Switching From Standard of Care Dual Antiplatelet Treatment (DAPT) Regimens With Aspirin Plus a P2Y12 Inhibitor to Dual Pathway Inhibition (DPI) With Low-dose Rivaroxaban in Adjunct to Aspirin in Patients With Coronary Artery Disease: The Switching Anti-Platelet and Anti-Coagulant Therapy (SWAP-AC) Study
Phase: PHASE4
Conditions: Coronary Artery Disease
Sponsor: University of Florida

Confidential 
February 8, 2019 Protocol version 2 
 
1 
 
 
Switching from standard of care dual antiplatelet treatment (DAPT) regimens with aspirin 
plus a P2Y12 inhibitor to dual pathway inhibition (DPI) with low-dose rivaroxaban in 
adjunct to aspirin in patients with coronary artery disease:  
The Switching Anti-Platelet and Anti-Coagulant Therapy (SWAP-AC) Study 
 
 
 
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 
 
 
 
 

Confidential 
February 8, 2019 Protocol version 2 
 
2 
 
STUDY BACKGROUND AND RATIONALE 
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 
percutaneous coronary intervention (PCI) with stent implantation [3,4]. However, the pivotal role 
of thrombin on thrombotic processes, as well as on inflammatory reactions, has also raised 
interest on strategies targeting thrombin-mediated effects. Recently, the results of the COMPASS 
(Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial have been reported 
[5]. In this trial, patients with stable coronary or peripheral artery disease and no indication for 
oral anticoagulation or DAPT were randomized to rivaroxaban 2.5 mg bid in combination with 
aspirin, rivaroxaban 5 mg bid monotherapy or aspirin monotherapy. The study was stopped early 
after a mean follow-up of 23 months due to evidence of a significant 24% relativereduction in 
ischemic outcomes (including a significant reduction in cardiovascular mortality) with 
rivaroxaban 2.5 mg bid plus aspirin combination strategy (4.1% versus 5.4%; P<0.001), at the 
price of a 70% increase in major bleeding compared with placebo (but no significant increase in 
fatal and intracranial bleeding) (3.1% versus 1.9%; P<0.001) [5]. 
The results of the COMPASS trial have questioned how to implement the aspirin plus 
rivaroxaban dosing regimen, also known as dual pathway inhibition (DPI), in clinical practice, 

Confidential 
February 8, 2019 Protocol version 2 
 
3 
 
particularly in patients who have been on guideline recommended treatment with DAPT after 
undergoing elective PCI or having experienced an ACS. In patients undergoing elective PCI, 
clopidogrel is the P2Y12 inhibitor of choice, while after an ACS, prasugrel and ticagrelor are 
preferred over clopidogrel in the absence of contraindications [6,7]. Standard of care DAPT 
duration is 6 months in patients undergoing elective PCI and receiving drug eluting stent and 12 
months after an ACS [6,7]. In patients who are not at high ischemic risk, P2Y12 inhibiting 
therapy is generally not continued beyond this time frame, while P2Y12 inhibiting therapy may 
be discontinued sooner in patients at high bleeding risk. On the contrary, prolonging DAPT may 
be considered in patients at high ischemic risk who have tolerated DAPT and are not at high 
bleeding risk [6,7]. Nevertheless, these patients may also be candidates for DPI therapy with 
aspirin plus low-dose rivaroxaban. However, in the COMPASS trial patients were mostly on 
single antiplatelet therapy with aspirin at the time of enrollment and in general remote from their 
index event (e.g., mean 7 years from MI) [5].  
These observations have raised practical considerations on how to implement the results 
of the COMPASS trial in clinical practice particularly for patients who are completing their 
minimum duration of DAPT and contemplating between continuing with a DAPT regimen 
versus switching to a DPI regimen with aspirin plus rivaroxaban. Therefore, the objectives of this 
investigation are to assess the feasibility of switching from a DAPT to DPI regimen and to 
compare the pharmacodynamic profiles of these treatment regimens.  
 
