
will make the “NIH Information Sheet on Employee Research Participation” available to employees who 
are considering enrolling in research (SOP 14F, Appendix B).    We intend to allow enrollment of staff who 
are affiliated or subordinate to the Principal Investigator, including technologists, nurses, scientists, 
students and family members.  We believe we can offer them the opportunity to participate without 
coercion.  Consent for such subjects will not be obtained from individuals in their supervisory chain of 
command.  Instead, an associate investigator authorized in the protocol to obtain consent in this protocol 
and who is also a co-worker may obtain consent from a NIH employee without independent monitoring, 
as the IRB has waived this requirement for this protocol.    Refer to the NIH Policy Manual, 2300-630-3 - 
Leave policy for NIH Employees Participating in NIH Medical Research Studies. See Appendix B 
This age group is the most likely to benefit from an early medical intervention strategy to reduce 
cardiovascular events in the future. 
Atherosclerosis and concomitant cardiovascular events are the leading cause of death in all major 
racial/ethnic subgroups in industrialized nations. Efforts to reduce the burden of cardiovascular disease 
are relevant to persons of all ethnicities.  Our planned enrollment has been selected to be representative 
of the general gender and ethnic demographic subgroups of the greater Washington DC area.   


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Reproducibility Sub study (No longer recruiting after Amendment O Protocol dated 7/02/2020) 
A subgroup of 30 participants who had CCTA defined coronary plaque will be asked to return 4 weeks 
after their initial CCTA scan for a second CT study using the same CCTA protocol.  Additionally, the initial 
CCTA and reproducibility CCTA will be in accordance for total annual radiation dose exposure at the NIH 
as determined by the radiation safety committee.  Eight to twelve patients will be selected from three 
groups: (a) patients with a calcium score of 0-99, (b) patients with a calcium score -100-399 and (c) 
patients with a calcium score of > 400.  These 30 scans will be interpreted by two readers, allowing 
assessment of both intra and interobserver variability as well as repeatability limits.     
Subjects who participate in the Reproducibility sub study will not have the cardiac MRI performed.  
7.2. 
PARTICIPATION OF CHILDREN: 
Atherosclerotic disease is not a disease of childhood and children will not be eligible for participation in 
this study, based on the fact they are unlikely to have this disease. 
7.3. 
EXCLUSION OF PREGNANT WOMEN: 
The risk from radiation exposure is increased in children and especially in the fetus. This can be explained 
by a higher rate of mitosis earlier in life (Hall 2009, Goodman and Amurao 2012). It is generally conceived 
that X-ray imaging should be only used in vital indications in pregnant women. In the context of this study 
this is not the case and therefore pregnancy is an exclusion criteria (§46.204 Code of Federal Regulations. 
Condition “Any risk is the least possible for achieving the objectives of the research” is not met) 
7.4. 
EXCLUSION OF PERSONS UNABLE TO GIVE CONSENT 
The research question on progression of atherosclerosis can be answered without enrolling subjects who 
are unable to give consent. According to NIH HRPP SOP 14E v1: 14E.6.1 A: “Ensure there is a compelling 
justification for including adults who cannot consent (e.g., the research question cannot be answered by 
enrolling only adults who can consent; participation offers the potential for important clinical benefit).” 
we do not plan to enroll subjects who are unable to give consent. 
7.5. 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS:  
Phlebotomy  
Associated risks include anemia and hematoma and minor pain at the puncture site.   
Beta-Blockers (Atenolol and Metoprolol) 
Atenolol and metoprolol are FDA approved selective β1 receptor blocker used in treatment of several 
diseases of the cardiovascular system, especially hypertension, angina or myocardial infarction. The side-
effects include tiredness and dizziness (10%), depression (5%), rash (5%), diarrhea (5%) shortness of 
breath (3%), chest pain (1%), wheezing (1%). Palpitations, congestive heart failure, peripheral edema, 
syncope, chest pain, dry mouth, gastric pain, constipation, flatulence, digestive tract disorders, heartburn, 


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hypotension, mental confusion, short-term memory loss, headache, somnolence, nightmares, and 
insomnia reported in very rare instances (<1%). 
Calcium-channel Blockers (Diltiazem) 
Diltiazem is a FDA approved cardiovascular medication for the treatment of hypertension, angina or rate 
control of atrial fibrillation/flutter or conversion of supraventricular tachycardia.  The side-effects of 
chronic use include lower extremity edema (2-15%), headache (5-12%), first degree AV block (2-8%), 
bradycardia (2-6%), hypotension (<2%-4%), vasodilation (2-3%), extrasystoles (2%), flushing (1-2%), 
dizziness (3-10%), nervousness (2%), rash (1-4%), dyspepsia (1-6%), constipation (<2-4%), vomiting (2%), 
diarrhea (1-2%), weakness (1-4%), myalgia (2%), rhinitis (<2-10%), pharyngitis (2-6%), dyspnea (1-6%), 
bronchitis (1-4%), cough (<3%) and sinus congestion (1-2%). 
Nitroglycerine 
Nitroglycerine is a FDA approved medication for the treatment of angina pectoris due to coronary artery 
disease. Nitroglycerine pumpspray given to 51 chronic stable angina patients in single doses of 0.4, 0.8 
and 1.6 mg as part of a study exhibited an adverse event profile that was generally mild to moderate. 
Adverse events occurring at a frequency greater than 2% included: headache, dizziness, and paresthesia. 
Less frequently reported events in this trial included (≤2%): dyspnea, pharyngitis, rhinitis, vasodilation, 
peripheral edema, asthenia, and abdominal pain. A notable drug interaction with phosphodiesterase 
inhibitors is known which can amplify the vasodilatory effects of Nitroglycerine, resulting in severe 
hypotension. 
Statin Therapy 
This study uses statin drugs for the FDA approved indications of treatment of hypercholesterolemia and 
atherosclerosis.  The study is not designed or intended to test new indications, dosages, routes or study 
populations for statin drugs.   
In this study a subgroup of subjects who - based on current AHA guidelines – would receive moderate 
intensity statin therapy (e.g. Atorvastatin 20 mg) would receive Rosuvastatin. In this context the issue of 
drug safety of Rosuvastatin will be addressed.  
HMG CoA-Reductase inhibitors (statins) are generally well tolerated.    Clinically important adverse effects 
of the drugs include increases in serum transaminase concentrations and myositis, with and without 
complicating rhabdomyolysis (Knopp 1999).  
Statin induced myopathy  
In 7 studies reporting rates of clinical myositis, elevation of creatinine kinase (CK) > 10 times the upper 
limit of normal and rhabdomyolysis, the combined incidence of these events has been less than 0.7%  
(Sacks, Pfeffer et al. 1996, Downs, Clearfield et al. 1998, Colhoun, Betteridge et al. 2004, LaRosa, Grundy 
et al. 2005, Pedersen, Faergeman et al. 2005). The highest reported rate of rhabdomyolysis was 0.53%, 
observed with simvastatin 80 mg daily (de Lemos, Blazing et al. 2004). 
The use of high dose, intensive statin therapies to achieve very low LDL levels is a recent development. 
Available data, including three large randomized controlled trials (the A to Z,  TNT and IDEAL studies), 


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indicate that high-dose statins (atorvastatin 80 mg daily, simvastatin 80 mg daily) are associated with low 
rates of serious musculoskeletal (<0.6%) and hepatic (<1.3%) injury (de Lemos, Blazing et al. 2004, LaRosa, 
Grundy et al. 2005, Pedersen, Faergeman et al. 2005) (Davidson and Robinson 2007).   
We expect the population in this planned study to be similar to the JUPITER trial population in which 
Rosuvastatin was tested (primary prevention, age>50, no prior CVD). In the JUPITER trial (Ridker, Pradhan 
et al. 2012) the rate of myopathy was extremely low and not significantly different between experimental 
and placebo group (10 vs. 9 cases, 17802 trial participants). There was only one case of Rhabdomyolysis 
that occurred after closure of the trial in a 90 year old patient with pneumonia and trauma induced 
muscle damage. Other analyses show that Rosuvastatin compares favorably to other less potent statins 
when comparing the occurrence of CK elevations (see graph) (Brewer 2003). 
Liver toxicity 
Statin monotherapy can result in elevation of liver enzymes, most often ≤3 times the upper limit of 
normal.  These elevations typically normalize without lasting injury upon discontinuation of the drug.  
Their clinical significance is uncertain given the extremely rare occurrence of statin related toxic hepatitis 
(Bays 2006, Bays, Cohen et al. 2014). 
 
