Clinical trial NCT03718429
Conditions: Coronary Artery Disease Peripheral Arterial Disease Atrial Fibrillation
Keywords: aspirin clopidogrel ticagrelor rivaroxaban pharmacodynamic (PD)
Sponsor: University of Florida
Start date: 2019-01-14; Completion date: 2020-08-30
Enrollment: 86 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Recent studies indicate that anti-factor-Xa inhibition with low-dose rivaroxaban may have a role in the reduction of ischemic recurrences in patients with atherosclerotic disease manifestations.

To date there is very little data, and not conducted in human subjects, on the interplay between anti-Xa blockade with low-dose rivaroxaban and antiplatelet therapies, and in particular how this affects profiles of platelet reactivity and thrombin generation. Given the potential role for the use of low-dose rivaroxaban for the prevention of ischemic recurrences in patients with atherothrombotic disease manifestations, including coronary artery disease (CAD) and peripheral arterial disease (PAD), the study team proposes a prospective pharmacodynamic (PD) investigation assessing the impact of low-dose rivaroxaban when used in combination with antiplatelet treatment regimens commonly used in clinical practice.

Detailed description:
Recent studies indicate that anti-factor-Xa inhibition with low-dose rivaroxaban may have a role in the reduction of ischemic recurrences in patients with atherosclerotic disease manifestations.

However, although the introduction of newer antithrombotic strategies has been associated with a reduction in ischemic recurrences in high-risk patients, these have been consistently associated with an increase in bleeding complications. These have been observed particularly with the combination of an oral anticoagulant agent, including low-dose rivaroxaban, with standard DAPT, also known as "triple therapy". Observations from laboratory and clinical studies suggest that in the presence of effective blockade of other pathways triggering thrombotic complications aspirin may not offer added antithrombotic effects but contribute to the increased bleeding. These observations have set the basis for a large number of clinical outcomes studies evaluating whether dropping aspirin in the presence of more potent and effective blockade of other pathways triggering thrombosis has a better safety profile without a tradeoff in efficacy. Amongst these strategies, the use of low-dose rivaroxaban in adjunct to a P2Y12 inhibitor, also known as dual therapy, has been proposed. This approach may be of potential benefit to reduce atherothrombotic complications in high-risk patients following an acute coronary event. On the other hand, regimens with more modest antithrombotic effects compared with a combination of low-dose rivaroxaban and a P2Y12 receptor inhibitor such as low-dose rivaroxaban alone or in combination with aspirin may be more suitable in more stabilized patients.

To date there is very little data, and not conducted in human subjects, on the interplay between anti-Xa blockade with low-dose rivaroxaban and antiplatelet therapies, and in particular how this affects profiles of platelet reactivity and thrombin generation. Given the potential role for the use of low-dose rivaroxaban for the prevention of ischemic recurrences in patients with atherothrombotic disease manifestations, including coronary artery disease (CAD) and peripheral arterial disease (PAD), the study team proposes a prospective pharmacodynamic (PD) investigation assessing the impact of low-dose rivaroxaban when used in combination with antiplatelet treatment regimens commonly used in clinical practice.

Arms: arm 1: Patients on aspirin 81 mg daily will be treated with adjunctive low-dose rivaroxaban (2.5 mg/bid) for 7-10 days, after which aspirin therapy will be suspended for 7-10 days. arm 2: Patients on aspirin (81 mg daily) plus clopidogrel (75 mg daily) will be treated with adjunctive low-dose rivaroxaban (2.5 mg/bid) for 7-10 days, after which aspirin therapy will be suspended for 7-10 days. arm 3: Patients on aspirin (81 mg daily) and ticagrelor (90 mg bid) will be treated with adjunctive low-dose rivaroxaban (2.5 mg/bid) for 7-10 days, after which aspirin therapy will be suspended for 7-10 days. arm 4: A control cohort of subjects with atrial fibrillation on full dose rivaroxaban (20 mg daily) as per standard of care will be recruited and will undergo a single PD assessment.
Interventions: intervention 1: Rivaroxaban 2.5 mg Tablet
Intervention descriptions: intervention 1: PD assessments will be conducted at 3 time points: i) baseline (while on standard of care antiplatelet therapy), ii) 7-10 days after adjunctive treatment with low dose rivaroxaban, and iii) 7-10 days after dropping aspirin.

Protocol documents:
Prot_SAP_000.pdf: 
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Pharmacodynamic effects of low-dose rivaroxaban in combination with antiplatelet 
therapies in patients with coronary and peripheral artery disease manifestations 
(NCT03718429) 
 
 
Study Sponsor 
Dominick J Angiolillo, MD, PhD, FACC, FESC, FSCAI 
Director of Cardiovascular Research 
Professor of Medicine 
Division of Cardiology 
University of Florida College of Medicine - Jacksonville 
655 West 8th Street 
Jacksonville, FL – 32209 
Tel: 904-2443933, Fax: 904-2443102 
dominick.angiolillo@jax.ufl.edu 
 
 
Funding Source 
Janssen Scientific Affairs, LLC 
1125 Trenton-Harbourton Road 
Titusville, NJ 08560 
 
 
 
 


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BACKGROUND 
Recent studies indicate that anti-factor-Xa inhibition with low-dose rivaroxaban may 
have a role in the reduction of ischemic recurrences in patients with atherosclerotic disease 
manifestations [1,2]. These observations indeed challenge a dogma in cardiovascular medicine 
which for decades has emphasized that atherothrombotic complications are primarily platelet 
mediated and accordingly should be treated with platelet inhibiting therapies. In particular, a 
single antiplatelet agent, most commonly aspirin, is the standard of care in stable settings, while 
the combination of aspirin plus a P2Y12 receptor inhibitor, also known as dual antiplatelet 
therapy (DAPT), has been the cornerstone of treatment following an acute coronary syndrome or 
stent implantation [3,4]. The benefits associated with P2Y12 receptor inhibitors in these high-risk 
patients is likely attributed to the central role of P2Y12 mediated signaling in platelet activation 
and aggregation processes [5,6]. Moreover, potent P2Y12 receptor blockade has shown to also 
affect non-purinergic signaling pathways as well as modulate thrombin generation [5-9]. The 
pivotal role of thrombin on thrombotic processes, as well as on inflammatory reactions, has also 
raised interest on strategies targeting thrombin-mediated effects. These include blockade of the 
PAR-1 receptor on the platelet surface with vorapaxar and inhibition of circulating thrombin 
through blockade of an upstream target in the coagulation cascade with the anti-Xa inhibitor 
rivaroxaban [3,4,10,11].  
However, although the introduction of newer antithrombotic strategies has been 
associated with a reduction in ischemic recurrences in high-risk patients, these have been 
consistently associated with an increase in bleeding complications [3,4,10,11]. These have been 
observed particularly with the combination of an oral anticoagulant agent, including low-dose 
rivaroxaban, with standard DAPT, also known as “triple therapy” [1,3,4,11,12]. Observations 


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from laboratory and clinical studies suggest that in the presence of effective blockade of other 
pathways triggering thrombotic complications aspirin may not offer added antithrombotic effects 
but contribute to the increased bleeding [2,7,13-15]. This has also led to the challenge of another 
dogma which is whether aspirin therapy is needed in patients with atherothrombotic disease 
manifestations. These observations have set the basis for a large number of clinical outcomes 
studies evaluating whether dropping aspirin in the presence of more potent and effective 
blockade of other pathways triggering thrombosis has a better safety profile without a tradeoff in 
efficacy [16]. Amongst these strategies, the use of low-dose rivaroxaban in adjunct to a P2Y12 
inhibitor, also known as dual therapy, has been proposed [2]. Moreover, the interplay between 
thrombin and P2Y12-mediated platelet signaling may support a synergistic effect on thrombus 
formation by inhibition of these pathways [5,6,10]. This approach may be of potential benefit to 
reduce atherothrombotic complications in high-risk patients following an acute coronary event. 
On the other hand, regimens with more modest antithrombotic effects compared with a 
combination of low-dose rivaroxaban and a P2Y12 receptor inhibitor such as low-dose 
rivaroxaban alone or in combination with aspirin may be more suitable in more stabilized 
patients. 
 