 
 
 

Confidential 
February 8, 2019 Protocol version 2 
 
4 
 
REASERCH PLAN 
Study design 
This will be a prospective study conducted in cohorts of patients with CAD on treatment 
per standard of care with DAPT for at least 6 months after elective PCI and 12 months after an 
ACS. Patients treated with either aspirin (81mg/qd) plus clopidogrel, aspirin (81mg/qd) plus 
ticagrelor (90mg/bid), or aspirin (81mg/qd) plus prasugrel (10mg/bid) will be identified. The 
study will be performed at the Division of Cardiology of University of Florida Health, 
Jacksonville, Florida. 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 randomized to either 
maintain DAPT or to DPI. DPI consists in treatment with aspirin (81mg/qd) plus rivaroxaban 
(2.5mg/bid). Patients randomized to DAPT will continue the guideline recommended DAPT 
regimens. Therefore, in adjunct to low-dose aspirin (81mg), clopidogrel (75mg/qd) and prasugrel 
(10mg/qd) will be mainted at the same dosing regimen, while ticagrelor dosing will be reduced 
from 90mg/bid to 60mg/bid. Randomized treatment will be maintained for 30±3 days. PD 
assessments will be conducted at 3 time points: i) baseline (while on standard of care DAPT 
therapy) before the administration of the morning doses of antiplatelet therapy; ii) 30±3 days 
after randomization before the administration of the morning doses of antithrombotic therapy 
(trough levels); iii) 30±3 days after randomization 2 hours after the administration of the 

Confidential 
February 8, 2019 Protocol version 2 
 
5 
 
morning doses of antithrombotic therapy (peak levels). Figure 1 illustrates the overall study 
design.  
 
Figure 1. Study design 
 
 
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 
and peak levels of effects of antithrombotic agents, in order to better assess profiles of response 
to low-dose rivaroxaban. 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), serious 
adverse events (bleeding and other adverse events), as well as non-serious adverse events 

Confidential 
February 8, 2019 Protocol version 2 
 
6 
 
considered to be related to rivaroxaban will be collected. After completing the study, patients 
will resume an antithrombotic treatment regimen at the discretion of the treating physician.    
 
Study population 
A total of 90 CAD patients will be recruited (30 patients per cohort). Patients with CAD 
who have completed their required duration of DAPT after an elective PCI (i.e., 6 month) or an 
after experiencing an ACS (i.e., 12 months), but still on treatment, will be screened. Specific 
study entry criteria  are described below. 
 
Inclusion criteria: 
• Willing and able to provide written informed consent 
• Above 18 years of age 
• Have known CAD and have completed their required duration of standard of care DAPT 
(aspirin in combination with either clopidogrel, prasugrel, or ticagrelor) and still be on 
treatment:   
o ≥ 6 months after an elective PCI  
o ≥ 12 months after experiencing an ACS (irrespective of revascularization at the 
time of ACS; thus patients treated by PCI, CABG, or medically managed can be 
considered) 
 
Exclusion criteria: 
• Deemed to be at high risk of bleeding, active bleeding or history of major bleeding 
Stroke within 1 month or any history of hemorrhagic or lacunar stroke 
• Estimated glomerular filtration rate <15 mL/min by MDRD equation 
• Need for dual antiplatelet therapy, other non-aspirin antiplatelet therapy, or oral 
anticoagulant therapy 
• Known non-cardiovascular disease that is associated with poor prognosis (e.g., metastatic 
cancer) or that increases the risk of an adverse reaction to study interventions. 

Confidential 
February 8, 2019 Protocol version 2 
 
7 
 
• History of hypersensitivity or known contraindication for rivaroxaban. 
• Systemic treatment with strong inhibitors of both CYP 3A4 and p-glycoprotein (e.g., 
systemic azole antimycotics, such as ketoconazole, and human immunodeficiency virus 
[HIV]-protease inhibitors, such as ritonavir), or strong inducers of CYP 3A4, i.e. 
rifampicin, rifabutin, phenobarbital, phenytoin, and carbamazepine 
• Any known hepatic disease associated with coagulopathy 
• Subjects who are pregnant, breastfeeding, or are of childbearing potential, and sexually 
active and not practicing an effective method of birth control (e.g. surgically sterile, 
prescription oral contraceptives, contraceptive injections, intrauterine device, double 
barrier method, contraceptive patch, male partner sterilization) 
• Concomitant participation in another study with investigational drug 
• Known contraindication to any study related procedures 
• Hemoglobin ≤9 mg/dL 
• Platelet count <80x106/mL 
 