New onset diabetes 
Meta-analyses of 91,140 subjects in statin trials showed a small but unexpected increase of new onset 
diabetes type 2 in patients treated with statins (Sattar, Preiss et al. 2010);  greater age was a risk factor for 
new onset diabetes, but not BMI or LDL reduction.  A smaller meta-analysis 3 clinical trials identified other 
possible risk factors for new onset diabetes in atorvastatin treated patients (Waters, Ho et al. 2011). We 
reflect this information on the consent form, as age and greater risk for onset of diabetes during statin 


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therapy.   
 
Conclusion 
Overall Rosuvastatin is a drug that has been tested in multiple large trials and has vast post marketing 
experience indicating a very low risk for adverse events. 
Ionizing Radiation 
Low dose CTA angiography and FDG PET/CT (as used in this protocol) carries a conservatively estimated 
lifetime additional risk of malignancy less than 0.2% in women and less than 0.1% in men, on a 
background lifetime risk of approximately 30% (Cronin, Marsden, & O’Doherty, 1999; Einstein, Henzlova, 
& Rajagopalan, 2007; Mejia et al., 1991). The primary prevention population targeted for this study is 
unlikely to receive significant degrees of medical radiation during the 36 months of study follow up. 
Note that study participants cannot participate in all three studies (the main study, PET sub study, and 
reproducibility sub study) when total radiation exposure exceeds RSC limits (5.0 rem/12 months) 
The following table provides radiation exposure at all required time points for participants, including 
optional sub-study participation: 
Radiation dose estimates:  Average maximum radiation exposure 
Examination component 
Baseline – < 12 
months (rem) 
12 month 
visit (rem) 
24 month   
visit  (rem) 
36 month   
visit (rem) 
CT: Main Study 
2.134 
2.134 
2.134 
2.134 
PET sub-study 
 
0.285*2 = 
0.57 (total) 
N/A 
0.285 
 
N/A 
 


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CT Reproducibility sub-
study 
 
2.134 
N/A 
N/A 
N/A 
Yearly Totals 
Baseline – < 12 
months  (rem) 
    12 month 
    visit (rem) 
     24 month 
    visit (rem) 
    36 month 
   visit (rem) 
Total for Subjects 
undergoing Main CT 
plus  PET* 
2.704 
2.134 
2.419 
2.134 
Total for Subjects 
undergoing Main CT 
plus Reproducibility  CT* 
4.268 
2.134 
2.134 
2.134 
Total for Subjects 
undergoing Main CT 
only 
2.134 
2.134 
2.134 
2.134 
*No subjects undergo both PET substudy and reproducibility substudy (No longer recruiting after 
Amendment O Protocol dated 7/02/2020) 
 
Statin Use 
Statins will be used for approved indications. 
Iodinated contrast  
The primary known risks of nonionic iodinated contrast as utilized in MDCT angiography are 
hypersensitivity reactions and contrast induced nephropathy. Mild to moderate adverse events such as 
nausea, injection site pain or urticaria occur in less than 3 percent of patients.  Serious adverse events, 
such as hypotensive collapse, shock and death are reported in less than 1 in 10,000 patients.  These 
reactions are generally considered idiosyncratic. Contrast induced nephropathy (CIN) is defined by an 
increase in creatinine more than 1 mg/dL or 50% above baseline.  The risk of CIN in patients with normal 
renal function is considered to be negligible. The inclusion criteria for this study require baseline GFR >45 
mL/min/m2 as calculated by the MDRD equation to minimize risk of nephropathy. Furthermore, injection 
of less than 100 ccs of iodinated contrast medium is considered to present minimal risk of CIN.   
7.6. 
RISKS/BENEFITS ANALYSIS 
The principal risks to participants are high intensity statin therapy , exposure to ionizing radiation as part 
of the coronary CT angiogram and receipt of iodinated contrast. As noted in 7.3, above, large clinical trials 
have demonstrated low rates of significant adverse events due to statins, few if any of which persist after 
drug discontinuation.  The study population has been specifically selected to be at the lowest risk for 


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ionizing radiation, and the CT protocol carefully tailored to ensure delivery of the lowest possible dosage 
necessary to generate diagnostic images.   
7.7. 
CONSENT PROCESS AND DOCUMENTATION 
Note: Effective January 21, 2019, a witness to the signature of the written long form research consent at 
an NIH site (whether initially approved by an IRB before or after January 21, 2019) is no longer a 
requirement. 
Patients asked to participate in PET imaging will be consented separately for their participation in the 
main protocol and the sub study. Patients asked to participate in the Reproducibility sub study will be 
consented separately for their participation in the main protocol and the sub study.  The investigational 
nature and objective of this trial, the procedures involved and their possible risk and discomforts, 
potential benefits, and possible alternative therapies will be explained to participants.  The subject will be 
provided with a copy of the consent with enough time to review it and ask questions prior to the consent 
process.  Participants will be enrolled after eligibility criteria have been determined and a signed informed 
consent document has been obtained.  Consent for NIH employee will not be obtained from individuals in 
their supervisory chain of command. 
The investigators roles are listed on the Study Personnel page, which identify who is authorized to obtain 
informed consent from the study subjects.  
 
Telephone Consent and or Telehealth platform 
Participants may be contacted by telephone, and or Telehealth NIH-approved platform to obtain informed 
consent for new subjects.  For subjects actively participating in the study who may need to be re-
consented due to changes to the informed consent or procedures.  For instance, when new risk 
information relevant to a subject’s ongoing participation is discovered, notification to the subject may be 
required (applies to all consent documents).  Many subjects may have travelled to the NIH CC previously 
and a return trip would be inconvenient. The telephone consents will be obtained by  those investigators 
designated as authorized to obtain inform consent on the Study Personnel page. Telehealth procedure 
will follow the NIH- approved policy.Procedures for obtaining telephone consent are as follows: 
• The informed consent document will be sent to the patient either by mail (U.S. Postal Service or Fed-Ex), 
fax, or e-mail prior to the phone conversation. If mailed, a pre-addressed return envelope may be 
included. 
• A telephone call will be scheduled between the participate and designated investigator to allow time for 
the participate to thoroughly read over the consent. The protocol will be discussed and explained during 
the scheduled telephone call and any questions will be answered.  
• If the patient agrees to participate, the patient will print, sign and date the informed consent document 
with the date of the telephone conversation. 
• The patient is to return the signed document by mail or fax to the investigator. Upon receiving consent, 
the investigator will print, sign and date the consent with date the telephone conversation occurred and 
date of receipt of the consent document. this document will be designated as both the original and 
telephone consent.   
• A copy of the fully executed document will be returned to the patient by mail or secure email for the 
patient’s record. The original consent will be sent to medical records to be placed in the patients 
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• The informed consent process will be documented on a CRIS progress note (Progress Note – 
Documentation of Consent) by the investigator. 
 
7.8. 
DATA SAFETY AND MONITORING 
The entire study data set will be managed by the principal investigator.  The entire data set will be 
contained in a secure database located on the NIH server.  The forms to record data for this study will be 
generated and carefully reviewed for completeness, discrepant, inappropriate, and illogical responses. 
The data will checked for duplicate entries, with range checks on each field and consistency checks 
between fields with linked information.  In cases of incoherent or missing data, the study coordinator will 
be immediately contacted and, if necessary, the form returned for CRF correction by the data manager. If 
multiple problems are found, a larger percentage of patient records will be audited. Non-image study data 
will be managed through the NICHD Clinical Trials Database system and stored on secure, redundant 
servers.  Study image data will reside on the PACS.  
NIH Intramural IRB: Prior to implementation of this study, the protocol and the proposed patient consent 
forms will be reviewed and approved by the properly constituted IRB operating according to the 45 CFR 
46.  This committee will also approve all amendments to the protocol or informed consent, and conduct 
continuing annual review so long as the protocol is open to accrual or follow up of subjects. 
A data safety and monitoring board lead by Victor Ferrari, M.D., at the University of Pennsylvania will 
review all laboratory and safety data.  At regular 12-month intervals the DSMB will monitor the safety of 
the lipid lowering therapy with Rosuvastatin. This will include evaluation of enrollment, compliance, 
follow-up, laboratory results, data management, and quality control. The DSMB will decide at each of 
these reviews whether the study will continue as originally designed. Analyses will be conducted for two 
interim analyses (at the end of year one and year two) and one final evaluation.  
Data confidentiality:   
Patient image data will be maintained on PACS database systems within the Department of Radiology 
with security and redundancy at the level of the clinical PACS system used by the NIH clinical center. The 
confidentiality and security of the data files containing PHI will be maintained by ensuring password 
protection on all computer accounts. Protection against loss of data is essential to our data management. 
Copies of the study database files will reside in an independent back-up hard drive.   
Data reporting will be done through presenting in national meetings and publishing in journals.     
7.9. 
COMPENSATION 
Patients will not receive direct financial compensation for participation in the main study.  They will 
receive the medications Rosuvastatin or Atorvastatin without charge. Participants will be compensated 
for travel to and from the NIH Clinical Center.  For NIH Employees enrolled on this study, refer to NIH 
Policy Manual, 2300-630-3 – Leave policy for NIH Employees Participating in NIH Medical Research 
Studies. (See Appendix B) 
 
Reimbursement for the PET and CT reproducibility sub studies will be consistent with NIH guidelines.   