STUDY RATIONALE 
To date there is very little data, and not conducted in human subjects, on the interplay 
between anti-Xa blockade with low-dose rivaroxaban and antiplatelet therapies, and in particular 
how this affects profiles of platelet reactivity and thrombin generation [17]. Given the potential 
role for the use of low-dose rivaroxaban for the prevention of ischemic recurrences in patients 
with atherothrombotic disease manifestations, including coronary artery disease (CAD) and 


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peripheral arterial disease (PAD), we hereby propose a prospective pharmacodynamic (PD) 
investigation assessing the impact of low-dose rivaroxaban when used in combination with 
antiplatelet treatment regimens commonly used in clinical practice.  
 
REASERCH PLAN 
Study design 
The proposed investigation will be a prospective PD study conducted in cohorts of 
patients with CAD or PAD on treatment per standard of care for at least 3 months with either 
aspirin (81mg/qd), aspirin (81mg/qd) plus clopidogrel (75mg/qd), or aspirin (81mg/qd) plus 
ticagrelor (90mg/bid) will be identified. The study will be performed at the University of Florida 
Health Science Center at UF Health Jacksonville - Division of Cardiology. Patients will be 
recruited in the Cardiology Clinics of our institution and will be screened by Cardiology 
Research staff, who will verify that all candidates meet inclusion and exclusion criteria. Results 
from blood tests performed within the last 90 days will be considered valid for screening 
purposes. If these are not available, a blood sample will be collected for the screening phase. 
After providing written informed consent, each cohort will be treated with adjunctive 
low-dose rivaroxaban (2.5 mg/bid) for 7-10 days, after which aspirin therapy will be suspended 
for 7-10 days. PD assessments will be conducted at 3 time points: i) baseline (while on standard 
of care antiplatelet therapy), ii) 7-10 days after adjunctive treatment with low dose rivaroxaban, 
and iii) 7-10 days after dropping aspirin. In addition, a control cohort of subjects with atrial 
fibrillation on full dose rivaroxaban (20 mg/qd) will be recruited and will undergo a single PD 
assessment. Figure 1 illustrates the overall study design.  
 
 


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Figure 1. Overall study design 
 
 
In addition to prospectively evaluate within each cohort the PD effects of adding low-
dose rivaroxaban to a standard antiplatelet regimen and the impact of dropping aspirin therapy, 
this approach will allow for the assessment of PD profiles associated with 10 different 
antithrombotic treatment regimens: 3 monotherapy, 5 dual therapy, and 2 triple therapy regimens 
(Figure 2).  PD measures will include a multitude of assays aimed to assess various measures of 
platelet reactivity, including purinergic and non-purinergic signaling pathways, and thrombin 
generation, as described below. PD assessment will be carried out at time points reflecting trough 
levels of effects of antithrombotic agents. Although the study will have an open-label design, 
laboratory personnel will be blinded to treatment assignments. Compliance with antithrombotic 
therapies will be assessed by interview and pill counting. During study treatment, major adverse 
cardiac events (death, myocardial infarction, stroke, and urgent revascularization procedures), 


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serious adverse events (bleeding and other adverse events), as well as non-serious adverse events 
considered to be related to rivaroxaban will be collected. After completing the study, patients 
will resume their standard of care treatment regimen.    
 
Figure 2. Antithrombotic treatment regimens 
 
 
Study population 
A total of 80 patients will be recruited (20 patients per cohort). Patients with either CAD 
or PAD who are clinically stable on their standard of care antiplatelet treatment for at least 3 
months will be recruited. The rationale for considering 3 months is that some patients may have 
had a recent stent implantation and the study implies dropping aspirin, the safety profile of which 
is still under investigation. Moreover, this approach will allow to recruit a stabilized patient 


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population, eliminating confounders on PD measures associated with a recent acute event. 
Patients at high risk of bleeding complications will be excluded.  
Inclusion criteria: 
• Age > 18 y.o. 
AND 
• Known CAD (defined as angiographic evidence of >50% coronary artery stenosis or prior 
coronary revascularization) or PAD (defined as a positive ABI or prior revascularization) 
• on treatment with either aspirin (81mg/qd), aspirin (81mg/qd) plus clopidogrel (75mg/qd), or 
aspirin (81mg/qd) plus ticagrelor (90mg/bid) for at least 3 months per standard of care 
OR 
• Atrial fibrillation (paroxysmal, persistent or permanent) on treatment with rivaroxaban 20 mg 
qd (if CrCl >50 mL/min) or 15 mg qd (if CrCl 15 - 50 mL/min) per standard of care. Patients 
with concomitant CAD or PAD who are also taking antiplatelet medications are not eligible. 
However, if these are only on oral anticoagulation with rivaroxaban (and no antiplatelet 
therapy) they will be eligible. 
 
Exclusion criteria: 
• Active pathological bleeding, history of clinically significant bleeding events, or deemed at 
increased risk of bleeding. 
• CrCL <20mL/min 
• Any clinical indication to be on triple antithrombotic therapy (DAPT plus an oral 
anticoagulant) 
• An acute coronary event in the past 90 days 


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• Prior hemorrhagic stroke or intracranial hemorrhage 
• Ischemic stroke/transient ischemic attack in the past 6 months 
• Chronic use of nonsteroidal anti-inflammatory drugs 
• On treatment with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, 
itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan) or inducers 
(e.g., carbamazepine, phenytoin, rifampin, St. John’s wort). 
• Known moderate or severe hepatic impairment (Child-Pugh B and C) 
• Prior hypersensitivity reaction to rivaroxaban 
• On treatment with prasugrel in the past 10 days.  
• Platelet count <80x106/mL 
• Hemoglobin <10g/dL 
• Hemodynamic instability 
• Pregnant females [women of childbearing age must use reliable birth control (i.e. oral 
contraceptives) while participating in the study]. 
 
Laboratory assessments 
Peripheral venous blood samples will be drawn through a short venous catheter inserted 
into a forearm vein and collected in citrate, EDTA, and serum tubes as appropriate for 
assessments. The first 2-4 mL of blood will be discarded to avoid spontaneous platelet activation. 
Blood sampling (20 mL per visit) for PD will be performed at 3 time points as indicated above in 
the study design section. To specifically evaluate the effects of aspirin withdrawal, experiments 
to assess the cyclooxygenase pathway, including measurement of thromboxane B2 levels, will be 
performed: 


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1. 
VerifyNow PRU 
2. 
VASP 
3. 
Light Transmittance Aggregometry (LTA)  
4. 
Serum thromboxane B2 
5. 
Thrombelastograph Coagulation Analyzer TEG 6s Series system 
6. 
Thrombin Generation 
 
Laboratory assessments including VerifyNow PRU, LTA, and TEG will be performed within 30-
60 minutes of sample collection. VASP samples will be processed and analyzed within 24 hours 
of blood collection. Serum thromboxane B2 and thrombin generation assessments will be 
performed on stored samples as final batch analysis. Samples will be stored under required 
refrigerated conditions at the Thrombosis Research Laboratory of the Cardiovascular Research 
Department of the University of Florida-Jacksonville. Only laboratory staff will have access to 
the samples. Subject identity will be protected. In particular, samples will be de-identified and 
data coded. This information will be stored in locked filing cabinets or in computers with 
security passwords. All laboratory assessments with the exception of thrombin generation 
measures will be performed at the Thrombosis Research Laboratory of the Cardiovascular 
Research Department of the University of Florida-Jacksonville. Thrombin generation 
assessments will be performed at CirQuest laboratories in Memphis, TN (Dr. Lisa Jennings). 
Blood samples will also be stored for further future assessments of markers of thrombosis and 
inflammation. 
 
