Clinical trial NCT02376010
Conditions: Atherosclerosis
Keywords: atherosclerosis coronary artery disease cardiac CT computed tomographic angiography
Sponsor: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Start date: 2015-04-02; Completion date: 2018-04-01
Enrollment: 110 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Current oral anti-coagulation for atrial fibrillation is most commonly performed with warfarin. Warfarin is a vitamin K antagonist that has been shown in non-randomized trials to increase vascular calcification. Increased vascular calcification has been tied to increased cardiovascular events (CVE). This study will randomize patients currently taking warfarin to either continue on warfarin or be switched to rivaroxaban. Rivaroxaban is an oral anti-coagulant that works by inhibiting Factor Xa, and has no interaction with vitamin K. This study is a randomized, open label study that will randomize 120 patients and have them undergo blood tests and a calcium scan at baseline, and again after 12 months. Patients will be seen quarterly for examinations, safety checks and supply of rivaroxaban, as well as follow up INR testing for warfarin.

Detailed description:
Rivaroxaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with warfarin. The rate of myocardial infarction was 9% lower in the rivaroxaban group than in the warfarin group in the Rocket AF study and similarly the myocardial infarction rate was 12% lower in the apixaban group in Aristotle, but the difference was not significant in either trial. The potential of long term benefit by avoiding VKA therapy may be much greater for a CV event reduction. The study proposed will evaluate markers of CAC progression and atherosclerosis development, which have long term outcome data supporting that slowing these processes will be associated with lower CV events.

Arms: arm 1: rivaroxaban will be given to this cohort, once daily orally (15 or 20 mg, depending on GFR) arm 2: warfarin orally once a day, titrated to INR of 2-3
Interventions: intervention 1: rivaroxaban intervention 2: Warfarin
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
Rivaroxaban versus Warfarin in the evaluation of progression of coronary calcium 
 
Protocol Version  1.6 -  November 2, 2015 
 
Protocol number LA Biomed Protocol 21429-01 
                                     RIVAROXAFL4004_Budoff 
  
 Trial registration number  
 NCT02376010   Unique Protocol ID: 21429 
 
Principal Investigator: 
-  
Matthew Budoff, MD 
 
1124 W Carson Street 
 
Torrance, CA 90502 
 
(310) 222-4107 
 
Budoff@ucla.edu 
 
Sponsoring Institution: 
 
Los Angeles Biomedical Research Institute 
 
Research funding and drug provided by: Janssen Scientific Affairs, LLC 
 
 
 
 


2 
 
TABLE OF CONTENTS  
TITLE PAGE  
 
 
 
 
 
 
 
1 
TABLE OF CONTENTS 
 
 
 
 
 
 
2 
PROTOCOL SYNOPSIS 
 
 
 
 
 
 
3 
1 
INTRODUCTION 
 
 
 
 
 
 
3 
2 
Background 
 
 
 
 
 
 
 
3 
2.2 
Study Rationale 
 
 
 
 
 
 
9 
STUDY OBJECTIVES 
 
 
 
 
 
9 
3 
ETHICAL CONSIDERATIONS 
 
 
 
 
9 
 
4 
INVESTIGATIONAL PLAN 
 
 
 
 
 
10 
4.1 
Study Design and Duration 
 
 
 
 
 
10 
4.2 
Recruitment 
 
 
 
 
 
 
 
11 
5. 
Eligibility 
 
 
 
 
 
 
 
13 
5.1 
Inclusion Criteria 
 
 
 
 
 
 
13 
6 
TREATMENT  
 
 
 
 
 
 
14 
 
7 
PRODUCT INFORMATION  
 
 
 
 
14 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
 
16 
9.  
RISK OF RIVAROXABAN 
 
 
 
 
 
18 
10. ADVERSE EVENT REPORTING 
 
 
 
 
20 
11. Reporting Procedures for Adverse Events and Pregnancies 
 
24 
12. Data Safety Monitoring 
 
 
 
 
 
 
27 
13. Statistical Considerations  
 
 
 
 
 
27 
14.   REFERENCES  
 
 
 
 
 
 
30 
 
 


3 
 
Brief synopsis of the proposed research 
 
Current oral anti-coagulation for atrial fibrillation is most commonly performed with warfarin.   
Warfarin is a vitamin K antagonist that has been shown in non-randomized trials to increase 
vascular calcification.  Increased vascular calcification has been tied to increased cardiovascular 
events (CVE).  This study will randomize patients currently taking warfarin to either continue on 
warfarin or be switched to rivaroxaban.  Rivaroxaban is an oral anti-coagulant that works by 
inhibiting Factor Xa, and has no interaction with vitamin K.  This study is a randomized, open 
label study that will randomize 120 patients and have them undergo blood tests and a calcium 
scan at baseline, and again after 12 months.  Patients will be seen quarterly for examinations, 
safety checks and supply of rivaroxaban, as well as follow up INR testing for warfarin.       
1. Introduction:  
Vitamin K-antagonists (VKA) are the most widely used anti-thrombotic drugs with substantial 
efficacy in reducing risk of arterial and venous thrombosis. Several lines of evidence indicate, 
however, that VKA inhibit not only post-translational activation of vitamin K-dependent 
coagulation factors but also synthesis of functional extra-hepatic vitamin K-dependent proteins 
thereby eliciting undesired side-effects. Vascular calcification is one of the recently revealed 
side-effects of VKA. Vascular calcification is an actively regulated process involving vascular 
cells and a number of vitamin K-dependent proteins. 
 
2. Background Information 
Coronary artery calcium (CAC) is strongly associated with atherosclerotic burden and predicts 
coronary heart disease (CHD) events and mortality.  Progression of CAC has also been shown 
to independently be associated with increased CVD events and all-cause mortality. Warfarin has 
recently been shown to not only increase calcification, but markers of atherosclerotic plaque in 
both animals and humans. 
Rivaroxaban has been shown to reduce the risk of stroke significantly and to be non-inferior to 
warfarin.  However, the rate of myocardial infarction was 9% lower in the rivaroxaban group 
than in the warfarin group in the Rocket AF study, and similarly the myocardial infarction rate 
was 12% lower in the apixaban group in the Aristotle study, but the difference was not 
significant in either trial.    The potential of long term benefit by avoiding VKA therapy may be 
much greater for a CV event reduction.  The study proposed will evaluate markers of CAC 
progression and atherosclerosis development, including adverse plaque characteristics such as 
positive remodeling and stenosis severity, which have long term outcome data supporting that 
slowing these processes will be associated with lower CV events.   
 
CAC and Progression 
Multiple studies have been done to demonstrate the feasiblity of measuring CAC change at 12 
months. Initial studies suggested that treatment with statins was associated with slower 
progression of CAC. Callister et al.i studied 149 patients. Patients underwent a baseline and 
follow-up EBT scan at 12 months and serial LDL cholesterol measurements were obtained.  


4 
 
Progression of calcium volume score was seen in all untreated patients (n = 44; mean LDL 147 ± 
22 mg/dl) and averaged 52 ± 36% per year. In contrast, the mean yearly calcium volume score 
change for all treated patients (n = 105; mean LDL 114 ± 23 mg/dl) was 5 ± 28% (p < 0.001 vs. 
untreated patients). Among the treated patients, 65 individuals attained a LDL level <120 mg/dl 
(mean LDL 100 ± 17 mg/dl) and showed a net regression of their calcium volume score (-7 ± 
22%). In patients who received HMG-CoA reductase inhibitors but maintained an average LDL 
>120 mg/dl (mean LDL 139 ± 18 mg/dl), the mean yearly calcium volume score progression was 
25 ± 22%. Similar one year studies by Budoff et al.,ii and Achenbach et al.,iii showed that statin 
therapy is associated with slowing of progression of coronary calcium.  
The BELLES trialiv was a prospective randomized study of 615 postmenopausal and 
dyslipidemic women randomized after initial CAC scan to atorvastatin 80 mg/day or pravastatin 
40 mg/day. A second scan was repeated in 12 months. The attained mean LDL cholesterol level 
was significantly lower with atorvastatin (94 mg/dl) than pravastatin (129 mg/dl). Nonetheless, 
the median relative change in the calcium volume score was not different between the two 
treatment arms (15.1% and 14.3% for atorvastatin and pravastatin, respectively, p = NS). 
Another large scale clinical trial using CAC at one year intervals was the Treat-to-Goal Study—a 
randomized, multicenter clinical trial—comparing the calcium-free, non-absorbable polymer 
sevelamer to traditional calcium-based phosphate binders.v Study endpoints included serum 
levels of phosphorus, calcium, intact parathyroid hormone (PTH), and lipids, as well as change 
in calcification of the coronary arteries and thoracic aorta quantified by CT. Two hundred adult 
hemodialysis patients, who had received hemodialysis for a median of 3 years prior to study 
entry, were randomized in 15 medical centers in Europe and the United States. During the study 
period, phosphate binders were adjusted to maintain serum phosphorus levels between 3.0 and 
5.0 mg/dL, serum calcium levels between 8.5 and 10.5 mg/dL, and serum PTH levels between 
150 to 300 pg/mL. EBT was performed at the start of the study, and after 6 and 12 months of 
treatment. In spite of a similar control of serum phosphorus and calcium, coronary and aortic 
calcification progressed significantly in the calcium-treated patients while there was no 
statistically significant change from baseline in the sevelamer group. At one year follow-up, the 
median relative change in coronary and aorta scores were 25% and 28% and 6% and 5% in the 
calcium and sevelamer group, respectively (p = 0.02 for all intergroup comparisons).  
One recent study by Fitch et alvi evaluated a 12 month, randomized, placebo controlled 
trial to investigate lifestyle modification (LSM) and metformin, alone and in combination was 
conducted among HIVinfected patients with metabolic syndrome. The primary endpoint was 
change in CAC score. Fasting lipids, insulin and measures of cardiorespiratory fitness were 
assessed. 50 subjects (age 47 ± 1 yr) were randomized, 76% were male, 48% White, 30% 
African American, and 18% Hispanic. Metformin-treated subjects demonstrated significantly 
less progression of CAC over 12 months (-1 ± 2 vs. 33 ± 17, P=0.004), less progression in 
calcified plaque volume (-0.4 ± 1.9 vs. 27.6 ± 13.8 mm3, P=0.008), improved HOMA-IR (-0.1 ± 
0.4 vs. 1.1 ± 0.4, P=0.05) and RANKL/OPG ratio (-0.0002 ± 0.0002 vs. 0.0003 ± 0.0002, 
P=0.02) compared to placebo. Subjects randomized to LSM vs. no LSM showed significant 
improvement in HDL (3 ± 1 vs. -1 ± 1 mg/dl, P=0.03), and CRP (-1.57 ± 0.70 vs. 0.08 ± 0.45 