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For the CT Reproducibility sub study, participants will receive up to $150 for the visit based on the 
following: 
• 
Phlebotomy: 1 inconvenience unit 
• 
IV placement: 1 inconvenience unit 
• 
CT with IV contrast: 10 inconvenience units 
• 
Maximum $30 for visit ($20 for the first hour and $10 for each following hour with a maximum of 
2 hours per visit) 
For the PET sub study, participants will receive up to $390 total for the 3 additional visits based on the 
following: 
• 
Phlebotomy: 1 inconvenience unit 
• 
IV placement: 1 inconvenience unit 
• 
PET with IV contrast: 8 inconvenience units 
• 
Maximum $30 for visit ($20 for the first hours and $10 for each following hours with a maximum 
of 2 hours per visit) 
7.10. CONFLICTS OF INTEREST 
This study has no external sponsors or funding sources.  No investigator has a relevant conflict of interest.  
8. 
SAFETY REPORTING REQUIREMENTS:  
8.1. DEFINITIONS  
Please refer to Policy 801 for current definitions. 
 
AE assessment: 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized to describe the 
severity of AEs. 
8.2. 
IRB REPORTING GUIDELINES 
Reports to the IRB and CD:   
Expedited Reporting:   
Events requiring expedited reporting will be submitted to the IRB per Policy 801 “Reporting Research 
Events”. 
 
Reports to the IRB at the time of Continuing Review: 
The PI or designee will refer to HRPP Policy 801 “Reporting Research Events”, to determine IRB reporting 
requirements. 
 
Reports to the CD: 


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The PI or designee will refer to NHLBI DIR guidelines to determine CD reporting requirements. 
8.3. 
IND/IDE: 
The magnetic resonance magnets and coils used to perform cardiac imaging are 510k approved devices 
being used in accordance with their labeling (21 CFR 812 § 812.2.(c)).  Imaging sequences that are not 
commercially available (research sequences or works-in-progress) may be used during image acquisition. 
However, custom tools (software) sequences may be different than what is normally done in a routine 
clinical scan, these sequences conform to marketed device standards with respect to FDA established 
safety criteria for static field strength, acoustic noise, dB/dt, RF heating, biocompatibility and 
performance, all scans done will be performed within FDA safety guidelines.  There is no potential for 
serious risk to the health, safety, or welfare of the subjects using the MRI scanner in these ways. The use 
of these custom components of the device constitutes a non-significant risk device study. This protocol is 
therefore eligible for abbreviated IDE requirements of 21 CFR 812.2(b).  Consistent with an IDE exempt 
investigation, any non-commercial imaging sequences will be used solely to address the research 
questions of this protocol, and not to address the safety or effectiveness of the sequences themselves.   
The CT scanners (Somatom Force, Siemens; Toshiba Aquilion ONE) used to perform CT angiography are 
510k approved devices and are used in accordance with the labeling (21 CFR 812 § 812.2.(c)).  
Computed tomography (CT) x-ray imaging has been utilized in the field of medicine for over 3 decades.  
During this period, introductions of advances in both hardware and software technology have expanded 
the diagnostic capability of the modality.  As CT continues to evolve with even greater capabilities, the 
potential for providing clinicians with information not currently available today continues to increase. 
The Toshiba Aquilion ONE CT system is currently being used for studies in both general CT radiology and 
CT cardiac imaging.  One of the unique aspects of the Aquilion ONE CT system is its ability to acquire 
whole organ volume images in a single rotation by utilizing an x-ray detector that is configured as 320 
detector rows with a 0.5 mm width, providing a z-axis coverage of 16 cm of anatomy.  In line with the 
evolutionary changes to CT systems, the Aquilion ONE will be upgraded with new technology that will 
expand its capabilities.  The changes being made to the Aquilion ONE will provide enhancements to image 
acquisition capabilities, reduce ionizing radiation dose, and improve subject access to the system.  All of 
these features assist in enhancing the safety of the currently installed Aquilion ONE CT system. 
The SOMATOM Force is a whole body X-ray Computed Tomography System which features two 
continuously rotating tube-detector systems and functions according to the fan beam principle. The 
SOMATOM Force produces CT images in DICOM format, which can be used by postprocessing applications 
commercially distributed by Siemens and other vendors. The system software is a command-based 
program used for patient management, data management, X-ray scan control, image reconstruction, and 
image archive/evaluation. 
9 
PHARMACEUTICAL INFORMATION  
Rosuvastatin (Package insert) 
1 INDICATIONS AND USAGE  


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1.1 Hyperlipidemia and Mixed Dyslipidemia CRESTOR is indicated as adjunctive therapy to diet to reduce 
elevated Total-C, LDL-C, ApoB, nonHDL-C, and triglycerides and to increase HDL-C in adult patients with 
primary hyperlipidemia or mixed dyslipidemia. Lipid altering agents should be used in addition to a diet 
restricted in saturated fat and cholesterol when response to diet and nonpharmacological interventions 
alone has been inadequate. Pediatric Patients 10 to 17 years of age with Heterozygous Familial 
Hypercholesterolemia (HeFH) Adjunct to diet to reduce Total-C, LDL-C and ApoB levels in adolescent boys 
and girls, who are at least one year postmenarche, 10-17 years of age with heterozygous familial 
hypercholesterolemia if after an adequate trial of diet therapy the following findings are present: LDL-C > 
190 mg/dL or > 160 mg/dL and there is a positive family history of premature cardiovascular disease (CVD) 
or two or more other CVD risk factors.  
1.2 Hypertriglyceridemia CRESTOR is indicated as adjunctive therapy to diet for the treatment of adult 
patients with hypertriglyceridemia.  
1.3 Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) CRESTOR is indicated as an adjunct to 
diet for the treatment of patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia).  
 1.4 Homozygous Familial Hypercholesterolemia CRESTOR is indicated as adjunctive therapy to other 
lipidlowering treatments (e.g., LDL apheresis) or alone if such treatments are unavailable to reduce LDL-C, 
Total-C, and ApoB in adult patients with homozygous familial hypercholesterolemia.  
1.5 Slowing of the Progression of Atherosclerosis CRESTOR is indicated as adjunctive therapy to diet to 
slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower Total-C 
and LDL-C to target levels.  
1.6 Primary Prevention of Cardiovascular Disease In individuals without clinically evident coronary heart 
disease but with an increased risk of cardiovascular disease based on age ≥ 50 years old in men and ≥ 60 
years old in women, hsCRP ≥ 2 mg/L, and the presence of at least one additional cardiovascular disease 
risk factor such as hypertension, low HDL-C, smoking, or a family history of premature coronary heart 
disease, CRESTOR is indicated to: • reduce the risk of stroke • reduce the risk of myocardial infarction • 
reduce the risk of arterial revascularization procedures  
1.7 Limitations of Use CRESTOR has not been studied in Fredrickson Type I and V dyslipidemias. 2 DOSAGE 
AND ADMINISTRATION 2.1 General Dosing Information The dose range for CRESTOR is 5 to 40 mg orally 
once daily. The usual starting dose is 10-20 mg. CRESTOR can be administered as a single dose at any time 
of day, with or without food. 4 When initiating CRESTOR therapy or switching from another HMG-CoA 
reductase inhibitor therapy, the appropriate CRESTOR starting dose should first be utilized, and only then 
titrated according to the patient’s response and individualized goal of therapy. After initiation or upon 
titration of CRESTOR, lipid levels should be analyzed within 2 to 4 weeks and the dosage adjusted 
accordingly. The 40 mg dose of CRESTOR should be used only for those patients who have not achieved 
their LDL-C goal utilizing the 20 mg dose  
5 WARNINGS AND PRECAUTIONS  
5.1 Skeletal Muscle Effects Cases of myopathy and rhabdomyolysis with acute renal failure secondary to 
myoglobinuria have been reported with HMG-CoA reductase inhibitors, including CRESTOR. These risks 
can occur at any dose level, but are increased at the highest dose (40 mg). CRESTOR should be prescribed 