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 for PD will be performed at 3 time points as described above and shown in the 
study design section. The following tests will be performed to explore platelet aggregation, 
thrombin generation, and thrombus formation 
1. 
VerifyNow PRU 
2. 
Light Transmittance Aggregometry (LTA)  
3. 
Thrombelastograph Coagulation Analyzer TEG 6s Series system 
4. 
Thrombin Generation 
 

Confidential 
February 8, 2019 Protocol version 2 
 
8 
 
Laboratory assessments including VerifyNow PRU, LTA, and TEG will be performed within 30-
60 minutes of sample collection. 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 
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 

Confidential 
February 8, 2019 Protocol version 2 
 
9 
 
platelets bind and aggregate fibrinogen-coated beads. The instrument measures this change in 
optical signal and reports results in P2Y12 Reaction Units (PRU). 
2) 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), thrombin 
receptor activating peptide (TRAP;15 μM) and ADP (5 and 20 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.  
3) TEG 6s Series system: the TEG 6s system (Haemonetics Corporation, Braintree, MA, USA) 
will be used according to manufacture instructions [9]. 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 

Confidential 
February 8, 2019 Protocol version 2 
 
10 
 
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 
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. 

Confidential 
February 8, 2019 Protocol version 2 
 
11 
 
4) Thrombin Generation Assay: TGA assays will be performed using PPP samples prepared 
from the various treatment groups [10]. 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 
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, thrombin generation, and thrombus formation between DAPT and low-dose 
rivaroxaban plus aspirin for each DAPT regimen at 30 days. Exploratory end points will include 
the intragroup comparison between aspirin plus ticagrelor 90 mg bid and low-dose rivaroxaban 
plus aspirin. Since there are no preliminary data exploring the PD effects of low-dose 
rivaroxaban in addition to aspirin and how this compare with DAPT, we arbitrarily chose a 
sample size of 90 patients (30 patients per cohort). This approach is in line with guidelines for 
pilot investigations [11]. 

Confidential 
February 8, 2019 Protocol version 2 
 
12 
 
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 intergroup comparisons of continuous 
variables will be performed with an analysis of covariance with a general linear model with 
baseline value of the corresponding platelet function test as a covariate. Intragroup comparisons 
will be performed with paired sample t-test or Wilcoxon test 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 6 
subjects monthly and complete enrollment in 15 months (total: 90 subjects enrolled). Months 16-
18 will be implied for statistical analysis and months 19-20 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 
[11]. 

Confidential 
February 8, 2019 Protocol version 2 
 
13 
 
 
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 30 days of therapy. We 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) 

Confidential 
February 8, 2019 Protocol version 2 
 
14 
 
An adverse event is any untoward medical occurrence in a clinical study subject administered a 
medicinal (investigational or non-investigational) product. An adverse event does not necessarily 
have a causal relationship with the treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational or non- investigational) product, whether or not related 
to that medicinal (investigational or non-investigational) product. (Definition per International 
Conference on Harmonisation [ICH]). 
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities. 
 
b. Adverse Events of Special Interest  
Events that Janssen Scientific Affairs is actively monitoring as a result of a previously identified 
signal (even if non-serious).  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 
 

Confidential 
February 8, 2019 Protocol version 2 
 
15 
 
The minimum information required is: 
• suspected Janssen product (doses, indication) 
• date of therapy (start and end date, if available) 
• batch or lot number, if available 
• subject details (subject ID and country) 
• gender 
• age at AE onset 
• reporter ID 
• adverse event detail (AE verbatim in English), onset date, relatedness, causality, action 
taken, outcome, (if available) 
• Janssen protocol ID 
 
d. Product Quality Complaint (PQC) 
A product quality compliant is related to a potential quality issue during manufacturing, 
packaging, release testing, stability monitoring, dose preparation, storage or distribution of the 
product, or delivery system.  Not all PQCs involve a subject.  Lot and batch numbers are of high 
significance and need to be collected whenever available. 
 