5 
 
mg/L, P=0.05). For CAC, the net effect of metformin (vs. placebo) controlling for LSM 
randomization was -42 and the net effect of LSM (vs. no LSM) controlling for metformin 
randomization was -24.  
Three randomized 1 year studies were performed by Budoff’s group, evaluating change in  CAC 
over 12 months in relatively small cohorts under the influence of different formulations of Aged 
Garlic Extract (AGE).  Budoff et al. (2004)vii showed that in 23 patients with known coronary 
artery disease (CAD) or high risk patients (Framingham Risk > 20% over 10 years), over one 
year, AGE reduced the progression of CAC compared to placebo (7.5 +/- 9.4% versus 22.2 +/-
18.5%, respectively) . Similarly, Budoff et al. (2009)viii showed significant results in 65 
intermediate risk patients (age 60 +/- 9 years) with Framingham risk of 10 – 20 % and baseline 
CAC > 30. In this study, AGE was administered with vitamin B12, folic acid, vitamin B6 and L-
arginine. In one year follow-up the CAC progression was significantly lower in the treatment 
group versus placebo (6.8% versus 26.5%, p = 0.005). Lastly, Zeb et al. (2012)ix enrolled 65 
asymptomatic intermediate risk (as defined by baseline CAC > 10) males, aged 55 +/- 6 years, 
and treated them with AGE plus co-enzyme Q10 (CoQ10) versus placebo. At 1 year, mean CAC 
progression was significantly lower in treatment group versus placebo (32 +/- 6 versus 58 +/- 8, 
p = 0.01).  
 
CAC and Events 
Coronary artery calcium (CAC) is strongly associated with atherosclerotic burden and predicts 
coronary heart disease (CHD) events and mortality (1-4). CAC scanning has been proposed as a 
measure to track CHD progression and the effects of risk factor modification on atherosclerosis 
(5-6).   Multiple studies suggests that CAC progression is associated with CHD events (7-8). 
Recently, follow-up based on a large registry of subjects receiving serial CT scans showed 
progression of CAC to be strongly associated with total mortality (9). We have previously 
demonstrated9 in a prospective evaluation of 4,609 patients that, after adjusting for baseline score, 
age, sex, and time between scans, CAC progression (mean progression was 247 in this group) was 
associated with a 3.34 fold risk of all-cause mortality (HR 3.34; 95% CI: 2.65 to 4.21; p < 0.0001).   
The MESA study also demonstrated that CAC progression was strongly associated with increased 
CV events(10), following 5682 persons over 7.6 years.  Among participants with baseline CAC, 
those with annual progression of >300 units had adjusted HR’s of 3.8 (1.5-9.6) for total and 6.3 
(1.9-21.5) for hard CHD compared to those without progression.   
 
Warfarin and CAC Progression. 
Vitamin K-antagonists (VKA) are the most widely used anti-thrombotic drugs with substantial 
efficacy in reducing risk of arterial and venous thrombosis. Several lines of evidence indicate, 
however, that VKA inhibit not only post-translational activation of vitamin K-dependent 
coagulation factors but also synthesis of functional extra-hepatic vitamin K-dependent proteins 
thereby eliciting undesired side-effects. Vascular calcification is one of the recently revealed 


6 
 
side-effects of VKA. Vascular calcification is an actively regulated process involving vascular 
cells and a number of vitamin K-dependent proteins. In experimental animal models as well as 
humans, VKA have been shown to promote medial elastocalcinosis. Mechanistic understanding 
of vascular calcification is essential to improve VKA-based treatments of both thrombotic 
disorders and atherosclerosis.  
Vascular calcification is a marker of increased cardiovascular morbidity and mortality.(11) 
Matrix Gla protein (MGP) is an important inhibitor of calcification.(12-15)  In animal studies, 
where carboxylation of MGP was blocked by vitamin K antagonists, excessive calcifications of 
the arteries were found.(16)  In humans, calcification of the coronary arteries (CAC) and heart 
valves is increased in patients on vitamin K antagonists, whereas intake of vitamin K is 
associated with less progression of CaC.(17-20) VKA use has been associated with increased 
vascular calcification, which may impart long term risk.  Several studies have demonstrated the 
contribution of VKA use to coronary artery calcification progression in AF patients. Rennenberg 
et al (21) selected 19 patients younger than 55 years who had no other cardiovascular risk factors 
and who had used coumarins for more than 10 years, and compared these to 18 matched healthy 
controls. The odds ratio for calcification in patients versus controls was 8.5 (95% confidence 
interval [CI] 2.01-35.95). Coumarin use and MGP were associated with calcification, even after 
adjusting for other risk factors. They concluded that long-term use of coumarins is associated 
with enhanced extracoronary vascular calcification, possibly through the inhibition of MGP 
carboxylation. 
A prospective study using coronary calcium scans (22) was performed in 157 AF patients 
without significant cardiovascular disease (108 males; mean age 57 ± 9 years). The duration of 
VKA treatment varied between 6 and 143 months (mean 46 months). No significant differences 
in clinical characteristics were found between patients on VKA treatment and non-anticoagulated 
patients. However, median coronary artery calcium scores differed significantly between patients 
without and patients with VKA treatment [0, inter-quartile range (IQR) 0-40, vs. 29, IQR 0-184; 
P = 0.001]. Mean coronary calcium scores increased with the duration of VKA use (no VKA: 53 
± 115, 6-60 months on VKA: 90 ± 167, and >60 months on VKA: 236 ± 278; P < 0.001). 
Multivariable logistic regression analysis revealed that age and VKA treatment were 
significantly related to increased coronary calcium score. Age and VKA treatment were 
independently related to increased coronary calcium score.  
As vascular calcification is considered an independent risk factor for plaque instability, 
Schurgers (23)  investigated the effect of VKA on coronary calcification in patients and on 
calcification of atherosclerotic plaques in the ApoE(-/-) model of atherosclerosis.  A total of 266 
patients (133 VKA users and 133 gender and Framingham Risk Score matched non-VKA users) 
underwent 64-slice MDCT to assess the degree of coronary artery disease (CAD). VKA-users 
developed significantly more calcified coronary plaques as compared to non-VKA users. ApoE(-
/-) mice (10 weeks) received a Western type diet (WTD) for 12 weeks, after which mice were fed 
a WTD supplemented with vitamin K(1) (VK(1), 1.5 mg/g) or vitamin K(1) and warfarin 
(VK(1)&W; 1.5 mg/g & 3.0 mg/g) for 1 or 4 weeks, after which mice were sacrificed. Warfarin 
significantly increased frequency and extent of vascular calcification. Also, plaque calcification 
comprised microcalcification of the intimal layer. Furthermore, warfarin treatment decreased 


7 
 
plaque expression of calcification regulatory protein carboxylated matrix Gla-protein, increased 
apoptosis and, surprisingly outward plaque remodeling. 
 