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with caution in patients with predisposing factors for myopathy (e.g., age ≥ 65 years, inadequately treated 
hypothyroidism, renal impairment). 7 The risk of myopathy during treatment with CRESTOR may be 
increased with concurrent administration of some other lipid-lowering therapies (fibrates or niacin), 
gemfibrozil, cyclosporine, lopinavir/ritonavir, or atazanavir/ritonavir [see Dosage and Administration and 
Drug Interactions]. CRESTOR therapy should be discontinued if markedly elevated creatinine kinase levels 
occur or myopathy is diagnosed or suspected. CRESTOR therapy should also be temporarily withheld in 
any patient with an acute, serious condition suggestive of myopathy or predisposing to the development 
of renal failure secondary to rhabdomyolysis (e.g., sepsis, hypotension, dehydration, major surgery, 
trauma, severe metabolic, endocrine, and electrolyte disorders, or uncontrolled seizures). All patients 
should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if 
accompanied by malaise or fever.  
5.2 Liver Enzyme Abnormalities and Monitoring It is recommended that liver enzyme tests be performed 
before and at 12 weeks following both the initiation of therapy and any elevation of dose, and periodically 
(e.g., semiannually) thereafter. Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been 
reported with HMG-CoA reductase inhibitors, including CRESTOR. In most cases, the elevations were 
transient and resolved or improved on continued therapy or after a brief interruption in therapy. There 
were two cases of jaundice, for which a relationship to CRESTOR therapy could not be determined, which 
resolved after discontinuation of therapy. There were no cases of liver failure or irreversible liver disease 
in these trials. In a pooled analysis of placebo-controlled trials, increases in serum transaminases to >3 
times the upper limit of normal occurred in 1.1% of patients taking CRESTOR versus 0.5% of patients 
treated with placebo. Patients who develop increased transaminase levels should be monitored until the 
abnormalities have resolved. Should an increase in ALT or AST of >3 times ULN persist, 8 reduction of dose 
or withdrawal of CRESTOR is recommended. CRESTOR should be used with caution in patients who 
consume substantial quantities of alcohol and/or have a history of chronic liver disease [see Clinical 
Pharmacology (12.3)]. Active liver disease, which may include unexplained persistent transaminase 
elevations, is a contraindication to the use of CRESTOR [see Contraindications (4)].  
5.3 Concomitant Coumarin Anticoagulants Caution should be exercised when anticoagulants are given in 
conjunction with CRESTOR because of its potentiation of the effect of coumarin-type anticoagulants in 
prolonging the prothrombin time/INR. In patients taking coumarin anticoagulants and CRESTOR 
concomitantly, INR should be determined before starting CRESTOR and frequently enough during early 
therapy to ensure that no significant alteration of INR occurs [see Drug Interactions (7.4)]. 
5.4 Proteinuria and Hematuria In the CRESTOR clinical trial program, dipstick-positive proteinuria and 
microscopic hematuria were observed among CRESTOR treated patients. These findings were more 
frequent in patients taking CRESTOR 40 mg, when compared to lower doses of CRESTOR or comparator 
HMG-CoA reductase inhibitors, though it was generally transient and was not associated with worsening 
renal function. Although the clinical significance of this finding is unknown, a dose reduction should be 
considered for patients on CRESTOR therapy with unexplained persistent proteinuria and/or hematuria 
during routine urinalysis testing.  
5.5 Endocrine Effects Increases in HbA1c and fasting serum glucose levels have been reported with HMG-
CoA reductase inhibitors, including CRESTOR [see Adverse Reactions (6.1)]. Although clinical studies have 
shown that CRESTOR alone does not reduce basal plasma cortisol concentration or impair adrenal 
reserve, caution should be exercised if 9 CRESTOR is administered concomitantly with drugs that may 


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decrease the levels or activity of endogenous steroid hormones such as ketoconazole, spironolactone, and 
cimetidine. 
Nitroglycerine (Package insert): 
The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle, producing a 
vasodilator effect on both peripheral arteries and veins with more prominent effects on the latter. 
Dilation of the post-capillary vessels, including large veins, promotes peripheral pooling of blood and 
decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure (pre-load). 
Arteriolar relaxation reduces systemic vascular resistance and arterial pressure (after-load). 
The mechanism by which nitroglycerin relieves angina pectoris is not fully understood. Myocardial oxygen 
consumption or demand (as measured by the pressure-rate product, tension-time index, and stroke-work 
index) is decreased by both the arterial and venous effects of nitroglycerin and presumably, a more 
favorable supply-demand ratio is achieved. 
While the large epicardial coronary arteries are also dilated by nitroglycerin, the extent to which this 
action contributes to relief of exertional angina is unclear. 
Nitroglycerin is rapidly metabolized in vivo, with a liver reductase enzyme having primary importance in 
the formation of glycerol nitrate metabolites and inorganic nitrate. Two active major metabolites, 1,2-and 
1,3-dinitroglycerols, the products of hydrolysis, although less potent as vasodilators, have longer plasma 
half-lives than the parent compound. The dinitrates are further metabolized to mononitrates (considered 
biologically inactive with respect to cardiovascular effects) and ultimately glycerol and carbon dioxide. 
Therapeutic doses of nitroglycerin may reduce systolic, diastolic and mean arterial blood pressure. 
Effective coronary perfusion pressure is usually maintained, but can be compromised if blood pressure 
falls excessively or increased heart rate decreases diastolic filling time. 
Elevated central venous and pulmonary capillary wedge pressures, pulmonary vascular resistance and 
systemic vascular resistance are also reduced by nitroglycerin therapy. Heart rate is usually slightly 
increased, presumably a reflex response to the fall in blood pressure. Cardiac index may be increased, 
decreased, or unchanged. Patients with elevated left ventricular filling pressure and systemic vascular 
resistance values in conjunction with a depressed cardiac index are likely to experience an improvement 
in cardiac index. On the other hand, when filling pressures and cardiac index are normal, cardiac index 
may be slightly reduced. 
In a pharmacokinetic study when a single 0.8 mg dose of Nitrolingual®Pumpspray was administered to 
healthy volunteers (n = 24), the mean Cmax and tmax were 1,041pg/mL • min and 7.5 minutes, 
respectively. Additionally, in these subjects the mean area-under-the-curve (AUC) was 12,769 pg/mL • 
min. 
In a randomized, double-blind single-dose, 5-period cross-over study in 51 patients with exertional angina 
pectoris significant dose-related increases in exercise tolerance, time to onset of angina and ST-segment 
depression were seen following doses of 0.2, 0.4, 0.8 and 1.6 mg of nitroglycerin delivered by metered 
pumpspray as compared to placebo. 


