Pharmacodynamic Effects of Low-dose Rivaroxaban in Combination With Antiplatelet Therapies in Patients With Coronary and Peripheral Artery Disease Manifestations
Phase: PHASE4
Conditions: Coronary Artery Disease, Peripheral Arterial Disease, Atrial Fibrillation
Sponsor: University of Florida

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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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• 
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 

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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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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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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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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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• 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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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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None 
 
Conflict of Interest 
Dr. Angiolillo is a consultant for Janssen and Bayer, the makers of rivaroxaban. 
 
 

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References 
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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 
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rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes 
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1808. 
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1:S10-6. 
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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. 
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CP, Tanguay JF, Granger CB, Mauri L, Holmes DR, Gibson CM, Faxon DP. 
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13. Björkman JA, Zachrisson H, Forsberg GB, von Bahr H, Hansson GI, Warner TD, 
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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. 
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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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 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.