Clinical trial NCT02545933
Conditions: Myocardial Infarction
Keywords: prasugrel ticagrelor vorapaxar
Sponsor: University of Florida
Start date: 2016-02-01; Completion date: 2020-01-01
Enrollment: 130 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor represents the standard of care for the long-term secondary prevention of atherothrombotic events in patients with myocardial infarction (MI). However, rates of ischemic recurrences remain high, which may be in part due to the fact that other platelet signaling pathways, such as thrombin-induced platelet aggregation, continue to be activated. Vorapaxar is a protease-activated receptor (PAR)-1 inhibitor, which exerts potent inhibition of thrombin-mediated platelet aggregation. It is approved for clinical use by the Food and Drug Administration for the reduction of thrombotic cardiovascular events in patients with a history of MI or with peripheral arterial disease. However, to date clinical trial experience with vorapaxar has been almost exclusively with the P2Y12 receptor inhibitor clopidogrel and the effects of vorapaxar in combination with antiplatelet therapy including prasugrel or ticagrelor, is largely unexplored. Further, the role of vorapaxar as part of a dual antithrombotic treatment regimen, in addition to a novel P2Y12 receptor inhibitor, with withdrawal of aspirin, represents another important area of clinical interest as it has the potential to maximize ischemic protection while reducing the risk of bleeding. The proposed prospective, randomized, parallel-design, open label, study conducted in a real world clinical setting of post-MI patients will aim to assess the pharmacodynamic effects of vorapaxar in addition to antiplatelet therapy with a novel P2Y12 receptor inhibitor (prasugrel or ticagrelor) with and without aspirin.

Detailed description:
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor represents the standard of care for the long-term secondary prevention of atherothrombotic events in patients with myocardial infarction (MI). The novel P2Y12 receptor inhibitors prasugrel and ticagrelor are characterized by more prompt, potent, and predictable antiplatelet effects compared with clopidogrel and are associated with a greater reduction of ischemic events in acute coronary syndrome patients. However, rates of ischemic recurrences remain high, which may be in part due to the fact that other platelet signaling pathways, such as thrombin-induced platelet aggregation, continue to be activated. Vorapaxar is a novel, orally active, competitive and slowly reversible protease-activated receptor (PAR)-1 inhibitor, which exerts potent inhibition of thrombin-mediated platelet aggregation. It is approved for clinical use by the Food and Drug Administration for the reduction of thrombotic cardiovascular events in patients with a history of MI or with peripheral arterial disease. A large-scale clinical trial showed that the use of vorapaxar (2.5 mg once/daily) in addition to standard antiplatelet therapy (including aspirin and a P2Y12 receptor inhibitor) was effective in the secondary prevention of recurrent thrombotic events in patients with previous atherothrombosis, in particular in patients with prior MI, at the expense of an increase in major bleeding. However, to date clinical trial experience with vorapaxar has been almost exclusively with the P2Y12 receptor inhibitor clopidogrel and the effects of vorapaxar in combination with state-of-the-art antiplatelet therapy in the post-MI setting, including prasugrel or ticagrelor, is largely unexplored. This may indeed represent a limitation for the uptake of vorapaxar in modern day clinical practice where these agents are being more broadly utilized. Further, the role of vorapaxar as part of a dual antithrombotic treatment regimen, in addition to a novel P2Y12 receptor inhibitor, with withdrawal of aspirin, represents another important area of clinical interest as it has the potential to maximize ischemic protection while reducing the risk of bleeding. The proposed prospective, randomized, parallel-design, open label, study conducted in a real world clinical setting of post-MI patients will aim to assess the pharmacodynamic effects of vorapaxar in addition to antiplatelet therapy with a novel P2Y12 receptor inhibitor (prasugrel or ticagrelor) with and without aspirin. Pharmacodynamic assessments will be performed at multiple time points and with different assays exploring multiple pathways of platelet aggregation. Exploratory assessments on the safety of such approach will also be evaluated.

Arms: arm 1: Aspirin plus prasugrel or ticagrelor plus vorapaxar 2.5mg od arm 2: Prasugrel or ticagrelor plus vorapaxar 2.5mg od arm 3: Aspirin in addition to prasugrel or ticagrelor
Interventions: intervention 1: Prasugrel intervention 2: Vorapaxar intervention 3: Aspirin intervention 4: Ticagrelor
Intervention descriptions: intervention 1: Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily) intervention 2: Vorapaxar will be administered at the dose of 2.5mg once daily intervention 3: Aspirin will be administered at the dose of 81mg once daily intervention 4: Patients will continue treatment with either prasugrel (10mg once daily) or ticagrelor (90mg twice/daily)