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Additionally the drug was well tolerated as evidenced by a profile of generally mild to moderate adverse 
events. 
Beta Blocker (Package insert) Clinical Pharmacology information: 
Lopressor is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal studies have shown that 
it has a preferential effect on beta1 adrenoreceptors, chiefly located in cardiac muscle. This preferential 
effect is not absolute, however, and at higher doses, Lopressor also inhibits beta2 adrenoreceptors, 
chiefly located in the bronchial and vascular musculature. 
Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, as shown 
by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood 
pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex 
orthostatic tachycardia. 
 Relative beta1 selectivity has been confirmed by the following: (1) In normal subjects, Lopressor is unable 
to reverse the beta2 -mediated vasodilating effects of epinephrine. This contrasts with the effect of 
nonselective (beta1 plus beta2) beta blockers, which completely reverse the vasodilating effects of 
epinephrine. (2) In asthmatic patients, Lopressor reduces FEV1 and FVC significantly less than a 
nonselective beta blocker, propranolol, at equivalent beta1-receptor blocking doses. 
 Lopressor has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only 
at doses much greater than required for beta blockade. Lopressor crosses the blood-brain barrier and has 
been reported in the CSF in a concentration 78% of the simultaneous plasma concentration. Animal and 
human experiments indicate that Lopressor slows the sinus rate and decreases AV nodal conduction. 
In controlled clinical studies, Lopressor has been shown to be an effective antihypertensive agent when 
used alone or as concomitant therapy with thiazide-type diuretics, at dosages of 100-450 mg daily. In 
controlled, comparative, clinical studies, Lopressor has been shown to be as effective an antihypertensive 
agent as propranolol, methyldopa, and thiazide-type diuretics, and to be equally effective in supine and 
standing positions.  
The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. 
However, several possible mechanisms have been proposed: (1) competitive antagonism of 
catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac 
output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression 
of renin activity. 
By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial 
contraction, and in blood pressure, Lopressor reduces the oxygen requirements of the heart at any given 
level of effort, thus making it useful in the long-term management of angina pectoris. However, in 
patients with heart failure, beta-adrenergic blockade may increase oxygen requirements by increasing left 
ventricular fiber length and end-diastolic pressure. 
Although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, there 
are situations in which sympathetic stimulation is vital. In patients with severely damaged hearts, 
adequate ventricular function may depend on sympathetic drive. In the presence of AV block, beta 


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blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta2-
adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic 
bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous 
bronchodilators in such patients. 
In controlled clinical trials, Lopressor, administered two or four times daily, has been shown to be an 
effective antianginal agent, reducing the number of angina attacks and increasing exercise tolerance. The 
dosage used in these studies ranged from 100-400 mg daily. A controlled, comparative, clinical trial 
showed that Lopressor was indistinguishable from propranolol in the treatment of angina pectoris. 
In a large (1,395 patients randomized), double-blind, placebo-controlled clinical study, Lopressor was 
shown to reduce 3-month mortality by 36% in patients with suspected or definite myocardial infarction.  
Patients were randomized and treated as soon as possible after their arrival in the hospital, once their 
clinical condition had stabilized and their hemodynamic status had been carefully evaluated. Subjects 
were ineligible if they had hypotension, bradycardia, peripheral signs of shock, and/or more than minimal 
basal rales as signs of congestive heart failure. Initial treatment consisted of intravenous followed by oral 
administration of Lopressor or placebo, given in a coronary care or comparable unit. Oral maintenance 
therapy with Lopressor or placebo was then continued for 3 months. After this double-blind period, all 
patients were given Lopressor and followed up to 1 year. 
The median delay from the onset of symptoms to the initiation of therapy was 8 hours in both the 
Lopressor- and placebo-treatment groups. Among patients treated with Lopressor, there were 
comparable reductions in 3-month mortality for those treated early (≤8 hours) and those in whom 
treatment was started later. Significant reductions in the incidence of ventricular fibrillation and in chest 
pain following initial intravenous therapy were also observed with Lopressor and were independent of the 
interval between onset of symptoms and initiation of therapy.  
The precise mechanism of action of Lopressor in patients with suspected or definite myocardial infarction 
is not known. 
In this study, patients treated with metoprolol received the drug both very early (intra-venously) and 
during a subsequent 3-month period, while placebo patients received no beta-blocker treatment for this 
period. The study thus was able to show a benefit from the overall metoprolol regimen but cannot 
separate the benefit of very early intravenous treatment from the benefit of later beta-blocker therapy. 
Nonetheless, because the overall regimen showed a clear beneficial effect on survival without evidence of 
an early adverse effect on survival, one acceptable dosage regimen is the precise regimen used in the 
trial. Because the specific benefit of very early treatment remains to be defined however, it is also 
reasonable to administer the drug orally to patients at a later time as is recommended for certain other 
beta blockers. 
Iodine contrast (Package Insert)  
Isovue (iopamidol)  injection, solution   


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Intravascular injection of a radiopaque diagnostic agent opacifies those vessels in the path of flow of the 
contrast medium, permitting radiographic visualization of the internal structures of the human body until 
significant hemodilution occurs. 
Following intravascular injection, radiopaque diagnostic agents are immediately diluted in the circulating 
plasma. Calculations of apparent volume of distribution at steady-state indicate that iopamidol is 
distributed between the circulating blood volume and other extracellular fluid; there appears to be no 
significant deposition of iopamidol in tissues. Uniform distribution of iopamidol in extracellular fluid is 
reflected by its demonstrated utility in contrast enhancement of computed tomographic imaging of the 
head and body following intravenous administration. 
The pharmacokinetics of intravenously administered iopamidol in normal subjects conform to an open 
two-compartment model with first order elimination (a rapid alpha phase for drug distribution and a slow 
beta phase for drug elimination). The elimination serum or plasma half-life is approximately two hours; 
the half-life is not dose dependent. No significant metabolism, deiodination, or biotransformation occurs. 
Iopamidol is excreted mainly through the kidneys following intravascular administration. In patients with 
impaired renal function, the elimination half-life is prolonged dependent upon the degree of impairment. 
In the absence of renal dysfunction, the cumulative urinary excretion for Iopamidol, expressed as a 
percentage of administered intravenous dose is approximately 35 to 40 percent at 60 minutes, 80 to 90 
percent at 8 hours, and 90 percent or more in the 72-to 96-hour period after administration. In normal 
subjects, approximately one percent or less of the administered dose appears in cumulative 72- to 96-
hour fecal specimens. 
ISOVUE may be visualized in the renal parenchyma within 30-60 seconds following rapid intravenous 
administration. Opacification of the calyces and pelves in patients with normal renal function becomes 
apparent within 1 to 3 minutes, with optimum contrast occurring between 5 and 15 minutes. In patients 
with renal impairment, contrast visualization may be delayed. 
Iopamidol displays little tendency to bind to serum or plasma proteins. 
No evidence of in vivo complement activation has been found in normal subjects. 
*Animal studies indicate that iopamidol does not cross the blood-brain barrier to any significant extent 
following intravascular administration. 
*ISOVUE (lopamidol Injection) enhances computed tomographic brain imaging through augmentation of 
radiographic efficiency. The degree of enhancement of visualization of tissue density is directly related to 
the iodine content in an administered dose; peak iodine blood levels occur immediately following rapid 
injection of the dose. These levels fall rapidly within five to ten minutes. This can be accounted for by the 
dilution in the vascular and extracellular fluid compartments which causes an initial sharp fall in plasma 
concentration. Equilibration with the extracellular compartments is reached in about ten minutes, 
thereafter the fall becomes exponential. Maximum contrast enhancement frequently occurs after peak 
blood iodine levels are reached. The delay in maximum contrast enhancement can range from five to 
forty minutes depending on the peak iodine levels achieved and the cell type of the lesion. This lag 
suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of 
iodine within the lesion and outside the blood pool, although the mechanism by which this occurs is not 