Description of laboratory assays 


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1) VerifyNow (VN) PRU: The VN System is a turbidimetric based optical detection system 
which measures platelet induced aggregation as an increase in light transmittance (Accumetrics, 
San Diego, CA) and will be utilized according to manufacturer’s instructions, as previously 
described [8]. The assay is based on microbead agglutination and uses specific reagents for the 
pathways of interest. The VN-PRU assay, by combining ADP+PGE1, measures changes in 
platelet function specific to P2Y12 receptor inhibitors. The assay is based upon the ability of 
activated platelets to bind fibrinogen. Fibrinogen-coated microparticles aggregate in proportion 
to the number of GP IIb/IIIa receptors expressed. Light transmittance increases as activated 
platelets bind and aggregate fibrinogen-coated beads. The instrument measures this change in 
optical signal and reports results in P2Y12 Reaction Units (PRU). 
2) Whole blood vasodilator-stimulated phosphoprotein (VASP): VASP phosphorylation 
(VASP-P) is a marker of P2Y12 receptor signaling. VASP will be assessed utilizing the ELISA 
VASP-P kit (Biocytex Inc., Marseille, France) as previously described [8]. Blood samples will be 
collected in tubes anticoagulated with trisodium citrate and processed and analyzed within 24 
hours of blood collection per the manufacturer instructions. After a first step of parallel whole 
blood sample activation with PGE1 and PGE1+ADP, platelets from the sample are lysed, 
allowing released VASP to be captured by an anti-human VASP antibody, which is coated in the 
microtiter plate. Then, a peroxidase-coupled anti-human VASP-P antibody binds to 
phosphorylated serine 239 antigenic determinant of VASP. The bound enzyme peroxidase is 
then revealed by its activity on TMB substrate over a predetermined time. After stopping the 
reaction, absorbance at 450 nm is directly related to the concentration of VASP-P contained in 
the sample. PGE1 increases VASP-P levels by stimulation of adenylate cyclase. Binding of ADP 
to P2Y12 leads to Gi-coupled inhibition of adenylate cyclase. Therefore, the addition of ADP to 


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PGE1-stimulated platelets reduces PGE1-induced VASP-P levels. If P2Y12 receptors are 
successfully inhibited, addition of ADP will not reduce the PGE1-stimulated VASP-P levels. The 
platelet reactivity index (PRI) will be calculated using optical density (OD 450 nm) of samples 
incubated with PGE1 or PGE1 and ADP according to the formula: VASP = [(OD450nm (PGE1) – 
OD450nm (PGE1+ADP)) / OD450nm (PGE1)] × 100. 
3) Light transmittance aggregometry (LTA): Platelet aggregation will be performed using LTA 
according to standard protocols. Blood will be collected in citrated (3.2%) tubes. LTA will be 
assessed using platelet-rich plasma (PRP) by the turbidimetric method in a 2-channel 
aggregometer (Chrono-Log 490 Model, Chrono-Log Corp., Havertown) as previously described 
[8]. Platelet agonists will include arachidonic acid (AA; 1 mM), collagen (3µg/ml), ADP (5 and 
20 µM) and thrombin receptor activating peptide (TRAP, 15 μM). TF-CaCl2 [17] reconstituted at 
a 2x concentration (Neoplastine Cl Plus, Diagnostica Stago reconstituted in 32.5 mM CaCl2) and 
a combination of 2 µg/ml collagen-related peptide + 5 µM ADP + TF-CaCl2 (CATF) will also be 
used as agonists. The reagent cocktail CATF will allow to assess the overall platelet response to 
a combination of agonists that leads to activation of multiple platelet pathways, including 
thrombin generation. PRP will be obtained as a supernatant after centrifugation of citrated blood 
at 1000 rpm for 10 minutes. The isolated PRP will be kept at 37° C before use. Platelet-poor 
plasma (PPP) will be obtained by a second centrifugation of the blood fraction at 2800 rpm for 
10 minutes. Light transmission will be adjusted to 0% with the PRP and to 100% for the PPP for 
each measurement. Curves will be recorded for 6 minutes and platelet aggregation will be 
determined as the maximal percent change (MPA) in light transmittance from baseline using PPP 
as a reference.  


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4) Serum thromboxane B2: The concentration of serum thromboxane B2 (TXB2) will be 
measured by using a Thromboxane B2 ELISA kit (R&D Systems, Inc, Minneapolis, MN) 
according to the instructions of the manufacturer [18]. Briefly, samples will be diluted with  
Calibrator Diluent RD5-57 to bring their concentrations within the range of the standard curve. 
No other purification will be performed on any of the samples. A standard curve will be 
established by serial dilution of TXB2 between 20ng/mL and 0.313 ng/mL using Calibrator 
Diluent RD5-57 as the matrix. The concentration of TXB2 in the samples will be calculated from 
a logistic 4-parameter fit of the standard concentrations versus percentage bound/maximum 
bound. 
5) TEG 6s Series system: the TEG 6s system (Haemonetics Corporation, Braintree, MA, USA) 
will be used according to manufacture instructions [19]. In brief, the CORA® system is a new 
generation portable thrombelastography technology able to evaluate all phases of hemostasis, 
including time to clot formation, rate of clot formation, strength of clot and residual clot strength 
due to antiplatelet drugs, rate of clot lysis. Disposable assay cartridges contain all of the 
components necessary to allow the analyzer to prepare samples and perform hemostasis tests. 
The analyzer automatically draws the blood into the active area of the cartridge, meters the exact 
amount required for the test, and mixes it with the reagents spotted in the cartridge. The analyzer 
then monitors the harmonic motion of a pendant drop of blood in response to external vibration. 
As the sample transitions from a liquid state to a gel-like state during clotting, the modulus of 
elasticity and resonant frequency increase. The instrument measures these variations in resonant 
frequency during clotting and lysis. The results are displayed in a table and on a graphical tracing 
that reflects a hemostasis profile of clot formation. The resulting hemostasis profile is a measure 
of the time it takes for the first measurable clot to be formed, the kinetics of clot formation, the 


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strength of the clot, and the breakdown of the clot, or fibrinolysis. In particular, the 
PlateletMapping Cartridge are used to assess platelet function in patients who have received 
platelet inhibiting drugs. The PlateletMapping assay consists of a set of agonists, ADP and AA 
together with ActivatorF, which can measure the inhibition of platelet function. This assay 
specifically determines the MA (Maximum Amplitude, a measure of clot strength) and the 
reduction in MA due to antiplatelet therapy and reports it as a percentage of reduction in clot 
strength. The HKH reagent, a combination of kaolin and heparinase, generates test data for the 
uninhibited MA resulting from thrombin activation of the blood sample, while the heparinase 
neutralizes the effects of heparin. The HKH test provides measures of R (Reaction time; the 
amount of time between the start of the test and the beginning of coagulation), K (the speed of 
formation of the clot from R time to a specific clot strength), Angle (the speed of clot 
strengthening), LY30 (Percent lysis 30 minutes after MA is finalized) and MA parameters. The 
AA and ADP test provide measures of MA, percent inhibition and percent aggregation. 
6) Thrombin Generation Assay: TGA assays will be performed using PPP samples prepared 
from the various treatment groups [20]. The TGA assay will be carried out using 
Technothrombin® fluorogenic assay kit (Diapharma) following manufacturer’s recommended 
guidelines. Briefly, a reaction mix is prepared containing low or high amounts of TF and 
phospholipid micelles, plus the fluorogenic thrombin substrate (1 mM Z-G-G-R-AMC, 15 mM 
CaCl2). Test samples will be analyzed in duplicate by adding the above prepared reaction mix to 
test samples at a 3:2 ratio in a 96-well plate. After addition of samples, plates will be incubated at 
37oC in a water bath, and kinetics of thrombin generation will be recorded for 60 min at 1 min 
intervals using Synergy-2 fluorescence plate reader set at ~360 nm/~460 nm excitation/emission. 
Data will be recorded in BioTek’s Gen 5 software and analyzed using BioTek FLx800 Gen 


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5_TGA Evaluation Software. Final results will be exported into Microsoft excel for data 
analysis. 
 