Examples of PQC include but not limited to: 
• Functional Problem: e.g., altered delivery rate in a controlled release product 
• Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
• Potential Dosing Device Malfunction: e.g.,  autoinjector button not working, needle 
detaching from syringe 
• 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: 
 

Confidential 
February 8, 2019 Protocol version 2 
 
16 
 
• 
Results in death 
• 
Is life-threatening 
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is a suspected transmission of any infectious agent via a medicinal product 
• 
Is medically important* 
 
*Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in other situations, such as important medical events that may 
not be immediately life threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should usually be considered serious. 
 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS 
ADVERSE EVENT. 
 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the hospitalization 
that is the serious event for which details must be provided. 
 
Any event requiring in-patient hospital admission (or the prolongation of hospitalization) must be 
reported as an SAE. Events that do not meet the criteria for SAE reporting are: 
• Reasons described in the Protocol, e.g. drug administration, Protocol-required testing 
• Social reasons, e.g. overnight stay because of distance between home and hospital 
• Surgery or procedure planned and documented prior to entry into the Study. 
 
Any event requiring hospitalization or prolongation of hospitalization that occurs during the 
study must be reported as a serious adverse event, except hospitalizations for the following: 

Confidential 
February 8, 2019 Protocol version 2 
 
17 
 
• Hospitalizations not intended to treat an acute illness or adverse event (e.g., social 
reasons such as pending placement in long-term care facility) 
• Surgery or procedure planned before entry into the study. [Note: Hospitalizations 
that were planned before the start of data collection and where the underlying 
condition for which the hospitalization was planned has not worsened will not be 
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) 

Confidential 
February 8, 2019 Protocol version 2 
 
18 
 
• Suspected transmission of any infectious agent via a medicinal  
• Unexpected therapeutic or clinical benefit from use of a Janssen medicinal product 
 
These safety events may not meet the definition of an adverse event; however, they are treated 
in the same manner as adverse events. Special situations should be recorded on the Adverse 
Event page of the CRF. 
 
Any special situation that meets the criteria of a serious adverse event should be recorded on a 
Serious Adverse Event Report Form and be reported to Janssen Scientific Affairs within 24 
hours of becoming aware of the event. 
 
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. 
 
 

Confidential 
February 8, 2019 Protocol version 2 
 
19 
 
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 
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 

Confidential 
February 8, 2019 Protocol version 2 
 
20 
 
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 annually and 
with the final study report. 
 
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. 
 
 

Confidential 
February 8, 2019 Protocol version 2 
 
21 
 
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 
• 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. 

Confidential 
February 8, 2019 Protocol version 2 
 
22 
 
 
 
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. 
 
X. 
SAEs Listing 
At a minimum, on a semi-annual basis and at the end of the Study, COMPANY will provide to the 
INSTITUTION and/or PRINCIPAL INVESTIGATOR, a listing of all SAEs reported to the 
COMPANY. SPONSOR and/or PRINCIPAL INVESTIGATOR will review this listing and will 
resolve any discrepancies with the data provided by the COMPANY. 
 
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. 
 

Confidential 
February 8, 2019 Protocol version 2 
 
23 
 
Potential Financial Risks or Benefits 
 
None 
 
Conflict of Interest 
Dr. Angiolillo is a consultant for Janssen and Bayer, the makers of rivaroxaban. 
 
 

Confidential 
February 8, 2019 Protocol version 2 
 
24 
 
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. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in 
Stable Cardiovascular Disease. N Engl J Med. 2017;377:1319-1330. 
6. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on 
Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A 
Report of the American College of Cardiology/American Heart Association Task Force 
on Clinical Practice Guidelines. Circulation 2016;134:e123-155. 

Confidential 
February 8, 2019 Protocol version 2 
 
25 
 
7. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet 
therapy in coronary artery disease developed in collaboration with EACTS: The Task 
Force for dual antiplatelet therapy in coronary artery disease of the European Society of 
Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery 
(EACTS). Eur Heart J 2018;39:213-260. 
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. 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. 
10. Hemker HC, Kremers R. Data management in thrombin generation. Thromb Res. 
2013;131:3-11 
11. Lancaster GA, Dodd S, Williamson PR. Design and analysis of pilot studies: 
recommendations for good practice. J Eval Clin Pract. 2004; 10: 307-12