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clear. The radiographic enhancement of nontumoral lesions, such as arteriovenous malformations and 
aneurysms, is probably dependent on the iodine content of the circulating blood pool. 
In CECT head imaging, ISOVUE (lopamidol Injection) does not accumulate in normal brain tissue due to the 
presence of the blood-brain barrier. The increase in x-ray absorption in normal brain is due to the 
presence of contrast agent within the blood pool. A break in the blood-brain barrier such as occurs in 
malignant tumors of the brain allows the accumulation of the contrast medium within the interstitial 
tissue of the tumor. Adjacent normal brain tissue does not contain the contrast medium. 
In non-neural tissues (during computed tomography of the body), iopamidol diffuses rapidly from the 
vascular into the extravascular space. Increase in x-ray absorption is related to blood flow, concentration 
of the contrast medium, and extraction of the contrast medium by interstitial tissue of tumors since no 
barrier exists. Contrast enhancement is thus due to the relative differences in extravascular diffusion 
between normal and abnormal tissue, quite different from that in the brain. 
The pharmacokinetics of iopamidol in both normal and abnormal tissue have been shown to be variable. 
Contrast enhancement appears to be greatest soon after administration of the contrast medium, and 
following intraarterial rather than intravenous administration. Thus, greatest enhancement can be 
detected by a series of consecutive two- to three-second scans performed just after injection (within 30 to 
90 seconds), i.e., dynamic computed tomographic imaging. 
12 CLINICAL PHARMACOLOGY 
Gadolinium:  The use of gadolinium for this protocol is not off-label.  For the subjects receiving gadolinium 
contrast agents, the placement of a peripheral intravenous line may result in mild discomfort, vasovagal 
reactions or bruising.  The gadolinium contrast agents that will be used are commercially available and 
routinely used in hospitals and radiology practices.  Experience with a large number of subjects has shown 
that these commercially available gadolinium chelates are safe and without side effects in the majority 
(>98%) of subjects.  When side effects do occur, they are usually mild and transient.  These include 
coldness in the arm during the injection, headache and nausea.  More severe reactions (shortness of 
breath, wheezing, or hypotension) are extremely rare. Gadolinium has been used in over 5000 studies at 
NIH within the dosage limits described without any major side effects. This protocol will follow the NIH 
Clinical Center Policy and Screening Procedures for Administration of Gadolinium Based Contrast Agents 
for MRI and the NHLBI DIR Policy for the Administration of Gadolinium-Based Contrast Agents for Clinical 
Research Protocols.  
The US Food and Drug Administration issued a warning that administration of gadolinium (updated 
September 9, 2010), the contrast imaging agent used in this protocol, has been associated with 
development of a disease called nephrogenic systemic fibrosis (NSF). The syndrome is rare (approximately 
600 cases reported worldwide as of September 2010 out of several million administrations of gadolinium), 
but disabling and in some cases, fatal. All cases to date have occurred in subjects with severe renal 
disease, including subjects on dialysis. Most of the reported cases have been attributed to the gadolinium 
contrast agent gadodiamide (Omniscan).  Most recent information indicates the condition is associated 
with severe renal insufficiency. Subjects with severe renal excretory dysfunction, estimated glomerular 
filtration rate < 30 mL/min/1.73m2 body surface area according to the Modification of Diet in Renal 
Disease criteria, will not receive gadolinium contrast agent during the PET/MRI. 


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On December 19, 2017, the FDA is requiring a new class warning and other safety measures for all 
gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI) concerning gadolinium 
remaining in patients’ bodies, including the brain, for months to years after receiving these drugs. 
Gadolinium retention has not been directly linked to adverse health effects in patients with normal kidney 
function, and FDA has concluded that the benefit of all approved GBCAs continues to outweigh any 
potential risks. However, after additional review and consultation with the Medical Imaging Drugs 
Advisory Committee, FDA is requiring several actions to alert health care professionals and patients about 
gadolinium retention after an MRI using a GBCA, and actions that can help minimize problems. These 
include requiring a new patient Medication Guide, providing educational information that every patient 
will be asked to read before receiving a GBCA. FDA is also requiring manufacturers of GBCAs to conduct 
human and animal studies to further assess the safety of these contrast agents. 
To date, the only known adverse health effect related to gadolinium retention is a rare condition called 
nephrogenic systemic fibrosis (NSF) that occurs in a small subgroup of patients with pre-existing kidney 
failure. FDA received reports of adverse events involving multiple organ systems in patients with normal 
kidney function. A causal association between these adverse events and gadolinium retention could not 
be established.  
In response to the December 2017 MedWatch warning on gadolinium accumulation from the FDA, the 
healthy subjects may undergo no more than two gadolinium exposures during a 12-month period, per 
NHLBI policy. 
In accordance with the FDA Drug Safety Communication of 05/16/2018, the Medication Guide for 
gadobutrol (or other macrocyclic gadolinium contrast agent if applicable) will be made available to all 
subjects with scans that will involve gadolinium-based contrast agent administration. 
12.2 Pharmacodynamics 
Gadobutrol leads to distinct shortening of the relaxation times even in low concentrations. At pH 7, 37°C 
and 1.5 T, the relaxivity (r1) ‐ determined from the influence on the relaxation times (T1) of protons in 
plasma ‐ is 5.2 L/(mmol∙sec) and the relaxivity (r2) ‐ determined from the influence on the relaxation 
times (T2) ‐ is 6.1 L/(mmol∙sec). Gadobutrol is a highly water‐soluble, extremely hydrophilic compound 
with a partition coefficient between n‐butanol and buffer at pH 7.6 of about 0.006. 
12.3 Pharmacokinetics 
Distribution 
After intravenous administration, gadobutrol is rapidly distributed in the extracellular space. After a 
gadobutrol dose of 0.1 mmol/kg body weight, an average level of 0.59 mmol gadobutrol/L was measured 
in plasma 2 minutes after the injection and 0.3 mmol gadobutrol/L 60 minutes after the injection. 
Gadobutrol does not display any particular protein binding. In rats, gadobutrol does not penetrate the 
intact blood‐brain barrier. 
Metabolism 


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Gadobutrol is not metabolized. Gadobutrol is excreted in an unchanged form via the kidneys. In healthy 
subjects, renal clearance of gadobutrol is 1.1 to 1.7 mL/(min∙kg) and thus comparable to the renal 
clearance of inulin, confirming that gadobutrol is eliminated by glomerular filtration. 
Within two hours after intravenous administration more than 50% and within 12 hours more than 90% of 
the given dose is eliminated via the urine. Extra‐renal elimination is negligible. 
Specific Populations 
Gender 
Gender has no clinically relevant effect on the pharmacokinetics of gadobutrol. 
After intravenous injection of 0.1 mmol gadobutrol/kg body weight, the elimination half‐life was 5.8 ± 2.4 
hours in mild to moderately impaired patients (80 > CLCR > 30 mL/min) and 17.6 ± 6.2 hours in severely 
impaired patients not on dialysis (CLCR    30 mL/min). The mean AUC of gadobutrol in patients with 
normal renal function was 1.1 ± 0.1 mmol∙h/L, compared to 4.0 ± 1.8 mmol∙h/L in patients with mild to 
moderate renal impairment and 11.5 ± 4.3 mmol∙h/L in patients with severe renal impairment. 
Complete recovery in the urine was seen in patients with mild or moderate renal impairment within 72 
hours. In patients with severely impaired renal function about 80% of the administered dose was 
recovered in the urine within 5 days.  
 
 


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established medical therapies." Journal of the American College of Cardiology 49: 263-270. 
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Node and N. Koga (2014). "High-intensity signals in coronary plaques on noncontrast T1-weighted 
magnetic resonance imaging as a novel determinant of coronary events." J Am Coll Cardiol 63(10): 
989-999. 
44. Noguchi, T., N. Yamada, M. Higashi, Y. Goto and H. Naito (2011). "High-intensity signals in carotid 
plaques on T1-weighted magnetic resonance imaging predict coronary events in patients with 
coronary artery disease." J Am Coll Cardiol 58(4): 416-422. 
45. Papadopoulou, S.-L., L. a. Neefjes, H. M. Garcia-Garcia, W.-J. Flu, A. Rossi, A. S. Dharampal, P. H. 
Kitslaar, N. R. Mollet, S. Veldhof, K. Nieman, G. W. Stone, P. W. Serruys, G. P. Krestin and P. J. de 
Feyter (2012). "Natural history of coronary atherosclerosis by multislice computed tomography." 
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46. Pedersen, T. R., O. Faergeman, J. J. Kastelein, A. G. Olsson, M. J. Tikkanen, I. Holme, M. L. Larsen, F. S. 
Bendiksen, C. Lindahl, M. Szarek and J. Tsai (2005). "High-dose atorvastatin vs usual-dose simvastatin 
for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial." 
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47. Perez-Rodriguez, J., S. Lai, B. D. Ehst, D. M. Fine and D. A. Bluemke (2009). "Nephrogenic systemic 
fibrosis: incidence, associations, and effect of risk factor assessment--report of 33 cases." Radiology 
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48. Priester, T. C. and S. E. Litwin (2009). "Measuring progression of coronary atherosclerosis with 
computed tomography: searching for clarity among shades of gray." J Cardiovasc Comput Tomogr 3 
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49. Ridker, P. M., A. Pradhan, J. G. MacFadyen, P. Libby and R. J. Glynn (2012). "Cardiovascular benefits 
and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial." Lancet 
380: 565-571. 
50. Sacks, F. M., M. A. Pfeffer, L. A. Moye, J. L. Rouleau, J. D. Rutherford, T. G. Cole, L. Brown, J. W. 
Warnica, J. M. Arnold, C. C. Wun, B. R. Davis and E. Braunwald (1996). "The effect of pravastatin on 
coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol 
and Recurrent Events Trial investigators." N Engl J Med 335(14): 1001-1009. 
51. Sandfort, V., J. A. Lima and D. A. Bluemke (2015). "Noninvasive Imaging of Atherosclerotic Plaque 
Progression: Status of Coronary Computed Tomography Angiography." Circ Cardiovasc Imaging 8(7): 
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52. Sandfort, V., C. T. Sibley, E. Turkbey, M. Ahlman, A. Zavodni, M. Mallek, S. Liu, J. Vargas and D. A. 
Bluemke (2014). "Rate of Carotid Disease Progression in Asymptomatic Low to Moderate Risk 
Individuals: The Right Study." Circulation 130(Suppl 2): A13890. 
53. Sattar, N., D. Preiss, H. M. Murray, P. Welsh, B. M. Buckley, A. J. M. de Craen, S. R. K. Seshasai, J. J. 
McMurray, D. J. Freeman, J. W. Jukema, P. W. Macfarlane, C. J. Packard, D. J. Stott, R. G. Westendorp, 
J. Shepherd, B. R. Davis, S. L. Pressel, R. Marchioli, R. M. Marfisi, A. P. Maggioni, L. Tavazzi, G. Tognoni, 
J. Kjekshus, T. R. Pedersen, T. J. Cook, A. M. Gotto, M. B. Clearfield, J. R. Downs, H. Nakamura, Y. 