Study endpoints and statistical analysis 
The primary end point of our study will be the comparison of markers of platelet 
aggregation (PRU, PRI, MPA, TXB2), thrombin generation, and thrombus formation with or 
without low-dose rivaroxaban in addition to each regimen of antiplatelet therapy (intragroup 
comparisons – visit 1 vs visit 2 within each treatment arm). Exploratory end points will include: 
1) intragroup comparisons before and after dropping aspirin (visit 2 vs visit 3 within each 
treatment arm) of all markers of platelet aggregation, thrombin generation, and thrombus 
formation; 2) comparisons of markers of platelet aggregation, thrombin generation, and 
thrombus formation among each treatment arm at visit 2 and visit 3. Since there are no 
preliminary data exploring the PD effects of low-dose rivaroxaban in addition to antiplatelet 
therapy, we arbitrarily chose a sample size of 20 patients per group (total 80 patients). This 
approach is in line with guidelines for pilot investigations [21]. 
For baseline characteristics, categorical variables will be expressed as frequencies and 
percentages; continuous variables will be presented as mean ± SD or median [IQR]. Continuous 
variables will be analyzed for normal distribution with the Kolmogorov-Smirnov test. 
Comparisons for the primary end point as well as for other intragroup comparisons of continuous 
variables will be performed with a linear mixed-effect model with treatment as fixed effects, 
patient as a random effect and baseline value of the corresponding platelet function test as a 
covariate. Intergroup comparisons will be performed with an analysis of variance, without 
adjustment for multiple comparisons. Results will be reported as mean and 95% CI, and 


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treatment differences as mean difference and 95% CI of the difference. A p-value < 0.05 will be 
considered statistically significant. Statistical analysis will be performed with SPSS version 24 
software (SPSS Inc.). 
 
Publication Strategy/Additional Information  
Study subjects will be identified first (months 1-20): we expect to enroll approximately 4 
subjects monthly and complete enrollment in 20 months (total: 80 subjects enrolled). Months 21-
22 will be implied for statistical analysis and months 23-24 for manuscript preparation. We 
intend to present data at a major scientific meeting at completion of the study. 
We anticipate no major problems with the described protocol since the approach is a 
straightforward prospective study and is based on well-established methods. However, since 
there is limited experience with the effects of low-dose rivaroxaban on platelet function, 
variability may be higher than expected and we cannot currently perform a detailed sample size 
calculation. We anticipate adding this to the protocol after inclusion of the study population has 
been completed. If the sample size after one year is estimated to be too small, additional patients 
will be included. This approach is in agreement with recommendations for pilot investigations 
[21]. 
 
Safety and Adverse Events 
In clinical trials, the most important adverse effect associated with the use of low-dose 
rivaroxaban was bleeding. The risk of major bleeding with rivaroxaban was 1-1.8%; the risk of 
intracranial hemorrhage was 0.4% at 2 years [1,2]. However, such bleeding prevalence occurred 
in the setting of long-term trial, while our study is limited to only 16-24 days of therapy. We 


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have also excluded from the study patients at increased risk of bleeding complications. Other 
rivaroxaban reported side effects include abnormal liver function tests (0.2%) [1].  
All adverse events described above, if they were to occur, as well as death, myocardial 
infarction, stroke, procedures of  urgent revascularization with PCI or coronary artery bypass 
grafting will be recorded. Serious adverse events will be evaluated by a local data safety 
monitoring board (DSMB) committee, comprised of 2 faculty members (2 cardiologists), not 
directly involved in the research. In the event of a report of a serious adverse event (as defined 
below) the DSMB will meet and antiplatelet treatment management will be managed, including 
stopping if of clinical concern, according to physician recommendation. 
 
I. 
Management of Safety Data 
This Study has been designated as an interventional study.  Janssen requirements for IIS 
interventional studies are all adverse events regardless of causality and special situations 
excluding those from subjects not exposed to a Janssen Medicinal Product and product 
quality complaints with or without an adverse event will be reported, once the subject has 
signed and dated an Informed Consent Form is obtained until the subject has completed 
participation in the study and for 30 days after the last dose of study drug. 
 
II. 
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]). 


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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).  These adverse events are: 
 
• 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 


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• 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 
• 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.) 


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November 15, 2018 Protocol version 5 
 
19 
 
• 
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 


Confidential 
November 15, 2018 Protocol version 5 
 
20 
 
condition for which the hospitalization was planned has not worsened will not be 
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. 
 
III. 
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 
 


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November 15, 2018 Protocol version 5 
 
21 
 
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. 
 
IV. 
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.  
 
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. 
 
V. 
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 


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November 15, 2018 Protocol version 5 
 
22 
 
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. 
 
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. 
 
A listing of non-serious AEs will also be provided to Janssen Scientific Affairs at end of 
study to cover the requirements of TV-SOP-10063. 


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November 15, 2018 Protocol version 5 
 
23 
 
 
VI. 
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. 
 
VII. 
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. 
 
VIII. 
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 


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November 15, 2018 Protocol version 5 
 
24 
 
• Telephone (if fax is non-functional). 
 
Please use the contact information and process information provided by Janssen Scientific Affairs. 
 
IX. 
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. 


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November 15, 2018 Protocol version 5 
 
25 
 
 
X. 
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. 
 
XI. 
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.   
 
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).  
 
 
Possible benefits 
The present investigation is aimed to evaluate the PD effects of low-dose rivaroxaban as 
an add-on therapy to standard antiplatelet treatment in patients with CAD. This study is not 
designed to evaluate differences in clinical benefit. However, differences in antiplatelet profiles 
may potentially prompt further investigations of the clinical implication of this difference by 
means of a larger scale clinical study. 
 
Potential Financial Risks or Benefits 
 


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November 15, 2018 Protocol version 5 
 
26 
 
None 
 
Conflict of Interest 
Dr. Angiolillo is a consultant for Janssen and Bayer, the makers of rivaroxaban. 
 
 


Confidential 
November 15, 2018 Protocol version 5 
 
27 
 
References 
1. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, 
Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, 
Verheugt FW, Gibson CM; ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in 
patients with a recent acute coronary syndrome. N Engl J Med. 2012;366:9-19. 
2. Ohman EM, Roe MT, Steg PG, James SK, Povsic TJ, White J, Rockhold F, Plotnikov A, 
Mundl H, Strony J, Sun X, Husted S, Tendera M, Montalescot G, Bahit MC, Ardissino 
D, Bueno H, Claeys MJ, Nicolau JC, Cornel JH, Goto S, Kiss RG, Güray Ü, Park DW, 
Bode C, Welsh RC, Gibson CM. Clinically significant bleeding with low-dose 
rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes 
(GEMINI-ACS-1): a double-blind, multicentre, randomised trial. Lancet. 2017;389:1799-
1808. 
3. Angiolillo DJ. The evolution of antiplatelet therapy in the treatment of acute coronary 
syndromes: from aspirin to the present day. Drugs. 2012;72:2087-116. 
4. Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. Nat Rev 
Cardiol. 2015;12:30-47. 
5. Cattaneo M. P2Y12 receptors: structure and function. J Thromb Haemost. 2015;13 Suppl 
1:S10-6. 
6. Hechler B, Gachet C. Purinergic Receptors in Thrombosis and Inflammation. Arterioscler 
Thromb Vasc Biol. 2015;35:2307-15. 
7. Armstrong PC, Leadbeater PD, Chan MV, Kirkby NS, Jakubowski JA, Mitchell JA, 
Warner TD. In the presence of strong P2Y12 receptor blockade, aspirin provides little 
additional inhibition of platelet aggregation. J Thromb Haemost. 2011;9:552-61. 