In this study, VKA use was associated with coronary artery plaque calcification in patients with 
suspected CAD and causes changes in plaque morphology with features of plaque vulnerability 
in ApoE(-/-) mice. These findings underscore the need for alternative anticoagulants that do not 
interfere with the vitamin K cycle. 
 
Rate of Progression of CAC 
 
Almost all randomized studies of coronary artery calcification progression were 1 year duration.   
Annualized studies have been performed with statins, ACE inhibitors, calcium channel blockers, 
garlic therapy, phosphate binders among others, all studies with 1 year duration.    
 
Relationship of Coronary Artery Calcium and Unstable Plaque 
 
The exact contribution of coronary artery calcification to the stability of atherosclerotic plaques 
is not clearly defined. Some studies describe that plaque calcification initially destabilizes a 
plaque by providing areas of interface between high- and low density where a plaque is more 
prone to rupture.(24) Plaques may also rupture because of physical stress exerted by calcified 
nodules.(25,26)  However, calcification may also represent beneficial scaffolding which could be 
seen as protective by strengthening atherosclerotic plaque prone to rupture. But still then 
enhancing the process of calcification by VKA may promote vasomotor dysfunction in the 
coronary arterial tree.  
 
Rivaroxaban 
 
Rivaroxaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of 
stroke in a similar population in comparison with warfarin. The rate of myocardial infarction was 
9% lower in the rivaroxaban group than in the warfarin group inthe Rocket AF study and 
similarly the myocardial infarction rate was 12% lower in the apixaban group in Aristotle, but 
the difference was not significant in either trial.  The potential of long term benefit by avoiding 
VKA therapy may be much greater for a CV event reduction.  The study proposed will evaluate 
markers of CAC progression and atherosclerosis development, which have long term outcome 
data supporting that slowing these processes will be associated with lower CV events.   
 
CCTA 
C- Coronary Plaque Volume/Composition via Computed Tomography Angiography:  (0 and 52 
weeks) 
Coronary plaque volume/composition will be measured using multi-detector computed 
tomography. Recent studies demonstrated the computed tomography angiography can accurate 
measure plaque characteristics including volume and composition with high reproducibility. 
Furthermore, they provide evidence that CT angiography is feasible and diagnostic utilizing 
radiation doses as low as 2 mSv without compromise of image quality, potentially removing one 
of the biggest barriers to more wide spread implementation of cardiac CT and empowers serial 
coronary plaque volume assessment with CT angiography (figure 1). 


8 
 
Multislice computed tomography is a non-invasive technique that can easily detect CAD at its 
earliest stages reflected by the presence and severity of coronary artery calcification.  Minor 
lesions in the main coronary arteries could be a sign of advanced vascular disease in the 
microvasculature which may lead to important ischaemia, possibly even influencing the AF 
substrate. A recent meta-analysis among 30 prospective studies revealed that the presence of 
calcifications is associated with a three- to four-fold higher risk for mortality and cardiovascular 
events.(27) 
CCTA is a novel non-invasive imaging test with high diagnostic performance for 
detection and quantification of anatomic stenosis compared to invasive coronary angiography 
(ICA) and intravascular ultrasound (IVUS).  Beyond stenosis severity, CCTA also permits 
anatomic quantification of numerous other atherosclerotic plaque characteristics (APCs) (28, 29).  
These APCs include additional measures of stenosis severity (% diameter stenosis, % area 
stenosis, minimum luminal diameter [MLD], minimum luminal area [MLA]), plaque 
composition (non-calcified, calcified, “mixed”; lowest attenuation density; “spotty” 
calcification); plaque remodeling (positive, negative, intermediate), plaque burden (volume); and 
plaque location (proximal versus distal; relation to bifurcation). APCs have been described—
both by intravascular methods and in studies with CCTA—to exhibit clinical import for plaque 
stability; and permit discrimination of patients experiencing stable angina versus acute coronary 
syndromes. We have performed and reported investigations demonstrating the unique value of 
plaque composition, low attenuation plaque, and coronary arterial remodeling for the 
identification of patients that exhibit myocardial ischemia and adverse cardiovascular outcome.  
Further, we have published several papers related to the diagnostic performance of CCTA 
for volumetric quantification of coronary artery plaque volume, composition and other APCs; as 
well as has determined the utility of automated computational-based methods for coronary artery 
plaque characterization and quantification (30,32). To determine reliability of CT APC 
evaluation, we identified a high diagnostic accuracy of measured plaque volume by CCTA 
versus IVUS in 36 patients. In a separate study of 30 patients who underwent 2 CT scans within 
200 days the number of plaques, and measured total, calcified plaque (CP) and non-calcified 
plaque (NCP) volume. Intra-, inter-, and inter-scan agreement for segments with no plaque was 
100%. Intraobserver-interscan correlations of total, CP, and NCP volumes (r=0.93-0.97, p<0.001 
for all), as well as interobserver-interscan correlations were also very good (r=0.81-0.96, P 
values<0.001).   
To enhance CT APC evaluation efficiency, reliability and accuracy, our team has developed 
the first automated computer software algorithm (AutoPlaq) validated against IVUS that enables 


9 
 
accurate and rapid quantification of NCP and CP from CT. In 20 patients undergoing CT and 
IVUS, the software demonstrated excellent correlation to IVUS for NCP (r=0.94, p<0.001) and 
expert core lab measures for plaque volume (r=0.92, p<0.001), with no significant mean 
differences. Importantly, diagnostic time for the automated method was <10% of manual 
measurements.  Reliability of the automated method was high compared to expert readers for CP 
and NCP volumes (R=0.88 and 0.94, p<0.001 for both) and plaque composition (R=0.90, 
p<0.0001). Our results are in keeping with a recent meta-analysis demonstrating high correlation 
of CT versus IVUS for cross-sectional area, plaque area, area stenosis, and volume. We have 
further corroborated these findings—and have demonstrated the robustness of CCTA (both by 
manual as well as automated methods—for the volumetric quantification of coronary 
atherosclerosis and arterial wall features. 
To date, however, the longitudinal changes of coronary artery and plaque 
characteristics—particularly as they relate to warfarin use—has not been examined.  This 
proposal encourages a comprehensive approach to identifying all aspects of coronary 
atherosclerosis progression related to medications that are vital to prevent strokes in persons with 
afib.  These CT measures are active in the coronary artery disease pathway, providing 
quantitative measures of not only luminal stenosis severity, but plaque volume, plaque 
composition, plaque distribution, plaque length, and arterial remodeling.  This proposal will 
significantly extend prior studies performed by our laboratory and others by examining the 
nature of coronary atherosclerosis progression, regression and stabilization under the influence of 
two different therapies.  The feasibility and practicability of this study is rooted in the 
longstanding collaboration of investigators with unparalleled expertise, as well as the numerous 
preliminary studies performed at the investigators’ institution.   
Study Rationale 
The OVERALL HYPOTHESIS of this study is that use of rivaroxaban will slow 
progression of vascular calcification and coronary atherosclerosis as compared to warfarin 
therapy in patients with AFIB.  
Study Objectives 
Objective 1: To demonstrate if treatment with rivaroxaban therapy, as compared to warfarin 
therapy, will slow the progression of calcified plaque, based upon the CAC score.   
Objective 2:  To evaluate if treatment with rivaroxaban therapy, as compared to warfarin therapy, 
will modify the progression, regression and stabilization of coronary atherosclerosis.  
Modifications will include differences in plaque volume, composition and arterial remodeling; as 
well as new atherosclerosis formation. 
 
3. ETHICAL CONSIDERATIONS 
 
The Investigator will follow all appropriate requirements, including Good Clinical Practice (GCP), 
International Conference on Harmonization (ICH), Code of Federal Regulations (CFR). 
The study will be conducted by qualified personnel and be approved by the local. IRB/IEC. 


10 
 
 
4. INVESTIGATIONAL PLAN AND STUDY DESIGN 
We propose a randomized, open label trial, to compare Rivaroxaban 20 mg oral once daily with 
food to warfarin (target international normalized ratio, 2.0 to 3.0) in patients with non-valvular 
atrial fibrillation. The primary endpoint will be CAC progression and key secondary objectives 
will be progression of total plaque, and development of new vulnerable plaques.  Patients will be 
educated to maintain a low cholesterol diet through education to patients as well as medication 
compliance. 
 