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Ohashi, K. Mizuno, K. K. Ray and I. Ford (2010). "Statins and risk of incident diabetes: a collaborative 
meta-analysis of randomised statin trials." Lancet 375: 735-742. 
54. Schelbert, E. B., J. J. Cao, S. Sigurdsson, T. Aspelund, P. Kellman, A. H. Aletras, C. K. Dyke, G. 
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and prognosis of unrecognized myocardial infarction determined by cardiac magnetic resonance in 
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55. Schmid, M., S. Achenbach, D. Ropers, S. Komatsu, U. Ropers, W. G. Daniel and T. Pflederer (2008). 
"Assessment of changes in non-calcified atherosclerotic plaque volume in the left main and left 
anterior descending coronary arteries over time by 64-slice computed tomography." The American 
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56. Sibley, C. T., A. L. Vavere, I. Gottlieb, C. Cox, M. Matheson, A. Spooner, G. Godoy, V. Fernandes, B. A. 
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plaque study." Heart 99(22): 1675-1680. 
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60. Underhill, H. R., C. Yuan, X. Q. Zhao, L. W. Kraiss, D. L. Parker, T. Saam, B. Chu, N. Takaya, F. Liu, N. L. 
Polissar, B. Neradilek, J. S. Raichlen, V. A. Cain, J. C. Waterton, W. Hamar and T. S. Hatsukami (2008). 
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61. van den Bouwhuijsen, Q. J., D. Bos, M. A. Ikram, A. Hofman, G. P. Krestin, O. H. Franco, A. van der Lugt 
and M. W. Vernooij (2015). "Coexistence of Calcification, Intraplaque Hemorrhage and Lipid Core 
within the Asymptomatic Atherosclerotic Carotid Plaque: The Rotterdam Study." Cerebrovasc Dis 
39(5-6): 319-324. 
62. van den Bouwhuijsen, Q. J., M. W. Vernooij, A. Hofman, G. P. Krestin, A. van der Lugt and J. C. 
Witteman (2012). "Determinants of magnetic resonance imaging detected carotid plaque 
components: the Rotterdam Study." Eur Heart J 33(2): 221-229. 
63. van Dijk, A. C., M. T. Truijman, B. Hussain, T. Zadi, G. Saiedie, A. A. de Rotte, M. I. Liem, A. F. van der 
Steen, M. J. Daemen, P. J. Koudstaal, P. J. Nederkoorn, J. Hendrikse, M. E. Kooi and A. van der Lugt 
(2015). "Intraplaque Hemorrhage and the Plaque Surface in Carotid Atherosclerosis: The Plaque At 
RISK Study (PARISK)." AJNR Am J Neuroradiol. 
64. Vogel, R. A. (2014). "The New Cholesterol GuidelinesFinally More Light Than Heat∗." Journal of the 
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65. Waters, D. D., J. E. Ho, D. a. DeMicco, A. Breazna, B. J. Arsenault, C.-C. Wun, J. J. Kastelein, H. Colhoun 
and P. Barter (2011). "Predictors of new-onset diabetes in patients treated with atorvastatin: results 
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Biometrics 42(1): 121-130. 
 
 
 
 


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APPENDICES 
Appendix A:   Study Calendar* 
1Visits within +/-  12 weeks due for unforeseen events. M (month).  Delays in visits will need to be discussed and pre-approved with 
the research team. 
2Baseline: H&P and laboratory studies (see section 2.3) should be completed within 4 weeks of initiating treatment. 
3Baseline MRI can be completed within 4 weeks of screening procedures.   
4 See section Screening Evaluation, E for a list of the screening labs. 
5Concomitant medication review will be performed to update subject medication list. 
6MRI Questionnaire will be completed prior to MRI scan (See Appendix C). 
7See section Clinical Laboratory Measures, 3.2 for list of Clinical  labs. 
8Subjects will be taken off treatment/study after the final visit and referred back to their primary physician or have the option to 
enroll on another protocol if one is available and they meet the eligibility criteria. 
9 Visit pertains only to those participants whose statin dose is increased on 3M visit in order to meet LDL target.  All other 
participants will be asked to return at M12 
* contacted via telephone, e-mail or Telehealth 
                Visit number1 
1 
2 
3 
 
(4)9 
 
5 
 *6 
7   
  *8    98 
 
Screen 
M03 
M
3 
 
M6 
 
M12 
M18 
  M24 
M30      M36 
Procedure 
 
 
 
 
 
 
 
 
 
 
Obtain consent 
X 
 
 
 
 
 
 
 
 
 
Enrollment criteria 
X 
 
 
 
 
 
 
 
 
 
History & Physical2 
X 
 
 
 
 
 
X 
 
    X 
  X 
Screen Labs4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event review 
X 
 
X 
 
X 
 
X 
X 
      X 
  X 
  X 
Concomitant Med. 
Review5 
X 
 
X 
 
X 
 
X 
X 
      X 
  X 
  X 
Cardiac MRI  
 
X 
 
 
 
 
 
 
     X 
 
MRI Questionnaire6 
 
X 
 
 
 
 
 
 
     X 
 
Creatinine 
X 
 
X 
 
X 
 
X 
 
     X 
 
  X 
CT angiography  
X 
 
 
 
 
 
X 
 
     X 
  X 
PET imaging subgroup 
X 
 
X 
 
 
 
 
 
      X 
 
Drug dosing/ 
adjustment  
 
X 
X 
 
X 
 
X 
X 
      X 
  X 
  X 
Clinical Labs7 
                                             
X 
 
 
X 
 
 
X 
 
 
X 
 
     X 
      
   
  X 
   


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Appendix B. SOP 14F: NIH INFORMATION SHEET ON STAFF RESEARCH PARTICIPATION (APRIL 2016) 
 
As an NIH employee, contractor, Special Volunteer, Guest Researcher, or trainee, you may participate in 
intramural research studies unless it is prohibited by your Institute or Center (IC), or if you are excluded 
by the criteria of the protocol in which you want to enroll. The inclusion of NIH staff in a particular 
protocol must also be approved by the IRB. You may be motivated by altruism, a commitment to 
research in your own or related fields, or want access to clinical trials of potential direct therapeutic 
benefit. When deciding, you should make an informed decision about participation. This information 
sheet offers some points to consider for NIH staff who are considering research participation at NIH. 
First, similar to any individual who is considering research participation, you should seek adequate 
information about the study purpose, what is required of you in terms of procedures, interventions and 
time, and the potential risks and benefits of participation. For more information, see the NIH Clinical 
Center’s public website “Are Clinical Studies for You?” at 
http://www.cc.nih.gov/participate/studies.shtml. 
When you are thinking about participation in a research study that is being conducted by your 
supervisor, or others with whom you work closely in your laboratory, branch, or unit, you should 
consider some additional factors: 
A. Possible bias: Are you confident that you can be unbiased about reporting answers, side effects, or 
other information that could influence the study outcome or risk to you? 
B. Confidentiality: Has the principal investigator (PI) spoken about what information will be collected 
from you as part of the study? Has the PI discussed what information will be available to those within, 
and outside, the study team? If applicable, are you comfortable sharing your medical history (including, 
for example, mental health history or STDs) and your social history (e.g. substance use) with study 
investigators who may be your coworkers, or with the possibility 
of them discovering something about your health during the study (e.g. pregnancy status or a new 
diagnosis)? Although every effort will be made to protect your information and keep it private and 
confidential, your information may, depending on the nature of the protocol, become available in 
medical records or to authorized users outside of the study team. Discuss any concerns with the PI. 
C. Pressure: Do you perceive any pressure or expectations from your supervisor or colleagues regarding 
participation? Could that pressure influence your decision or make it difficult for you to choose whether 
or not to participate? Remember that it is your choice whether or not to participate and that your 
decision to participate or not should not have an effect, either beneficial or adverse, on your position at 
NIH. 
 