Confidential 
November 15, 2018 Protocol version 5 
 
28 
 
8. Franchi F, Rollini F, Aggarwal N, Hu J, Kureti M, Durairaj A, Duarte VE, Cho JR, Been 
L, Zenni MM, Bass TA, Angiolillo DJ. Pharmacodynamic Comparison of Prasugrel 
Versus Ticagrelor in Patients With Type 2 Diabetes Mellitus and Coronary Artery 
Disease: The OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus)-4 Study. 
Circulation. 2016;134:780-92. 
9. Angiolillo DJ, Capranzano P, Desai B, Shoemaker SB, Charlton R, Zenni MM, Guzman 
LA, Bass TA. Impact of P2Y(12) inhibitory effects induced by clopidogrel on platelet 
procoagulant activity in type 2 diabetes mellitus patients. Thromb Res. 2009;124:318-22. 
10. Angiolillo DJ, Capodanno D, Goto S. Platelet thrombin receptor antagonism and 
atherothrombosis. Eur Heart J. 2010;31:17-28. 
11. Angiolillo DJ, Ferreiro JL. Antiplatelet and anticoagulant therapy for atherothrombotic 
disease: the role of current and emerging agents. Am J Cardiovasc Drugs. 2013;13:233-
50.  
12. Angiolillo DJ, Goodman SG, Bhatt DL, Eikelboom JW, Price MJ, Moliterno DJ, Cannon 
CP, Tanguay JF, Granger CB, Mauri L, Holmes DR, Gibson CM, Faxon DP. 
Antithrombotic Therapy in Patients With Atrial Fibrillation Undergoing Percutaneous 
Coronary Intervention: A North American Perspective-2016 Update. Circ Cardiovasc 
Interv. 2016;9. pii: e004395. 
13. Björkman JA, Zachrisson H, Forsberg GB, von Bahr H, Hansson GI, Warner TD, 
Nylander S. High-dose aspirin in dogs increases vascular resistance with limited 
additional anti-platelet effect when combined with potent P2Y12 inhibition. Thromb Res. 
2013;131:313-9. 


Confidential 
November 15, 2018 Protocol version 5 
 
29 
 
14. Kirkby NS, Leadbeater PD, Chan MV, Nylander S, Mitchell JA, Warner TD. Antiplatelet 
effects of aspirin vary with level of P2Y₁₂ receptor blockade supplied by either ticagrelor 
or prasugrel. J Thromb Haemost. 2011;9:2103-5. 
15. Warner TD, Armstrong PC, Curzen NP, Mitchell JA. Dual antiplatelet therapy in 
cardiovascular disease: does aspirin increase clinical risk in the presence of potent P2Y12 
receptor antagonists? Heart. 2010;96:1693-4. 
16. Gargiulo G, Windecker S, Vranckx P, Gibson CM, Mehran R, Valgimigli M. A Critical 
Appraisal of Aspirin in Secondary Prevention: Is Less More? Circulation. 
2016;134:1881-1906. 
17. Perzborn E, Heitmeier S, Laux V. Effects of Rivaroxaban on Platelet Activation and 
Platelet-Coagulation Pathway Interaction: In Vitro and In Vivo Studies. J Cardiovasc 
Pharmacol Ther. 2015;20:554-62. 
18. Capodanno D, Patel A, Dharmashankar K, Ferreiro JL, Ueno M, Kodali M, Tomasello 
SD, Capranzano P, Seecheran N, Darlington A, Tello-Montoliu A, Desai B, Bass TA, 
Angiolillo DJ. Pharmacodynamic effects of different aspirin dosing regimens in type 2 
diabetes mellitus patients with coronary artery disease. Circ Cardiovasc Interv. 
2011;4:180-7. 
19. Gurbel PA, Bliden KP, Tantry US, Monroe AL, Muresan AA, Brunner NE, Lopez-
Espina CG, Delmenico PR, Cohen E, Raviv G, Haugen DL, Ereth MH. First report of the 
point-of-care TEG: A technical validation study of the TEG-6S system. Platelets. 
2016;27:642-649. 
20. Hemker HC, Kremers R. Data management in thrombin generation. Thromb Res. 
2013;131:3-11 


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21. Lancaster GA, Dodd S, Williamson PR. Design and analysis of pilot studies: 
recommendations for good practice. J Eval Clin Pract. 2004; 10: 307-12. 
 
 


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31 
 
 Table 1. Summary of platelet function assays  
 
V1 
Baseline 
V2 
After rivaroxaban addition 
V3 
After stopping aspirin 
 
VN 
VASP 
 
LTA 
TXB2 
TEG 
TGA 
VN 
VASP 
LTA 
TXB2 
TEG 
TGA 
VN 
VASP 
LTA 
TXB2 
TEG 
TGA 
Group 
A 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Group 
B 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Group 
C 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Group 
D 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Group A: aspirin at baseline; Group B: aspirin and clopidogrel at baseline; Group C: aspirin and ticagrelor at baseline; Group D: rivaroxaban monotherapy. 
LTA: light transmittance aggregometry; TGA: thrombin generation assay; TEG: TEG 6s system; TXB2: thromboxane B2; VASP: whole blood vasodilator-stimulated 
phosphoprotein VN: VerifyNow PRU.  
 

ICF_001.pdf: 
 
IRB APPROVED 
 
AS MODIFIED 
 
May 06, 2019 
 
 
 
1 
 
 
 
University of Florida – Jacksonville 
 
SUBJECT INFORMATION AND CONSENT FORM 
 
TITLE: 
Pharmacodynamic effects of low-dose rivaroxaban in combination 
with antiplatelet therapies in patients with coronary and peripheral 
artery disease manifestations 
 
PROTOCOL NO.: 
None 
 
WIRB® Protocol #20180155 
 
NCT03718429  
 
SPONSOR: 
University of Florida 
 
FUNDING: 
Janssen Scientific Affairs, LLC 
 
INVESTIGATOR: 
Dominick J. Angiolillo, MD, PhD 
 
655 West 8th Street 
 
Jacksonville, Florida 32209 
 
United States 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Dominick J. Angiolillo, MD, PhD 
 
904-244-3933 
 
904-244-0411 (24 hours) 
 
 
Name of person seeking your consent:  ____________________________________________ 
 
 
Place of employment & position:  _________________________________________________ 
 
 
Name of Participant (“Study Subject”) 
 
______________________________________________________________________________ 
 
This consent form may contain words that you do not understand. Please ask the study doctor or 
the study staff to explain any words or information that you do not clearly understand. 
 


 
IRB APPROVED 
 
AS MODIFIED 
 
May 06, 2019 
 
 
 
2 
WHAT WILL BE DONE AS PART OF YOUR NORMAL CLINICAL CARE (EVEN IF 
YOU DID NOT PARTICIPATE IN THIS RESEARCH STUDY)? 
If you choose not to participate in this study, you will be treated and followed by your primary 
care team per normal standard of care. 
 
WHY IS THIS RESEARCH STUDY BEING DONE? 
You are being asked to participate in this study because you have coronary artery disease or 
peripheral artery disease and you are taking blood thinning (antiplatelet) medications such as 
aspirin alone or in combination with either clopidogrel (Plavix) or ticagrelor (Brilinta). You may 
also be asked to participate in this study if you have atrial fibrillation and are currently being 
treated with 20mg of rivaroxaban (Xarelto). You must be informed so you can decide whether 
you want to participate. 
 