Study Design: 
a. Design. The study will be a single-center, randomized, open label comparison of Rivaroxaban 
20 mg once daily with food compared to warfarin therapy (INR target 2-3) for 52 weeks on 
coronary calcium, coronary plaque composition and volume.  One hundred ten eligible subjects 
will be enrolled using a 1:1 ratio.  The sample size in this study is based on exploratory 
considerations. 
b. Randomization and Stratification. Subjects who meet the eligibility criteria will be randomly 
assigned to receive rivaroxaban or warfarin 
c. Endpoint Measures 
Primary - Rate of change in coronary calcium 
2.Secondary Endpoints 
1. To assess incident plaque rates and quantitative changes in different plaque types in 
patients randomized to warfarin vs. rivaroxaban using CTA, 12 months after an initial 
evaluation. 
2. Evaluation of plaque progression rates and incident plaque rates in subjects treated with 
warfarin vs. rivaroxaban. In that context, we will: 
a. determine whether subjects treated with rivaroxaban display slower rates of 
progression compared to warfarin treated subjects, after control for all CV risk 
factors and demographics 
 
The study design calls for the enrollment of 120 eligible subjects of diverse ethnic population.  
Given dropout rate, at least 100 patients should be available for final analysis at the conclusion 
of 52 week follow-up.  Baseline examination will include the results of their demographic, 
coronary risk factor, lab tests, coronary calcium, as well as coronary plaque volume/composition. 
All participants will be educated on a low-cholesterol diet at entry to the study.  Baseline 
information regarding risk factors for atherosclerotic cardiovascular disease (cigarette smoking 
status, systemic hypertension, family history of premature atherosclerosis, menopausal and 
hormone replacement status in women, sedentary lifestyle, current medications, chest pain 
questionnaire and measures of obesity) will be determined.  After randomization, participants 
will return quarterly (3, 6, 9 and 12 months to assess compliance with medication, and receive an 
additional supply of medicine. At 52 weeks follow up, coronary calcium and coronary plaque 
volume/composition will be measured by readers blinded to the randomization and clinical 
activities, who are not aware of study-group assignments 
 
 


11 
 
Patient Recruitment: 
Eligible patients will have atrial fibrillation at enrollment or two or more episodes of atrial 
fibrillation, as documented by electrocardiography, at least 2 weeks apart in the 12 months 
before enrollment.  
Patients randomized to warfarin will continue their monthly study visits focusing on control of 
the INR to warfarin clinic, and research study visits every 3 months to include an assessment of 
clinical outcomes and adverse events. For any patient who is lost to follow-up or withdraws 
consent, attempts will be made to determine vital status at the end of the trial. 
 
TIMELINE:Recruitment will take place over 6 months, follow up for the next 12 months and 
closeout for 3 months.  Entire study duration will conclude in less than 2 years. 
 
 
 
 
 
Day 
 
What you do 
Day 1 
 
You will have routine blood tests done and check your kidney function if needed. 
 
You will have a CT scan (without contrast), and a CT angiogram (with contrast) (If you are a 
female who is able to have children, you will have a urine pregnancy test done before these 
tests.) 
 
For Group 1, continue taking warfarin. 
Patient Population:
120 eligible patients to be 
recruited from Harbor UCLA 
warfarin clinic 
Recruitment Rate: 
120 patients in 1 yr , 
(25 subjects per quarter or 
6 - 7 subjects per week)
Observation Period Tests: 
Lab tests, H&P by MD,
 
 
and computed 
tomography angiography 
(once at baseline)
Group A:  (n=60)
Warfarin
Once Daily as per warfarin clinic 
management
Group B: ( n=60) 
Rivaroxaban 
 20 mg po q day 
 
With food
 
 
 
Post -Intervention
Period (4 weeks)
100 patients are 
expected to complete
the intervention period.
Post - Trial Period 
Tests :
Lab tests,
 computed
tomography
angiography
Long - term follow- up: 
Up to 12 months for 
hospitalization, and 
CV events
Safety & Tolerance monitoring; per visit H& P
4 weeks 
52 weeks, quarterly visits
4 weeks 
Intervention Period  (52weeks):120 patients
Randomize 60 eligible patients into 2 equal groups
Figure 2.


12 
 
 
For Group 2, begin taking assigned study drug once a day for the next 12 months. Keep 
taking until the end of study, unless told to stop by the study doctor or his staff. 
3 Months 
 
For Group 2, get new supply of study drug 
 
For both groups, we will ask you about changes in your health and medications and about visits 
to the doctor, emergency room or other outpatient clinic (for example, urgent care center). 
6 Months 
 
For Group 2, get a new supply of study drug 
 
For both groups, we will take blood for routine blood tests. 
 
For both groups, we will asked you about changes in your health and medications and about 
visits to the doctor, emergency room or other outpatient clinic (for example, urgent care center). 
9 Months 
 
For Group 2, get new supply of study drug 
 
For both groups, we will ask you about changes in your health and medications and about visits 
to the doctor, emergency room or other outpatient clinic (for example, urgent care center).  
12 Months 
 
We will take blood for routine blood tests, 
 
You will undergo a CT scan (without contrast) and CT angiogram (CT scan with contrast). (If you 
are a female who is able to have children, you will have a urine pregnancy test done before these 
tests.) 
 
You are done – the study is complete. 
 
 
 
Study Endpoints 
Events will be recorded.  Stroke will be defined as a focal neurologic deficit, from a 
nontraumatic cause, lasting at least 24 hours and categorized as ischemic (with or without 
hemorrhagic transformation), hemorrhagic, or of uncertain type (in the case of patients who do 
not undergo brain imaging or in whom an autopsy is not performed).  The rate of myocardial 
infarction, hospitalization for angina and revascularization will be recorded. The primary safety 
outcome will be major bleeding, defined, according to the ISTH criteria, as clinically overt 
bleeding accompanied by a decrease in the hemoglobin level of at least 2 g per deciliter or 
transfusion of at least 2 units of packed red cells, occurring at a critical site, or resulting in death. 
Additional safety outcome will be clinically relevant nonmajor bleeding, defined as clinically 
overt bleeding that does not satisfy the criteria for major bleeding and that led to hospital 
admission, physician-guided medical or surgical treatment, or a change in antithrombotic 
therapy. Other safety measures will include any bleeding, other adverse events, and liver-
function abnormalities. 
The primary and secondary efficacy and safety measures will be adjudicated on the basis of 
prespecified criteria by a clinical-events committee whose members will be blinded to the study-
group assignments. 
 
B.  Laboratory Measurements (0 , 6 and 12 months) 
 
All participants will be instructed to abstain from smoking, alcohol, and food intake, eg, 
overnight fasting or at least 10 hours before sample drawing. Venous blood samples of all patients 
will be drawn after admission in a fasting state. Routine blood specimens will be shipped to our 


13 
 
central clinical laboratory to be measure uniformly in a highly standardized center.  Blood samples, 
including CBC, Matrix Gla protein, and INR will be assessed at every visit. 
Cardiac multislice computed tomography data acquisition and analysis 
In all patients, a prospective non-enhanced coronary calcium scan will be performed with a 64-
slice MSCT scanner (GE 64; GE Healthcare, Milwaukee, WI). For quantitative assessment of 
coronary artery calcification, the Agatston score will be calculated, using a 3 mm CT slice 
thickness and a detection threshold of ≥130 HU involving ≥1 mm2 area/lesion (3 pixels). 
Cardiac CT angiography will be performed using a collimation of 64 × 0.625 mm and a rotation 
time of 0.4 s. The tube current will be 400–770 mA (depending on body weight), at 100-120 kV. 
Contrast material at a flow rate of 5.0 mL/s was administered in the antecubital vein, with 
volumes depending on the total scan time (60–80 mL). In the absence of contraindications, 
patients with a heart rate ≥60 b.p.m. will be administered 50–100 mg metoprolol oral and up to 
40 mg metoprolol intravenous.  Interpretation will be by expert reading by an experienced 
cardiologist and a radiologist blinded to all clinical data. Image analysis will be performed on 
dedicated workstations for post-processing and evaluation. 
 
5. ELIGIBILITY-INCLUSION/EXCLUSION 
Key Inclusion Criteria: 
1. 
Eligible patients with atrial fibrillation at enrollment or two or more episodes of 
atrial fibrillation or flutter, as documented by electrocardiography, at least 2 weeks apart in the 
12 months before enrollment 
2. 
Age 18-84 
3. 
On anticoagulation for 6 months prior to enrollment at a stable dose. 
4. 
Willingness to participate in the study and ability to sign informed consent 
5. 
Minimum CAC score of 10 
 
Key Exclusion Criteria: 
1. Atrial fibrillation due to a reversible cause, moderate or severe mitral stenosis, or conditions 
other than atrial fibrillation that require anticoagulation (e.g., a prosthetic heart valve)  
2. 
Prior rivaroxaban use. 
3. 
A need for aspirin at a dose of >165 mg a day or for both aspirin and clopidogrel,  
4. 
Renal insufficiency (serum creatinine level of 12.5 mg per deciliter or calculated 
creatinine clearance of <50 ml per minute). 
5. Serious bleeding event in the previous 6 months or a high risk of bleeding (eg, active peptic 
ulcer disease, a platelet count of <100,000/mm3 or hemoglobin level of <10 g/dL, stroke 
within the previous 10 days, documented hemorrhagic tendencies, or blood dyscrasias) 
6. 
Weight in excess of 325 pounds 
7. 
Resting hypotension (systolic blood pressure of <90mmHg) or resting hypertension 
(systolic blood pressure of >170mmHg or diastolic blood pressure of >110 mmHg). 
8. 
History of active malignancy requiring concurrent chemotherapy. 
9. 
Any unstable medical, psychiatric, or substance abuse disorder that in the opinion of the 
principal investigator is likely to affect the subject’s ability to complete the study. 
10. 
Known allergy to iodinated contrast material 


14 
 
11. 
Pregnancy or breast feeding 
 
 
6. TREATMENT 
 
Patients will be randomized to either stay on warfarin at current doses, managed by the warfarin 
clinic at Harbor-UCLA with target INR of 2-3 and come in for quarterly visits with INR checks 
and documented safety; or Rivaroxaban 20 mg once daily. 
7. PRODUCT INFORMATION 
Drug ordering and accountability: 
Janssen is supplying study drug, and will provide enough medication for the entire study to the 
research pharmacy. The Research Pharmacy at Los Angeles Biomedical Research Institute will be 
responsible for packaging and distributing the medications.  
The research pharmacy will be responsible for ensuring that the investigational product is stored 
under the appropriate environmental conditions (temperature, light, and humidity). 
 