Protocol documents:
Prot_SAP_000.pdf: 
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Adjunctive Vorapaxar Therapy in Patients with Prior Myocardial Infarction  
Treated with New Generation P2Y12 Receptor Inhibitors Prasugrel and Ticagrelor (VORA-
PRATIC): A Prospective, Randomized, Pharmacodynamic Study 
 
 
 
 
 
 
 
 
Dominick J. Angiolillo, MD, PhD 
University of Florida College of Medicine-Jacksonville 
655 West 8th Street 
Jacksonville, Florida, 32209 
Tel: +1-904-244-3933 
Fax: +1-904-244-3102 
E-mail: dominick.angiolillo@jax.ufl.edu    
 
 
 
 
 
 


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Summary  
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor represents the standard 
of care for the long-term secondary prevention of atherothrombotic events in patients with 
myocardial infarction (MI). The novel P2Y12 receptor inhibitors prasugrel and ticagrelor are 
characterized by more prompt, potent, and predictable antiplatelet effects compared with 
clopidogrel and are associated with a greater reduction of ischemic events in acute coronary 
syndrome patients. However, rates of ischemic recurrences remain high, which may be in part due 
to the fact that other platelet signaling pathways, such as thrombin-induced platelet aggregation, 
continue to be activated. Vorapaxar is a novel, orally active, competitive and slowly reversible 
protease-activated receptor (PAR)-1 inhibitor, which exerts potent inhibition of thrombin-mediated 
platelet aggregation. It is approved for clinical use by the Food and Drug Administration for the 
reduction of thrombotic cardiovascular events in patients with a history of MI or with peripheral 
arterial disease. A large-scale clinical trial showed that the use of vorapaxar (2.5 mg once/daily) in 
addition to standard antiplatelet therapy (including aspirin and a P2Y12 receptor inhibitor) was 
effective in the secondary prevention of recurrent thrombotic events in patients with previous 
atherothrombosis, in particular in patients with prior MI, at the expense of an increase in major 
bleeding. However, to date clinical trial experience with vorapaxar has been almost exclusively with 
the P2Y12 receptor inhibitor clopidogrel and the effects of vorapaxar in combination with state-of-
the-art antiplatelet therapy in the post-MI setting, including prasugrel or ticagrelor, is largely 
unexplored. This may indeed represent a limitation for the uptake of vorapaxar in modern day 
clinical practice where these agents are being more broadly utilized. Further, the role of vorapaxar 
as part of a dual antithrombotic treatment regimen, in addition to a novel P2Y12 receptor inhibitor, 


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with withdrawal of aspirin, represents another important area of clinical interest as it has the 
potential to maximize ischemic protection while reducing the risk of bleeding. The proposed 
prospective, randomized, parallel-design, open label, study conducted in a real world clinical setting 
of post-MI patients will aim to assess the pharmacodynamic effects of vorapaxar in addition to 
antiplatelet therapy with a novel P2Y12 receptor inhibitor (prasugrel or ticagrelor) with and without 
aspirin. Pharmacodynamic assessments will be performed at multiple time points and with different 
assays exploring multiple pathways of platelet aggregation. Exploratory assessments on the safety 
of such approach will also be evaluated.


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Background and Significance 
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor represents the 
standard of care for the long-term secondary prevention of atherothrombotic events in patients with 
myocardial infarction (MI) [1]. Clopidogrel is the most widely used P2Y12 receptor inhibitor and the 
use of DAPT with aspirin and clopidogrel has consistently demonstrated to reduce the risk of 
thrombotic recurrences in patients with acute coronary syndrome (ACS) [2]. However, clopidogrel 
is a prodrug characterized by high interindividual response variability [3]. The novel P2Y12 receptor 
inhibitors prasugrel and ticagrelor are characterized by more prompt, potent, and predictable 
antiplatelet effects compared with clopidogrel and are associated with a greater reduction of 
ischemic events in ACS patients, at the expense of an increase in major bleeding [4,5]. However, 
despite adequate cyclooxygenase-1 (COX-1) and ADP P2Y12-receptor blockade, rates of ischemic 
recurrences remain high, which may be in part due to the fact that other platelet signaling pathways, 
such as thrombin-induced platelet aggregation, continue to be activated and can thus contribute to 
thrombus formation [2,6,7]. In particular, the serine protease thrombin is one of the most potent 
platelet activators and the surface of activated platelets is the main source of circulating thrombin, 
especially following an ACS [6-8]. Vorapaxar is a novel, orally active, highly selective, competitive 
and slowly reversible protease-activated receptor (PAR)-1 inhibitor, which exerts potent inhibition 
of thrombin-mediated platelet activation and aggregation [9,10]. After oral administration vorapaxar 
is rapidly absorbed with high bioavailability (>90%) and is metabolized by cytochrome P450 (CYP) 
3A4. Pharmacokinetic studies have shown that vorapaxar has a dissociation half-life as long as 20 
hours which leads to consistent pharmacodynamic (PD) effects [9,10]. Importantly, there is an 