Platelets are parts of your blood that stick together to help form a clot. The stickier your platelets 
are, the greater your chances of having heart attacks or strokes. Platelets from patients with heart 
disease tend to stick together more, increasing the risk of having further heart attacks or stroke. 
To prevent a heart attack, there are antiplatelet drugs (blood thinners) to keep your platelets from 
sticking together. Clopidogrel (Plavix®) and Ticagrelor (Brilinta) are two of the antiplatelet drugs 
used in the treatment of patients with artery disease like yours and is typically used in association 
with baby aspirin. Moreover, it is not uncommon that patients who had a heart attack or received 
a stent also have cardiac arrhythmias, such as atrial fibrillation, and receive an anticoagulant 
(which is also a blood thinner). The most common anticoagulant is warfarin and it helps to 
prevent clots from forming. However, treatment with aspirin plus clopidogrel and warfarin is 
associated with increased risk of bleeding. Another anticoagulant, called rivaroxaban (Xarelto), 
has been approved by the U.S. Food and Drug Administration (FDA) for use in place of 
warfarin, however the dose being used in this study is investigational. Rivaroxaban is able to 
reduce stroke as good as warfarin but it causes less bleeding. However, the effects on platelets of 
adding rivaroxaban to patients already taking aspirin and clopidogrel or ticagrelor is unknown. 
 
The purpose of this study is to evaluate the effects of very low dose rivaroxaban used in 
combination with aspirin alone or with clopidogrel or ticagrelor (on a background of aspirin). In 
particular, subjects participating in this study will have a very low dose of rivaroxaban (2.5mg) 
added to their drug therapy regimen for 7-10 days. After 7-10 days the aspirin will be dropped. 
Afterwards you will receive your standard-of-care therapy. Patients taking rivaroxaban alone for 
atrial fibrillation will also be enrolled but will not receive any additional treatment. 
 
The dose in which rivaroxaban is being used in this research has not been approved by the FDA. 
Moreover, patients taking part in this study do not have a clinical indication to be on rivaroxaban 
and its use is investigational. 
 
HOW MANY PEOPLE ARE EXPECTED TO TAKE PART IN THIS RESEARCH 
STUDY? 
Up to 80 people are expected to take part in this study. 
 
HOW LONG WILL YOU BE IN THIS RESEARCH STUDY? 
If you are eligible, you will be expected to take part in the research for up to 30 days. 
 


 
IRB APPROVED 
 
AS MODIFIED 
 
May 06, 2019 
 
 
 
3 
WHO CAN PARTICIPATE IN THIS STUDY? 
Your study doctor will determine if you are able to participate in this research study. Please feel 
free to ask the study doctor about the study requirements for participation. 
 
WHAT WILL BE DONE ONLY BECAUSE YOU ARE IN THIS RESEARCH STUDY? 
Your study doctor will fully explain the study, other possible treatments, and any known or 
possible side effects of participating in this study. If you consent to participate in this study, your 
study doctor will collect data from your medical records. You will be evaluated to see if you 
meet criteria to enter into the research protocol. If you are a woman of childbearing potential, a 
pregnancy test will be done prior to taking any study medication. If you are found to be pregnant, 
you will not be randomized and your participation in this study will end. 
 
At the screening visit, if results from blood tests performed in the last 90 days are not available, 
blood will be collected for determination of complete blood count and renal function. After 
undergoing screening, if you are eligible to participate, you will come for a total of 3 visits and a 
total of 1 blood draw per visit. Approximately 20 cc (or one tablespoon) of blood will be 
collected at each visit from you by inserting a needle directly into your vein or from a catheter in 
your vein. Baseline platelet function tests (while you are taking your standard of care 
medications) will be done to see how sticky your platelets are. 
 
After this baseline visit, you will have a very low dose of rivaroxaban 2.5 mg added. If you are 
currently taking 20mg of rivaroxaban for atrial fibrillation you will just have a one-time baseline 
blood draw and your participation will be completed. No changes to your medications will take 
place. During the first phase of the study, you will continue treatment for 7-10 days and then you 
will be asked to come to our clinical site in the morning, 12±4 hours after the last dose of 
rivaroxaban, to re-assess how sticky your platelets are. After completing this first phase you will 
start immediately the second phase of the study. 
 
During this second phase, you will stop taking aspirin. Therefore, if your standard of care 
medication was aspirin alone, you will be taking rivaroxaban alone. If your standard of care 
medication was aspirin plus either clopidogrel or ticagrelor, you will be taking clopidogrel or 
ticagrelor and rivaroxaban. After approximately 7-10 days you will be asked to return to our 
clinical site in the morning, 12±4 hours after the last dose of rivaroxaban, to perform the last 
blood draw. After this blood draw, the study will be over and you will resume your standard of 
care therapy as instructed by your treating physician. 
 
Most of your blood samples will be processed immediately. However, others will need to be 
stored and processed after the end of the study. Only laboratory staff will have access to these 
samples and your identity will be protected.  
 
WHAT ARE THE POSSIBLE DISCOMFORTS AND RISKS? 
Your study doctor will be responsible for reviewing and monitoring your well-being. 
 
The following are potential risks: 
i. 
Blood drawing. There is the discomfort of blood drawing and you may experience 
bruising, and/or bleeding where the needle is inserted.  Occasionally some people become 
dizzy or feel faint. 


 
IRB APPROVED 
 
AS MODIFIED 
 
May 06, 2019 
 
 
 
4 
ii. 
Since rivaroxaban is a blood thinner, it may make it more difficult for you to form blood 
clots that prevent you from bleeding too much. Therefore, there is a risk of bleeding from 
anywhere in your body whether or not you have a cut or injury. This may include 
bleeding that you can see like bruising (black and blue marks), or dark stool, or bleeding 
that you cannot see, like a low blood cell count. Bleeding signs may also include 
weakness, pallor (paleness or whitish skin color), dizziness, headache, chest pain or 
angina, shortness of breath, low blood pressure, or unexplained swelling. Bleeding if 
severe, may require transfusion. Bleeding from rivaroxaban is rarely fatal (seen in less 
frequently than 0.1%; less than 1 out of 1000 patients). 
 
The following terms are used to describe how often side effects have been seen in patients: 
- 
Very common: Means that it affects 1 in 10 or more patients (10% or more) 
- 
Common: Means that it affects between 1 and 10 in 100 patients (between 1% and 10%) 
- 
Uncommon: Means that affects between 1 and 10 in 1,000 patients (between 0.1% and 
1%) 
- 
Rare: Means that it affects between 1 and 10 in 10,000 patients (less than 0.1%) 
 
COMMON: Seen in 1% (1 in 100 patients) to 10% (1 in 10 patients) 
Internal bleedings which may occur in your stomach and intestines may result in a low blood 
count (anemia) or decrease in your blood pressure (hypotension). Other common bleeding sites 
include eye bleeds, bleeding from your 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) 
*this was observed after major orthopedic surgery of the lower limbs 
 
UNCOMMON: Seen in 0.1 % (1 in 1,000 patients) to 1% (1 in 100 patients): 
- 
Increased platelet count (increased number of platelets in your blood) 
- 
Increase heart rate 
- 
Dry mouth 


 
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- 
Feeling unwell 
- 
Allergic reactions and skin allergic reactions 
- 
Wound oozing 
- 
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 patients): 
- 
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 
 
After marketing authorization, the following side effects for rivaroxaban have been reported. 
Their frequency cannot be estimated from post approval experience. 
- 
Angioedema and allergic edema (swelling of the face, lips, mouth, tongue or throat) 
- 
Cholestatis (decreased bile flow), hepatitis including hepatocellular injury (inflamed 
liver, including liver injury) 
- 
Thrombocytopenia (low number of platelets which are cells that help blood to clot) 
 
Rivaroxaban is not recommended for you if a doctor has told you that you have a severe form of 
antiphospholipid syndrome, a disease which can cause blood clots. Please discuss with your 
doctor if you have been told that you have this condition. 
 