Product Description and Dosage Form 


15 
 
SAMPLE PRODUCT INFORMATION TABLE: 
Administration and handling 
Important Food Effect Information 
The 15 mg and 20 mg XARELTO tablets should be taken with food.  In the nonvalvular atrial 
fibrillation efficacy study XARELTO was taken with the evening meal. 
 
For those randomized to Xarelto from Warfarin: 
From warfarin to XARELTO, discontinue warfarin and start XARELTO as soon as the 
International Normalized Ratio (INR) is below 3.0 to avoid periods of inadequate 
anticoagulation. 
.. 
Dosing in Nonvalvular Atrial Fibrillation 
 
For patients with creatinine clearance (CrCl) >50 mL/min, the recommended dose of XARELTO 
is 20 mg taken orally once daily with the evening meal. For patients with CrCl 15 to 50 mL/min, 
the recommended dose is 15 mg once daily with the evening meal 
 
In case of Missed Dose 
If a dose of XARELTO is not taken at the scheduled time, administer the dose as soon as 
possible on the same day as follows: 
• For patients receiving 20 mg or 15 mg once daily: The patient should take the missed 
XARELTO dose immediately. 
 
At Study Conclusion (for those randomized to Xarelto: 
Switching from XARELTO to Warfarin - No clinical trial data are available to guide converting 
patients from XARELTO to warfarin. XARELTO affects INR, so INR measurements made 
during coadministration with warfarin may not be useful for determining the appropriate dose of 
warfarin. Our approach will be to discontinue XARELTO and begin both a parenteral 
anticoagulant and warfarin at the time the next dose of XARELTO would have been taken 
 
Product Description: 
Product 
Description 
and Dosage 
Form 
Potency 
Primary 
Packagin
g 
(Label 
Type 
 
Appearance 
Storage 
Conditions 
(per label) 
Rivaroxaban 
pill 
20 mg 
30 per 
bottle 
 
pills 
15-25ºC 


16 
 
8. STUDY ASSESSMENTS AND PROCEDURES 
8.1 Standard Safety Laboratory Panel 
Hematology 
• Hemoglobin 
• Hematocrit 
• Red blood cell count 
• White blood cell count and differential 
• Platelet count 
Serum chemistry 
• Aspartate Aminotransferase (AST, SGOT) 
• Alanine Aminotransferase (ALT, SGPT) 
• Alkaline Phosphatase (reflex to GGTP) 
• Creatine Kinase (Creatine Phosphokinase) (CK) (CPK) (reflex to troponin) 
• Total Bilirubin 
• Uric Acid 
• Blood Urea Nitrogen (BUN) 
• Electrolytes - sodium, potassium, chloride, Total Protein, Albumin 
• Serum Creatinine (Scr) 
 
EGFR will be estimated by the method of Cockroft-Gault: 
Cockcroft-Gault CrCl = (140-age) * (Wt in kg) * (0.85 if female) / (72 * Cr) 
The eGFR is expressed in mL/min/1.73m2 
 
• Females only: urine HCG pregnancy test (HCG minimum sensitivity of 25 IU/L). If 
a urine HCG test is positive, patient will be excluded 
 
Data to be Collected:  Routine demographic and cardiovascular clinical data have been 
collected for all patients in the study.  For CAC, we will collect Agatston and Volume scores, 
number of lesions and density for each plaque.  For CCTA-specific variables, we will quantify 
and characterize the following APCs by both manual and automated plaque characterization 
methods: 
 Coronary artery plaque volume 
 Non-calcified plaque volume 
 Calcified plaque volume 
 Plaque location 
 Plaque length 
 Plaque distribution 
 Arterial remodeling 
 Low attenuation plaque (Hounsfield unit density <30 HU) 
 Spotty calcifications 
 
 
2b1a.Overview: In a single session at baseline and followup, after phlebotomy and physical 
examination, each subject will receive sequential non-contrast followed by contrast scans.  The 
entire scanning procedure will take approximately 30 minutes. 


17 
 
Screening. Subjects will be screened for contraindications for beta-blockers and nitroglycerin 
(PDE5 inhibitors).  The desired heart rate for adequate image quality is ≤ 70 bpm. If the heart 
rate is above this level, a beta-blocker will be prescribed.  If a beta blocker is contraindicated, a 
calcium channel blocker will be given instead. 
2b1b.Noncontrast scan: This will be performed to measure CAC. Patients will be positioned 
within the scanner with ECG leads, and a rhythm strip will be viewed.  After a scout film is 
obtained, standard calcium scoring imaging will be performed at the end of inspiration. 
2b1c.Contrast Scan. One minute prior to the CT angiogram acquisition, sublingual nitroglycerin 
will be administered.  Iodinated X-ray contrast will then be injected.  When significant heart rate 
variability exists, retrospective imaging will be utilized.  Breath hold acquisition will be 
performed over approximately 20 seconds.  After the study, patients will be observed for at least 
10 minutes. 
2b1d.Image reconstruction: Cross-sectional cardiac CT images will be reconstructed using 
prospective ECG triggering from 65 to 85% by 5% increments, and transmitted to the reading 
site.   
2b1e.Reading Center: The Reading Center for CTA will be based at our Academic-based 
Medical facility. The Center will coordinate and oversee the collection of the data, store backup 
copies of the data, read each scan, send the results to the DCC and maintain quality control. 
2b2.Coronary Artery Calcification (CAC) 
CAC will be calculated from the non-contrast images using standard methods and scores will be 
reported using the Agatston method as elsewhere described (33).  A total CAC score will be 
determined by summing the individual lesion scores from each of 4 anatomic sites (left main, left 
anterior descending, circumflex, and right coronary). A volume score, independent of density, is 
also calculated using a standard algorithm. A single experienced reader, blinded to subject 
identity and randomization, will interpret all the scans using commercially available software. 
 
2b3. CT Angiography (CTA) 
2b3a.Imaging Analysis. The resulting thin CT sections will be transferred to a dedicated 
workstation for image analysis. Images will be post-processed in an independent workstation 
(GE Advanced Workstation®) by the reader independently, during a dynamic reading process. 
Curved maximum intensity projection (MIP) multiplanar reconstructions will be performed for 
each coronary artery segment at the end-diastolic frame or the frame with the least motion 
artifact. Based on the curved MIP, the reader will identify an area of abnormality and determine 
the point of minimum luminal diameter within the abnormal area. Multiplanar reformatting will 
also be used to generate cross-sectional images of coronary segments using semiautomated 
software (AW 4.6, GE Healthcare, Milwaukee WI). This yields a vessel centerline using the full-
width-half-maximum standard method to delineate the contrast-filled vessel, as well as automatic 
maximum and minimum diameters at any cross-section along the vessel centerline. A cross-
sectional 5mm MIP image will be reconstructed at this location and semi-automatic software will 
be used to outline the intimal surface providing cross-sectional vessel area. In cases where 
coronary segments are normal, the most proximal cross-sectional image will be used for analysis. 
CT values will be measured in the most visible images such as axial source or multiplanar 
images of the long axis at each site of the coronary arteries. For determining image quality, both 
qualitative and quantitative analysis will be performed. Each segment will be classified as poor, 
acceptable, good or excellent quality regarding the presence of motion artifact, which is defined 
as any discontinuation or blurring of the sharply defined vessel contour. 