Appendix B: LEAVE POLICY FOR NIH EMPLOYEES PARTICIPATING IN NIH MEDICAL RESEARCH STUDIES 
(NIH POLICY MANUAL 2300-630-3)  
A. Policy  
An NIH employee may take part in an NIH funded biomedical research protocol approved by the NIH 
Institutional Review Board (IRB), if that protocol specifies that employees may participate. 
Commissioned Corps Officers should contact the Commissioned Corps Office (301) 402-9239 for 
authorization requirements and limitations in participating in a biomedical research protocol study.  
The protocol statement should include the time period and duration that participants will be expected 
to spend in the study and whether or not compensation will be offered. A copy of this statement shall 
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The employee’s supervisor should request a copy of the protocol statement from the employee to 
determine the appropriate leave that may be granted. Supervisors should contact the Principal 
Investigator to ascertain whether or not the employee will receive financial compensation and/or will 
accrue medical benefits.  
The employee’s supervisor shall determine if the employee may be absent from duty for the necessary 
period(s) of time. With the approval of the supervisor, an employee may be granted appropriate leave 
to participate in an NIH biomedical research study as a volunteer subject during his/her normal tour of 
duty.  
Annual Leave or Leave Without Pay shall be requested by an employee participating in an NIH 
biomedical research study from which compensation is offered and accepted by the employee.  
Annual Leave, Sick Leave or Leave Without Pay shall be requested by an employee participating in an 
NIH biomedical research study from which medical benefits are gained by the employee. 
Excused Absence may be granted to an employee if:  
The employee earns no money, and 
 The employee gains no medical benefits from participating in the study.  
An employee may participate in an NIH biomedical research study after the employee’s tour of duty 
without being charged annual leave, sick leave or leave without pay. An employee participating in a 
biomedical research study outside of his/her tour of duty must notify their supervisor of this activity 
when participation may impact the employee’s ability to perform work during his/her tour of duty.  
An employee may be granted excused absence to donate blood or blood products through the facilities 
of the Clinical Center, Department of Transfusion Medicine provided there is no compensation 
received. The donation of blood or blood products is not considered to constitute participation in a 
biomedical research study and is not covered by this manual. Further information on the leave policy 
for blood donors is contained in the NIH Civilian Leave Guide. 
B. References:  
HHS Personnel Instruction 630-1 (Absence and Leave)  
NIH Leave Guide for Civilian Employees  
Commissioned Corps Officer’s Handbook, 1998 
C. Internal Controls:  
The purpose of this manual issuance is to assure that all work and related activities are conducted in 
full accord with statutory, regulatory and policy requirements. 
Office Responsible for Reviewing Internal Controls Relative to this Chapter is OD/OHR/WRD/Benefits 
and Payroll Liaison Branch (Issuing Office).  
Through this issuance, the Office of Human Resources, Office of the Director, NIH is accountable for the 
method used to ensure that internal controls are implemented and working.  
Frequency of Review: Every 3 years  
Method of Review: Conduct surveys among Ics  
Review Report is sent to the Director, Office of Human Resource, NIH  
D. Records Retention and Disposal:  
All records (e-mail and non-e-mail) pertaining to this chapter must be retained and disposed of under 
the authority of NIH Manual 1743, “Keeping and Destroying Records,” Appendix 1, NIH Records Control 
Schedule, Item 1900-D-3, Time and Attendance Report Files.  
NIH e-mail messages. NIH e-mail messages (messages, including attachments, that are created on NIH 
computer systems or transmitted over NIH networks) that are evidence of the activities of the agency 
or have informational value are considered Federal records. These records must be maintained in 


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accordance with current NIH Records Management guidelines. Contact your IC Records Officer for 
additional information.  
All e-mail messages are considered Government property, and, if requested for a legitimate 
Government purpose, must be provided to the requester. Employees’ supervisors, NIH staff conducting 
official reviews or investigations, and the Office of Inspector General may request access to or copies of 
the e-mail messages. E-mail messages must also be provided to members of Congress or Congressional 
committees if requested and are subject to Freedom of Information Act requests. Since most e-mail 
systems have back-up files that are sometimes retained for significant periods of time, e-mail messages 
and attachments may be retrievable from a back-up file after they have been deleted from an 
individual’s computer. The back-up files are subject to the same request as the original messages. 
 
  
 
 
Appendix C:  MRI Safety Questionnaire 


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Appendix D:  Targeted enrollment table  
 
 
 
 


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Appendix E:  Pre-Screening Questionnaire 
 
NIH Protocol #16-H-0089 Screening Questionnaire  
Thank you for your interest in our study!  To help us evaluate whether or not you are 
eligible for participation, please provide as much of the following information as you are 
able to. 
 
 
Have you ever been a patient at the National Institutes of Health before?   
 
First/Middle/Last Name:   
 
 
 
Date of Birth: 
 
 
 
 
Street Address:   
 
 
 
City/State/Zip Code:   
 
 
 
Telephone Numbers:   
 
 
 
Please note we are asking for the following information in order to calculate your 
cardiovascular risk to determine if you are a good candidate for our study.  The 
information will not be used for any other purposes. 
 
Please provide your Gender: _________________ 
Please provide your Race (optional): ___________________ 
Please provide your Age: ____ 
 
From your last cholesterol test: 
Total Cholesterol:_ __________ 
HDL: ______ 
LDL: ______ 
Date test was performed: _____________ 
 
Have you been diagnosed with high blood pressure?     
 
 
 Yes 
 
 No 


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    What was your last blood pressure reading (home measurement is acceptable): 
_________ 
     List any medications you take for high blood pressure: 
___________________________ 
 
Do you have diabetes?  
 
 
 
 
 
 Yes 
 No 
If yes, do you take insulin? 
 
 
 
 Yes 
 No 
Do you take any other medications for diabetes? 
 Yes 
 No 
 
Have you ever smoked before?       
 
 Yes 
 No 
If yes, did you smoke within the last 30 days?        
 Yes 
 No 
 
Do you have any allergies to foods or medications? Please list the allergen and reaction:  
________________________________________________________________________ 
Did you ever have a CT scan of your heart or Calcium Score performed before? If yes, 
please provide details: 
________________________________________________________ 
 
Are you claustrophobic?  
 
 Yes 
 No 
 
Do you have kidney disease or have you ever been told that your kidneys are not working 
well? If yes, please provide your most recent creatinine result (a measure of kidney 
function): __________ 
 
Do you any history of the following: 
Chest pain/angina 
 
 Yes 
 No 
Heart attack       
 
 Yes 
 No 
Stroke   
 
 Yes 
 No 
Heart surgery /Stent 
 Yes 
 No 
Heart failure  
 
 Yes 
 No 
Atrial fibrillation 
 
 Yes 
 No 
Kidney disease 
 
 Yes 
 No 
Hyperthyroidism    
 
 Yes 
 No 
If you answered yes to any of the above, please provide details: 
__________________________ 
________________________________________________________________________
_____ 
 
Do you have any other ongoing medical problems? (if yes, please provide a brief 
description):     
________________________________________________________________________
___ 


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________________________________________________________________________
___  
 
What cholesterol “statin” medication and dose do you currently take? 
____________________ 
When did you start taking this medication? _____________________ 
Please list any other cholesterol medications you have taken in the last 5 years:  
____________ 
_______________________________________________________________________
______ 
 
Please list any prescription medications and doses you currently take: 
______________________ 
_______________________________________________________________________
_______ 
_______________________________________________________________________
_______ 
 
Your approximate height and weight: ______________ 
 
Once you have completed this form, please email or fax to: 
Andrew Keel, RN 
Email: Andrew.Keel@nih.gov  
Fax: (301) 648-5674 
We will be in touch with more information once we receive this form. Thank you!