As rivaroxaban is still being studied in new indications, there may be side effects which are not 
yet known. It is important that you tell the study staff about any discomforts and health issues 
you may have during the study since these could be side effects of the study drug. If you have 
ever had an allergic reaction to rivaroxaban, you should not enroll in the study. 
 
Sometimes during a study, the sponsor may learn new facts about the study drug. It is possible 
that this information might make you change your mind about being in the study. If new 
information is discovered your study doctor will tell you about it right away. 
 
Tell your doctors or dentist that you are in a study and taking a blood thinner. This is very 
important if you have any planned or emergency surgery, dental procedures, or other procedures 
such as a colonoscopy. 
 


 
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Risks of antiplatelet therapies (Ticagrelor and Clopidogrel): 
 
• Dyspnea (shortness of breath) 
• Headache 
• Cough 
• Atrial fibrillation 
• Mild to moderate diarrhea 
• Nausea 
• Hypotension (low blood pressure) 
• Hypertension 
• Dizziness 
• Non-cardiac chest pain 
• Back Pain 
• Fatigue 
• Cardiac (heart) chest pain 
 
Risks of aspirin therapy: 
 
• bruising, 
• gastric irritation, and 
• hypersensitivity reactions. 
 
General Risk of Bleeding 
 
• Medications that restrict platelet function including aspirin, ticagrelor and clopidogrel 
increase the risk of bleeding.  Ticagrelor increased the overall risk of bleeding slightly 
more than clopidogrel. 
 
If you are a woman: 
- 
The risks of rivaroxaban to the human embryo, fetus, or breastfed infant are 
unknown. Use of rivaroxaban during pregnancy could cause serious bleeding 
resulting in emergency delivery 
- 
You cannot take part in this study if you are pregnant or breastfeeding a child 
- 
You must agree not to become pregnant while you are in this study 
- 
If you are heterosexually active and able to get pregnant you must use birth 
control during the study. The type of birth control you use must be discussed with 
the study doctor before you begin the study. The study doctor must approve the 
method you use before you can enter the study 
- 
If you get pregnant during the study, you must tell the study doctor immediately. 
You will have to stop taking the study drug. The study doctor will advise you 
about your medical care and will ask you to allow him/her to collect information 
about your pregnancy, your delivery and the health of your baby 
 


 
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If you are a man: 
- 
If your partner becomes pregnant in the time between when you start taking the 
study drug until your last dose of study drug, you must tell the study doctor 
immediately. The sponsor may ask you and your partner to allow them to collect 
information about her pregnancy, delivery, and the health of the baby 
 
i. 
You have the theoretically increased risk of forming a clot from stopping your aspirin. 
ii. 
Loss of confidentiality. 
 
To protect you from above concerns: 
i. 
The blood tests will be drawn by experienced personnel. 
ii. 
Patients who are known to have bleeding problems will not participate in this study to 
reduce this risk. 
iii. 
The data will be stored as secured coded access. 
 
This study may include risks that are unknown at this time. 
 
Taking part in more than one research study or project may further increase the risks to you. If 
you are currently enrolled or have recently taken part in another research study, you must tell the 
person reviewing this consent form with you. 
 
Throughout the study, the researchers will notify you of new information that may become 
available and might affect your decision to remain in the study. 
 
If you wish to discuss the information above or any discomforts you may experience, you may 
ask questions now or call the Principal Investigator or contact person listed on the front page of 
this form. 
 
WHAT ARE THE POSSIBLE BENEFITS TO YOU? 
Participation in this study will not help to improve your condition. It is also possible that your 
condition may worsen. There is no guarantee that you will personally benefit by participating in 
this research study. 
 
HOW COULD OTHERS POSSIBLY BENEFIT FROM THIS RESEARCH STUDY? 
Your participation in this study may help the investigators to learn more about the effects of 
administering rivaroxaban (Xarelto) in addition to clopidogrel/ticagrelor with and without 
aspirin, or aspirin alone, and may help other people in the future. 
 
HOW COULD THE RESEARCHERS BENEFIT FROM THIS RESEARCH STUDY? 
The sponsor is paying the University of Florida for conducting this research study. In general, 
presenting research results helps the career of a scientist. Therefore, the study doctor may benefit 
if the results of this study are presented at scientific meetings or in scientific journals. 
 
CONFLICT OF INTEREST 
Dr. Angiolillo is a paid consultant for Bayer pharmaceuticals the maker of rivaroxaban (Xarelto) 
which is used in the study. Jannsen co-markets the drug and is funding the study. Please feel free 
to ask any questions you may have about this matter. 


 
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IF YOU CHOOSE TO TAKE PART IN THIS STUDY, WILL IT COST YOU 
ANYTHING? 
The Sponsor will pay for the medical services that you receive as part of your participation in 
this study which are described in the section of the consent form headed by the question “What 
Will Be Done Only Because You Are In This Research Study”. This may include some medical 
services that you would have received if you were not in this study.  All other medical services 
will be billed to you or your insurance company.  You will be responsible for paying any 
deductible, co-insurance, or co-payments for those services, and for any non-covered or out-of-
network services. Some insurance companies may not cover costs associated with research 
studies.  Please contact your insurance company for additional information. 
 
WILL YOU BE PAID FOR TAKING PART IN THIS RESEARCH STUDY? 
You will be paid $30.00 in Visa debit cards for each completed study visit to help cover time and 
travel. It may take up to 48 hours to process your debit card. If you do not complete all of your 
visits you will be paid for the visits that were completed. 
 
If you are paid more than $75 for taking part in this study, your name and social security number 
will be reported to the appropriate University employees for purposes of making and recording 
the payment as required by law. You are responsible for paying income taxes on any payments 
provided by the study. Payments to nonresident aliens must be processed through the University 
of Florida Payroll and Tax Services department.  If the payments total $600 or more in a calendar 
year, the University must report the amount you received to the Internal Revenue Service (IRS). 
The IRS is not provided with the study name or its purpose. If you have questions about the 
collection 
and 
use 
of 
your 
Social 
Security 
Number, 
please 
visit: 
http://privacy.ufl.edu/SSNPrivacy.html. 
 
Your payment for participation in this research study is handled through the University of 
Florida’s Human Subject Payment (HSP) Program. Your information which will include your 
name, address, date of birth, and SSN (depending on amount of money you are paid) is 
protected.  Access to the (HSP) Program site is limited to certain staff with the assigned security 
role.  You will be randomly assigned a specific identification (ID) number to protect your 
identity. 
 
The study team will provide you with an informational form called the Prepaid Card Facts 
document.  If you have any problems regarding your payment call the HSP Office (352) 392-
9057. 
 
WHAT IF YOU ARE INJURED BECAUSE OF THE RESEARCH STUDY? 
The Principal Investigator will determine whether your injury is related to your participation in 
this study. 
 
If you are injured as a direct result of your participation in this study, only professional medical 
care that you receive at the University of Florida Health Science Center will be provided without 
charge. Hospital expenses will be billed to you or your insurance. 
 


 
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You will be responsible for any deductible, co-insurance, or co-payments. Some insurance 
companies may not cover costs associated with research studies. Please contact your insurance 
company for additional information. 
 
No additional compensation is routinely offered. 
 
The Principal Investigator and others involved in this study may be University of Florida 
employees. As employees of the University, they are protected under state law, which limits 
financial recovery for negligence. 
 
Please contact the Principal Investigator Dominick J. Angiolillo M.D. at (904) 244-3933 
weekdays between the hours of 8:00 a.m. and 5:00 p.m., after regular business hours, you may 
call (904) 244-0411 if you experience an injury or have questions about any discomforts that you 
experience while participating in this study. 
 
WHAT OTHER CHOICES DO YOU HAVE IF YOU DO NOT WANT TO BE IN THIS 
RESEARCH STUDY? 
If you choose not to participate in this study, you will still continue receiving your medical care 
just as you normally do. 
 