18 
 
2b3b.Plaque evaluation. Plaque will be evaluated from both axial source images and multiplanar 
reconstruction images of the long axis at each site of the coronary arteries. CP will be defined as 
any structure with a density greater than the contrast-enhanced lumen that could be visualized 
separately from the lumen, which could be assigned to the coronary artery wall, and that could be 
identified in at least two independent planes. NCP will be defined as any discernible structure 
that could be clearly assignable to the vessel wall, which had a CT density less than the contrast-
enhanced coronary lumen but greater than the surrounding connective tissue, and that could be 
identified in at least two independent planes (1). Each coronary segment (15 AHA standardized 
coronary segments) will be classified as either normal, containing NCP, containing MP with 
either predominantly NCP (<50% of plaque area occupied by calcium) or containing CP. 
Reviewer will independently evaluate the contrast-enhanced scans by assessment of the axial 
slices of multiplanar reformations and of three thin-slab maximum intensity projections. 
Percentage of coronary arterial stenosis will be estimated on a cross-sectional image obtained 
from reconstruction of standardized coronary segments. Stenosis will be evaluated in a scale of 
0-4: 0 (normal segment without stenosis or plaque present), 1 (1% to 29% stenosis), 2 (30% to 
49% stenosis), 3 (50-69% stenosis), and 4 (≥70% stenosis). Segments with diameter <1.5 mm 
will be graded as small and therefore unable to evaluate for stenosis. Segment Stenosis Score” 
(SSS) will be determined by summing the number of evaluable coronary segments with 
individual stenosis scores (maximum score = 60 (score of 4 for all 15 segments). 
2b3c.Plaque Composition. The presence of noncalcified atherosclerotic plaque tissue will be 
defined as any discernible structure in the coronary artery wall with a CT density less than the 
contrast enhanced coronary lumen but greater than the surrounding connective tissue. 
Measurements will be obtained from manually traced regions of interests encompassing the 
noncalcified plaque proportions.  
2b3d.Plaque Quantification.  The calculation of the coronary plaque burden and volume will be 
performed on axial cross sectional images in a blinded fashion. The plaque area of each coronary 
plaque visualized in at least 2 adjacent slices (reconstructed slice thickness 0.6 mm) will be 
determined on all affected slices, and plaque volume will be assessed by multiplying the area by 
the slice thickness.  Summing the total plaque per segment will be done, and compared with the 
subsequent scan in a blinded manner. Plaque burden will be reported in both a semi-quantitative 
and a quantitative (volumetric) manner; a plaque burden score will be developed to semi-
quantitate the plaque in each participant.  The AHA 15 segment model of the coronary arteries 
and visual semi-quantification of coronary artery calcific and non-calcific plaque will be used. 
Each plaque will be multiplied by 1 for small plaque volume, 2 for medium plaque volume and 3 
for large plaque volume.  “Plaque Burden Score” (PBS) will be determined by summing the 
number of evaluable coronary segments with individual plaque scores (maximum score = 45 
(score of 3 for all 15 segments).  The “Percent Plaque Score” (%PS) will be calculated by 
(number of segments with plaque / total number of evaluable segments) x 100.  Both plaque 
burden score and percent plaque score will be evaluated as independent variables and compared 
to other measures in the study, as aforementioned. The protocol for quantitative plaque 
assessment (volume, in mm3) is fully described elsewhere (2). For each lesion identified, 
minimal lumen diameter and minimal lumen area will be determined as elsewhere described.   
 
9.   RISK OF RIVAROXABAN 
Potential Discomforts, Side Effects, and Risks Associated with Rivaroxaban 


19 
 
 
The following terms are used to describe how often side effects have been seen in patients: 
 Very common:   it affects 1 in 10 or more subjects (10% or more) 
 Common:   it affects between 1 and 10 in 100 subjects (between 1% and 10%) 
 Uncommon:   affects between 1 and 10 in 1,000 subjects (between 0.1% and 1%) 
 Rare:   it affects between 1 and 10 in 10,000 subjects (less than 0.1%) 
 
COMMON: Seen in 1% (1 in 100 people) to 10% (1 in 10 people) 
 Internal bleedings which may occur in stomach and intestines may result in a low blood 
count (anemia) or decrease in blood pressure (hypotension). Other common bleeding sites 
include eye bleeds, bleeding from gums, nose bleeds, dark urine, heavy menstrual 
bleedings, hematomas (collection of blood) on the skin and small bleeds under the skin, 
coughing up blood, bleedings from wounds and after surgical procedures. 
 Abdominal and stomach pains  
 Upset stomach  
 Nausea 
 Constipation  
 Diarrhea 
 Vomiting 
 Fever  
 Swelling (edema; swelling caused by a fluid build-up in the body) 
 Decreased general strength and energy 
 Bruises 
 Some enzyme levels in blood may increase (such as liver enzymes called transaminases) 
 Pain in limbs (arm or leg pain) 
 Dizziness (feeling dizzy) 
 Headache  
 
 Kidney problems* 
 Itching 
 Rash (skin rash) 
 
UNCOMMON:  Seen in 0.1 % (1 in 1,000 people) to 1% (1 in 100 people): 
 Increased platelet count (increased number of platelets in your blood) 
 Increase heart rate 
 Dry mouth 
 Feeling unwell 
 Allergic reactions and skin allergic reactions, like swelling of your face, skin or your 
limbs (angioedema, allergic edema) 
 Wound oozing 


20 
 
 Some enzyme levels in blood may increase (i.e. lipase, amylase, alkaline phosphatase, 
lactate dehydrogenase, gamma-glutamyl transpeptidase and bilirubin) 
 Bleeding into your joints (Intraarticular bleeding or Hemarthrosis) 
 Brain bleeding or intracranial bleeding (especially in patients with high blood pressure 
and the elderly) 
 Fainting (syncope) 
 Hives (urticaria) 
 
RARE: Seen in less than 0.1% (less than 1 in 1,000 people): 
 Localized swelling  
 Yellow skin (jaundice; liver problems that causes yellowing of the skin or eyes) 
 Blood collection outside an arterial wall (vascular pseudoaneurysm) 
 Elevation of bilirubin in the blood (break down blood product), with or without an 
elevation of a liver enzyme called alanine aminotransferase  
 Hematomas (collection of blood) or bleeds in the muscle tissue  
 
*this was observed after major orthopedic surgery of the lower limbs 
 
10. ADVERSE EVENT REPORTING 
 
I. 
Definitions 
a. Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a clinical study subject administered 
a medicinal (investigational or non-investigational) product. An adverse event does not 
necessarily have a causal relationship with the treatment. An adverse event can therefore be 
any unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational or non- investigational) 
product, whether or not related to that medicinal (investigational or non-investigational) 
product. (Definition per International Conference on Harmonisation [ICH]). 
This includes any occurrence that is new in onset or aggravated in severity or frequency from 
the baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
 
b. Adverse Events of Special Interest  
Events that Janssen Scientific Affairs is actively monitoring as a result of a previously 
identified signal (even if non-serious).   


21 
 
The following are considered as events of special interest, and should be reported as a serious 
AE:  
  Suspected severe toxic effect on the bone marrow, such as severe thrombocytopenia 
(platelet count less than 50,000/μL), severe neutropenia (white blood cell count less than 
500/μL), pancytopenia, aplastic anemia  
  Suspected severe hypersensitivity reaction (eg, anaphylaxis, angioedema, severe 
urticaria, bronchospasm, etc.)  
  Severe skin reactions such as Stevens-Johnson Syndrome  
  Suspected severe liver injury 
 
c. Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory reporting 
requirements. 
 an identifiable subject (not disclosing the subject’s name and address) 
 an identifiable reporter (investigational site) 
 a Janssen medicinal product 
 an adverse event, outcome, or certain special situation 
      
     The minimum information required is: 
 suspected Janssen product (doses, indication) 
 date of therapy (start and end date, if available) 
 batch or lot number, if available 
 subject details (subject ID and country) 
 gender 
 age at AE onset 
 reporter ID 
 adverse event detail (AE verbatim in English), onset date, relatedness, causality, action 
taken, outcome, (if available) 
 Janssen protocol ID 
 
 
 
d. Product Quality Complaint (PQC) 
A product quality compliant is related to a potential quality issue during manufacturing, 
packaging, release testing, stability monitoring, dose preparation, storage or distribution of 
the product, or delivery system.  Not all PQCs involve a subject.  Lot and batch numbers are 
of high significance and need to be collected whenever available. 
 
Examples of PQC include but not limited to: 
 Functional Problem: e.g., altered delivery rate in a controlled release product 
 Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
 Potential Dosing Device Malfunction: e.g.,  autoinjector button not working, needle 
detaching from syringe 


22 
 
 Suspected Contamination 
 Suspected Counterfeit. 
 
e. Serious Adverse Event (SAE) 
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at any dose: 
 
 
Results in death 
 
Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe.) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is a suspected transmission of any infectious agent via a medicinal product 
 
Is medically important* 
 
*Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in other situations, such as important medical events that may 
not be immediately life threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should usually be considered serious. 
 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS 
ADVERSE EVENT. 
 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the 
hospitalization that is the serious event for which details must be provided. 
 
Any event requiring in-patient hospital admission (or the prolongation of hospitalization) 
must be reported as an SAE. Events that do not meet the criteria for SAE reporting are: 
 Reasons described in the Protocol, e.g. drug administration, Protocol-required 
testing 
 Social reasons, e.g. overnight stay because of distance between home and hospital 
 Surgery or procedure planned and documented prior to entry into the Study. 
 
Any event requiring hospitalization or prolongation of hospitalization that occurs during the 
study must be reported as a serious adverse event, except hospitalizations for the following: 
 Hospitalizations not intended to treat an acute illness or adverse event (e.g., social 
reasons such as pending placement in long-term care facility) 
 Surgery or procedure planned before entry into the study. [Note: Hospitalizations 
that were planned before the start of data collection and where the underlying 
condition for which the hospitalization was planned has not worsened will not be 


23 
 
considered serious adverse events. Any adverse event that results in a 
prolongation of the originally planned hospitalization is to be reported as a new 
serious adverse event.] 
 
The cause of death of a subject in a study within 30 days of the last dose of study drug, 
whether or not the event is expected or associated with the study drug, is considered a 
serious adverse event. 
 
f. Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An adverse event is considered unlisted if the nature or severity is not consistent with the 
applicable product reference safety information. For a medicinal product(s) with a marketing 
authorization, the expectedness of an adverse event will be determined by whether or not it is 
listed in the applicable product information. 
 
II. 
Special Situations  
Safety events of interest for a Janssen medicinal product that require expediting reporting 
and/or safety evaluation include, but are not limited to: 
 Drug exposure during pregnancy (maternal and paternal) 
 Overdose of a Janssen medicinal product  
 Exposure to a Janssen medicinal product from breastfeeding  
 Suspected abuse/misuse of a Janssen medicinal product 
 Inadvertent or accidental exposure to a Janssen medicinal product  
 Any failure of expected pharmacological action (i.e., lack of effect) of a Janssen 
medicinal product 
 Medication error involving a Janssen medicinal product (with or without patient 
exposure to the Janssen medicinal product, e.g., name confusion) 
 Suspected transmission of any infectious agent via a medicinal  
 Unexpected therapeutic or clinical benefit from use of a Janssen medicinal product 
 
These safety events may not meet the definition of an adverse event; however, they are treated 
in the same     manner as adverse events. Special situations should be recorded on the Adverse 
Event page of the CRF. 
 
Any special situation that meets the criteria of a serious adverse event should be recorded on a 
Serious Adverse Event Report Form and be reported to Janssen Scientific Affairs within 24 
hours of becoming aware of the event. 
 
III. 
Pregnancy  
All initial reports of pregnancy must be reported to Janssen Scientific Affairs by the Sponsor 
Investigator within 24 hours of their awareness of the event using the Serious Adverse 
Event Form. Abnormal pregnancy outcomes (e.g. spontaneous abortion, stillbirth, and 
congenital anomaly) are considered serious adverse events and must be reported using the 
Serious Adverse Event Form.  


24 
 
 
Any subject who becomes pregnant during the study must be promptly withdrawn from the 
study and discontinue further study treatment. 
 
Because the effect of the Janssen medicinal product on sperm is unknown, pregnancies in 
partners of male subjects exposed to a Janssen medicinal product will be reported by the 
Sponsor Investigator within 24 hours of their awareness of the event using the Serious 
Adverse Event Form.  Depending on local legislation this may require prior consent of the 
partner. 
 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in 
the infant will be required. 
11. Reporting Procedures for Adverse Events and Pregnancies [and/or Pregnancies in 
Partners] 
All adverse events, whether serious or non-serious, related or not related, special situations, 
pregnancy exposures and/or pregnancies in partners following exposure to a Janssen medicinal 
product are to be documented by the investigator and recorded in the CRF and in the subject’s 
source records. Investigators must record in the CRF their opinion concerning the relationship 
of the adverse event to a Janssen medicinal product.  
All (serious and non-serious) adverse events reported for a Janssen medicinal product should 
be followed-up in accordance with clinical practice. 
 
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs: 
 The event resolves 
 The event stabilizes 
 The event returns to baseline, if a baseline value/status is available 
 The event can be attributed to agents other than the study drug or to factors unrelated to 
study conduct 
 It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts) 
 
All serious adverse events, pregnancy exposures and/or pregnancies in partners for Janssen 
medicinal products under study should be reported directly by the Sponsor Investigator, 
within 24 hours of becoming aware, to Janssen Scientific Affairs using the Janssen 
Scientific Affairs Serious Adverse Event Report Form. In the event the study is blinded, the 
Sponsor Investigator will submit an unblinded SAE or pregnancy exposure report to Janssen 
Scientific Affairs. 


25 
 
 
All follow-up information for serious adverse events that are not resolved at the end of the 
study or by the time of patient withdrawal must be reported directly by the Sponsor 
Investigator, within 24 hours becoming aware, to Janssen Scientific Affairs using the 
Janssen Scientific Affair’s Serious Adverse Event Report Form. 
Product Quality Complaints for Janssen Medicinal Products 
 
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, and 
complete reporting and analysis of PQC information from studies are crucial for the 
protection of patients, investigators, and Janssen Scientific Affairs, and are mandated by 
regulatory agencies worldwide. Janssen Scientific Affairs has established procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of PQC 
information.  Lot and/or Batch #s shall be collected or any reports of failure of expected 
pharmacological action (i.e., lack of effect). 
 
All initial PQCs involving a Janssen product under study must be reported to Janssen 
Scientific Affairs by the Sponsor Investigator within 24 hours after being made aware of 
the event. 
 
If the defect for a Janssen product under study is combined with either a serious adverse 
event or non-serious adverse event, the Sponsor Investigator must report the PQC to Janssen 
Scientific Affairs according to the serious adverse event reporting timelines.  A sample of the 
suspected product should be maintained for further investigation if requested by Janssen 
Scientific Affairs. 
 
Maintenance of Safety Information 
All safety data should be maintained in a clinical database in a retrievable format. The 
Institution and Sponsor Investigator shall provide all adverse events, both serious and non-
serious, in report format. However, in certain circumstances more frequent provision of 
safety data may be necessary, e.g. to fulfill a regulatory request, and as such the data shall be 
made available within a reasonable timeframe at Janssen Scientific Affair’s request. 
 
Transmission Methods: 
The following methods are acceptable for transmission of safety information to Janssen 
Scientific Affairs: 
 Electronically via Janssen SECURE Email service (preferred) 
 For business continuity purposes, if SECURE Email is non-functional: 
o Facsimile (fax), receipt of which is evidenced in a successful fax transmission 
report 
 Telephone (if fax is non-functional). 
 
Please use the contact information and process information provided by Janssen Scientific 
Affairs. 


26 
 
 
Procedures for Reporting Adverse Events (AE), Serious Adverse Events (SAE), 
Pregnancy, and Product Quality Complaints (PQC) to Janssen Scientific Affairs 
 
A. AEs, SAEs, Special Situations and Pregnancy Reporting. 
The Institution and the Sponsor Investigator will transmit SAEs and Special Situations in a 
form provided by Janssen Scientific Affairs in accordance with Section VIII Transmission 
methods, in English within 24-hours of becoming aware of the event(s). 
 
All available clinical information relevant to the evaluation of a related SAE or Special 
Situation is required. 
 
 The Institution and/or Sponsor Investigator are responsible for ensuring that these cases 
are complete and if not are promptly followed-up. A safety report is not considered 
complete until all clinical details needed to interpret the case are received. Reporting of 
follow-up information should follow the same timeline as initial reports. 
 
 Copies of any and all relevant correspondences with regulatory authorities and ethics 
committees regarding any and all serious adverse events, irrespective of association with 
the Janssen Product under study, are to be provided to Janssen Scientific Affairs using a 
transmission method in Section VIII within 24 hours of such report or correspondence 
being sent to applicable health authorities. 
 
 
B. PQC Reporting 
The Institution and the Sponsor Investigator will report any suspected PQC to the Janssen 
contact within 24 hours of becoming aware of the complaint.  The product should be 
quarantined immediately and if possible, take a picture. 
 
Reconciliation of SAEs 
At a minimum, on a quarterly basis and at the end of the Study, Janssen Scientific Affairs 
will provide to the Institution and/or Sponsor Investigator, a listing of all SAEs reported to 
Janssen Scientific Affairs.  The Sponsor Investigator will review this listing and provide any 
discrepancies to Janssen Scientific Affairs. 
 
Upon request, Institution and/or Sponsor Investigator shall provide Janssen Scientific Affairs 
with a summary list of all SAEs, and AEs of Special Interest and Special Reporting Situation 
reports to date, for reconciliation purposes. 
 
Dissemination 
of 
Safety 
Information 
from 
Janssen 
Scientific 
Affairs 
to 
Institution/Sponsor Investigator Sponsor Investigator will be responsible for submitting IND 
safety reports for the Study Product to Institution’s IRB in accordance with Federal regulations 
21 CFR 312.66.   
 