Aspirin, clopidogrel, ticagerol, and rivaroxaban are all marketed drugs. You might be able to 
receive the rivaroxaban as add-on treatment without being in this study. 
 
DO YOU HAVE TO BE IN THIS STUDY? 
Your participation in this study is voluntary. You may decide not to participate or you may leave 
the study at any time. Your decision will not result in any penalty or loss of benefits to which 
you are entitled. 
 
If you leave this study for any reason, please contact Dominick J. Angiolillo, M.D., Ph.D. at 904-
244-3933 or 904-244-0411 (24 hours).  They will tell you how to stop your participation safely. 
 
CAN YOU BE WITHDRAWN FROM THIS RESEARCH STUDY? 
The FDA, your study doctor, your local institution, has the right to stop your participation in the 
study, or cancel the study, without your consent at any time. Your study doctor may take you off 
the study at any time for any of the following reasons: 
• if he/she decides it is in your best interest. 
• if you do not consent to continue in the study after being told of changes in the research 
that may affect you; 
• or for any reason. 
 


 
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AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR RESEARCH 
PURPOSES 
If you agree to participate in this study, the study doctor will create, collect, and use private 
information about you and your health. This information is called protected health information or 
PHI. In order to do this, the study doctor needs your authorization. The following section 
describes what PHI will be collected, used and shared, how it will be collected, used, and shared, 
who will collect, use or share it, who will have access to it, how it will be secured, and what your 
rights are to revoke this authorization. 
 
Your protected health information may be collected, used, and shared with others to determine if 
you can participate in the study, and then as part of your participation in the study. This 
information can be gathered from you or your past, current or future health records, from 
procedures such as physical examinations, x-rays, blood or urine tests or from other procedures or 
tests. This information will be created by receiving study treatments or participating in study 
procedures, or from your study visits and telephone calls.  More specifically, the following 
information may be collected, used, and shared with others: 
 
• Complete past medical history to determine eligibility criteria 
• Records of physical exams 
• Laboratory, x-ray, MRI, and other test results 
• Records about study medications or drugs 
 
This information will be stored in locked filing cabinets or in computers with security passwords. 
 
Some of the information collected could be included in a "limited data set" to be used for other 
research purposes.  If so, the limited data set will include only information that does not directly 
identify you. For example, the limited data set cannot include your name, address, telephone 
number, social security number, or any other photographs, numbers, codes, or so forth that link 
you to the information in the limited data set.  If limited data sets are created and used, 
agreements between the parties creating and receiving the limited data set are required in order to 
protect your identity and confidentiality and privacy. 
 
Your PHI may be collected, used, and shared with others to make sure you can participate in the 
research, throughout your participation in the research, and to evaluate the results of the research 
study.  More specifically, your PHI may be collected, used, and shared with others for the 
following study-related purpose(s): 
 
• to determine the effectiveness of the study drug  in treating coronary or peripheral artery 
disease and atrial fibrillation 
• to evaluate a possible new use for the study drug  
 
Once this information is collected, it becomes part of the research record for this study. 
 


 
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Only certain people have the legal right to collect, use and share your research records, and they 
will protect the privacy and security of these records to the extent the law allows. These people 
include: 
 
• the study doctor, and research staff associated with this project 
• other professionals at the University of Florida or Shands Hospital that provide study-
related treatment or procedures 
• The University of Florida Institutional Review Board 
 
Your PHI may be shared with: 
 
• the study sponsor University of Florida. 
• United States and foreign governmental agencies who are responsible for overseeing 
research, such as the Food and Drug Administration, the Department of Health and Human 
Services, and the Office of Human Research Protections 
• Government agencies who are responsible for overseeing public health concerns such as 
the Centers for Disease Control and federal, state and local health departments 
• Western Institutional Review Board 
• Your insurance company for purposes of obtaining payment 
 
Otherwise, your research records will not be released without your permission unless required by 
law or a court order. It is possible that once this information is shared with authorized persons, it 
could be shared by the persons or agencies who receive it and it would no longer be protected by 
the federal medical privacy law. 
 
Your PHI will be used and shared with others until the end of study. 
 
This information will be destroyed 2 years after research is conducted or longer per University of 
Florida and/or FDA requirements. 
 
You may not be allowed to see or copy certain information in your medical records collected in 
connection with your participation with this study while the research is in progress if the research 
includes treatment. When the research study is completed you will have access to inspect or copy 
your records with certain exceptions under applicable law. 
 
You are not required to sign this consent and authorization or allow researchers to collect, use 
and share your PHI. Your refusal to sign will not affect your treatment, payment, enrollment, or 
eligibility for any benefits outside this research study. However, you cannot participate in this 
research unless you allow the collection, use and sharing of your protected health information by 
signing this consent and authorization. 
 
You have the right to review and copy your protected health information. However, we can make 
this available only after the study is finished. 
 


 
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You can revoke your authorization at any time before, during, or after your participation in this 
study.  If you revoke it, no new information will be collected about you. However, information 
that was already collected may still be used and shared with others if the researchers have relied 
on it to complete the research. You can revoke your authorization by giving a written request 
with your signature on it to the study doctor. 
 
Your withdrawal must be made in writing and sent to Dominick J. Angiolillo, M.D. Ph.D., 655 
West 8th Street, Jacksonville, Florida 32209. 
 
NEW INFORMATION ON THE STUDY DRUG 
You will be informed about any new information, such as adverse reactions (side effects) that 
could affect your decision to continue in this study. You may be asked to sign a new consent 
form if that should occur. 
 
WHAT IF I BECOME PREGNANT DURING THE STUDY? 
If you are pregnant or nursing before you enroll in the study, you may not participate in the 
study. 
 
WHERE CAN I FIND INFORMATION ABOUT THE STUDY? 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
WHO WOULD YOU CALL IF YOU HAVE ANY QUESTIONS? 
If you have questions about the study, please ask us before signing this form. If you require 
further general information regarding the research study, if at any time you feel you have had 
a research-related injury or reaction to the study drug, or if you have questions, concerns or 
complaints about the research please contact: 
 
Dominick J. Angiolillo, M.D., Ph.D. at 904-244-3933 or 904-244-0411 (24 hours). 
 
If you have questions about your rights as a research subject or if you have questions, concerns or 
complaints about the research, you may contact: 
 
Western Institutional Review Board® (WIRB®) 
1019 39th Avenue SE Suite 120 
Puyallup, Washington  98374-2115 
Telephone:  1-800-562-4789 or 360-252-2500 
E-mail: Help@wirb.com 
 
or 
 
The University of Florida in Jacksonville at (904) 244-9478. 
 
WIRB is a group of people who perform independent review of research. 
 


 
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WIRB will not be able to answer some study-specific questions, such as questions about 
appointment times.  However, you may contact WIRB if the research staff cannot be reached or 
if you wish to talk to someone other than the research staff. 
 
CONSENT TO PARTICIPATE IN THIS RESEARCH STUDY 
I have been informed about this study’s purpose, procedures, possible benefits and risks. I have 
also been told alternatives to being in the study and how my protected health information will be 
collected, used, and shared with others. I have been given the opportunity to ask questions. My 
questions have all been answered satisfactorily. I agree to be in this research study. I have 
received a copy of this form. 
 
By signing this consent form, I have not given up any of my legal rights. 
 
I authorize the release of my medical records for research or regulatory purposes to those agencies 
listed under the Authorization section of this consent form. 
 
 
 
 
Name of Participant (Print) 
Date 
 
 
 
 
Signature of Participant 
 
As an investigator or the investigator’s representative, I have explained to the participant the 
purpose, the procedures, the possible benefits, and the risks of this research study, the alternative 
to being in the study; and how the subject’s protected health information will be collected, used, 
and shared with others: 
 
 
 
 
 
 
Printed name of person conducting informed consent discussion 
Position 
 
 
 
 
 
 
Signature of person conducting informed consent discussion 
Date