27 
 
Janssen Scientific Affairs agrees to provide to the Sponsor Investigator IND safety reports for 
the Study Product as they become available until all subjects in the Protocol have completed 
their last Study visit according to the Protocol (i.e. Last Subject Last Visit has occurred).  
.  
Other Safety Considerations 
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded as a nonserious or serious AE, as 
appropriate, and reported accordingly. 
 
12. Data Safety Monitoring Board (DSMB) A DSMB consisting of individuals with 
expertise in each of the efficacy areas (anti-coagulation therapy, atrial fibrillation, and 
cardiac CT), as well as in anti-coagulation trials and statistics will be established. The PI 
will prepare interim reports to the DSMB on a regular basis, every 6 months or more 
often as it deems appropriate.  Reports that include general study information such as 
accrual, dropout, and ineligibility rates and other performance parameters, will be 
available to the study leadership and will be discussed with them at open sessions.  Data 
relating to safety and efficacy that are presented by treatment arm will be considered 
highly confidential and will be available only to the DSMB and the statistician preparing 
the reports, and will be discussed at closed sessions of the DSMB. The DSMB will have 
an initial meeting prior to the opening of the study to review the report format and 
content proposed by the PI and determine if they are satisfactory or need to be modified. 
Interim reports to the DSMB will focus on analyses of the safety data -- primarily 
bleeding -- but other safety-related outcomes, such as CT related adverse effects, will 
also be reviewed in an unblinded fashion. The DSMB will decide on the basis of these 
data and the stopping boundaries whether to recommend modifying or stopping the trial 
and will make recommendations to the sponsor and the study leadership.  A copy of the 
DSMB minutes and reports will be provided to Janssen as well. 
 
13. STATISTICAL CONSIDERATIONS 
Statistical analysis 
 
All analyses will be performed on a full analysis set basis (those who stay in the trial to the 
follow up scan).  For the primary analysis, ITT (defined as all those randomized into the study) 
will be used.   Continuous variables will be expressed as mean and standard deviation; 
categorical variables expressed as absolute numbers and percentages. Baseline variables will be 
compared with an independent t-test (two tailed) after performing Levene’s test for equality of 
variances in all normally distributed continuous variables and the Mann–Whitney test (two-
tailed) in all not normally distributed variables. Categorical variables will be tested with two-
sided Fisher’s exact test.  An analysis of variance (ANOVA) model with treatment as the main 
effect will be used to compare the treatment effect of rivaroxaban and warfarin treatment 


28 
 
strategies.  For all measures, the analysis of covariance (ANCOVA) model controlling for 
baseline demographics and baseline CACS values will be performed.  Treatment groups also will 
be compared with respect to incidence rates of adverse events, laboratory abnormalities, bleeding 
rates, and concomitant medication use.  Measurements and change from baseline in coronary 
artery calcium scores, vital signs (blood pressure and pulse rate), continuous laboratory variables 
and compliance values will be summarized using descriptive statistics (mean, standard deviation, 
minimum, median and maximum) by treatment groups and visit.  If the interaction of treatment 
by baseline laboratory values or CACS is significant at the 0.10 level or below, the nature of the 
interaction will be further explored. Spearman’s rank correlation coefficient will be used for 
testing correlation between the mean Agatston score. All parameters showing a significant 
univariate relation with an increased coronary Agatston score and those representing a plausible 
mechanism in terms of calcification [age, VKA duration, left atrium (LA) diameter, statins, 
angiotensin-converting enzyme (ACE)-inhibitors] will be included as covariates in a logistic 
regression model (retention level set at 0.1), odds ratios and 95% confidence intervals (CIs) 
calculated, and results checked for interaction.  
 
Statistical analysis will be performed with SPSS statistical software (SPSS, Inc. release 18.0) and 
statistical significance assumed for P < 0.05. The primary and secondary efficacy analyses will 
include all patients who undergo randomization (intention-to-treat population) and include all 
events from the time of randomization until the end of the study. The analyses of bleeding events 
will include all patients who receive at least one dose of a study drug and included all events 
from the time the first dose of a study drug was received until 2 days after the last dose is 
received.  
 
Sample Size 
Sample Size Estimation. Sample sizes for each efficacy area have been calculated assuming 
performance of two-sided 0.05 level tests and 90% power for the primary endpoint and >85% 
power for the secondary endpoint to detect differences considered clinically meaningful and 
plausible based on prior studies. We have based sample sizes on at least 90% power in all end 
points because false negatives could lead to abandoning further study of a treatment that could 
have a major positive impact on myocardial infarction in this population. The primary endpoint 
is progression of atherosclerosis after 1 year of treatment with warfarin compared to rivaroxaban 
as measured by the annualized relative change in the coronary calcium score, as assessed by the 
Agatston score.  The primary endpoint will be the percentage change in CAC from the baseline, 
which was calculated as follows: (CAC score at 1 year - CAC score at baseline/CAC score at 
baseline) / 100.  From multiple 1 year randomized studies in Dr. Budoff’s lab, the mean 
annualized relative change in the Agatston calcium score was 27.2±9.5% and on pilot-treatment 
group, we observed an average change of 7.5 ±9. 4%. Given a 19.7 % annual change difference 
(27.2% vs. 7.5%) between two groups was observed from primary data, the trial requires 100 in 
total (50 patients per arm) to attain power of 90% to detect the effect size according to a two-
tailed two-sample t-test at a significance level 0.05 (see figure). If we consider the secondary 


29 
 
endpoint (noncalcified plaque volume change), we will have >85% power without drop-off at a 
two-tailed significance level 0.05 with 120 subjects.  
 
The secondary endpoint is noncalcified plaque volume, using cardiac CTA.  Cardiac CTA has 
been used successfully by Budoff to measure progression of atherosclerosis (30-32). In one 
relevant study, the mean annualized relative change in the non-calcified plaque volume among 
62 subjects given statin was -0.037 with a standard deviation of 0.351. This secondary 
comparison has power of 0.80 to detect an effect size of 0.5, the mean difference in the 
annualized relative change in the non-calcified plaque volume between the rivaroxaban and 
warfarin, according to a two sample t-test at a two-tailed significance level 0.05.  
STUDY SUMMARY:   
 
This study will represent a comprehensive evaluation of the atherosclerotic changes over 
time on both rivaroxaban and warfarin. 
 
COMPETING STUDIES: 
A 348 person study comparing rivaroxaban to OAT has been listed on ClinicalTrials.gov.  This 
study will evaluate CAC, Echocardiography, Intima Media Thickness of carotid artery (IMT) 
and Flow Mediated Vasodilatation (FMD), Electrocardiography (ECG) in respect to both open 
label randomization of OAT and rivaroxaban.   It has some similar features to our study, but also 
some significant differences. We are using CT angiography to be much more precise with both 
calcification and atherosclerosis measures and are not undertaking a broad based ‘test all’ 
method to see if there are differences.  There are no suggesting that rivaroxaban will affect 
endothelial function, carotid intima-media thickness, diastolic dysfunction or 
electrocardiography any differently than OAT.   We are focusing on the known benefits of 
rivaroxaban with the most precise measures of atherosclerosis and calcification known.  Our 
study, being of smaller and more directed scope, will complete significantly earlier than the 
study on ClinicalTrials.gov.   
A second study is a 2 month study evaluating the calcification score by scanography, measuring 
the rate of coronary calcification and the arterial site of calcification at the level of lower limbs 
between an inhibitor of the FXa activity by oral way versus a vitamin K antagonist.  There is no 
study ever done that shows we can see changes in vascular calcification in 2 months, the shortest 
study ever done was 6 months, using a measurement tool that is more accurate and quantitative 
than scenography.   Furthermore the study on ClinicalTrials.gov is riddled with errors  and mis-
statements, such as “20 mg once daily for patients with growth factor > 49 ml per minute and 15 
mg rivaroxaban once daily for patients with growth factor of 15 to 49 ml.”  Note the errors of use 
of ‘growth factor’ instead of ‘GFR’.   I have little confidence that this “VICTORIA” Study will 
yield any useful information so this study is ongoing to decidedly answer the question.    
 
CONCLUSIONS:   We conclude that there is a growing need for better understanding of 
the effects of anticoagulants on vascular calcification and atherosclerosis.  Other proposed 


30 
 
studies will not answer the question in the methods directed by our study design.   This study 
will add considerable knowledge to the potential effects of rivaroxaban and VKA in the 
progression of both CAC and CT angiographic plaque.  A successful 1 year pilot study could 
lead to a larger outcome study evaluating the long term CV benefits of avoiding VKA therapy in 
persons needing anticoagulation.   If successful, the work in this proposal will provide the 
rationale for a prospective randomized CV outcome study.  
 
 
 
 
 
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33 
 
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