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interplay between purinergic and thrombin mediated platelet signaling pathways which may result 
in enhanced P2Y12 inhibition when vorapaxar is added to DAPT [11].  
Recently, vorapaxar (2.5 mg once daily) has been approved for clinical use by the US Food 
and Drug Administration (FDA) for the reduction of thrombotic cardiovascular events in patients 
with a history of MI or with peripheral arterial disease (PAD), and must be used in addition to 
standard-of-care antiplatelet therapy with aspirin and/or clopidogrel [12]. Vorapaxar has been also 
approved by the European Medicines Agency for the treatment of patients with previous MI [13]. 
These indications are largely attributed to the findings of the TRA 2P-TIMI 50 (Thrombin Receptor 
Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events - Thrombolysis in 
Myocardial Infarction 50) trial [14]. In particular, the trial showed that the use of vorapaxar (2.5 mg 
once/daily) in addition to standard antiplatelet therapy [including aspirin (94% of patients), a 
thienopyridine, or both (DAPT in 58% of patients; the thienopyridine was clopidogrel in 99.3% of 
patients)] was effective in the secondary prevention of recurrent thrombotic events (cardiovascular 
death, MI, or stroke) in patients with previous atherothrombosis, in particular in patients with prior 
MI, at the cost of increased bleeding [14,15]. However, the effects of vorapaxar in combination with 
state-of-the-art antiplatelet therapy in the post-MI setting, including prasugrel or ticagrelor, is 
largely unexplored.  
 
Study Rationale 
To date clinical trial experience with vorapaxar has been almost exclusively with the P2Y12 
receptor inhibitor clopidogrel and the effects of vorapaxar in combination with state-of-the-art 
antiplatelet therapy in the post-MI setting, including prasugrel or ticagrelor, is largely unexplored. 


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This may indeed represent a limitation for the uptake of vorapaxar in modern day clinical practice 
where these agents are being more broadly utilized [1,2]. This knowledge gap represents an 
important area for exploratory research as it represents how vorapaxar could potentially be used in 
daily clinical practice. Further, given the potent and comprehensive antiplatelet effects achieved 
with the novel P2Y12 receptor inhibitors, the role of aspirin when added to these agents have been 
questioned [16,17]. Prasugrel and ticagrelor are effective in inhibiting both ADP P2Y12-dependent 
and thromboxane A2-dependent pathways of platelet aggregation [16,17]. In particular, the platelet 
inhibition achieved by combining aspirin and a potent P2Y12-receptor blocker was shown to be no 
greater than that produced by the P2Y12-receptor blocker alone in healthy volunteers [16,17]. 
Therefore, the role of vorapaxar as part of a dual antithrombotic treatment regimen including 
prasugrel or ticagrelor and stopping aspirin, represents another important area of clinical interest as 
it has the potential to maximize ischemic protection while reducing the risk of bleeding. 
 
Study Aims 
 
To assess the pharmacodynamic effects of vorapaxar in addition to antiplatelet therapy with 
a novel P2Y12 receptor inhibitor (prasugrel or ticagrelor) with and without aspirin in a real-world 
setting of post-MI patients. Exploratory assessments on the safety will also be evaluated.  
 
Research Plan 
Study Population 
Inclusion criteria: 
1. Patients with a prior MI within the previous 12 months. 


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2. On DAPT with low-dose aspirin (81mg od) and either prasugrel (10mg od) or ticagrelor (90mg 
bid) as per standard-of-care. 
3. Free from bleeding and ischemic events after the index MI event. 
4. Age between 18 and 75 years old. 
Exclusion criteria: 
 
1. History of stroke, transient ischemic attack, or intracranial hemorrhage. 
2. Active pathological bleeding, history of bleeding events or increased risk of bleeding. 
3. Known severe hepatic impairment. 
4. Age >75 years. 
5. Body weight <60 Kg. 
6. Use of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, clarithromycin, 
nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and 
conivaptan) or inducers (e.g., rifampin, carbamazepine, St. John’s Wort and phenytoin). 
7. On treatment with any oral anticoagulant (vitamin K antagonists, dabigatran, rivaroxaban, 
apixaban, edoxaban). 
8. On treatment with any antiplatelet agent other than aspirin, prasugrel and ticagrelor in the past 
14 days.  
9. Creatinine clearance <30 mL/minute. 
10. Platelet count <80x106/mL 
11. Hemoglobin <10g/dL 
12. Hemodynamic instability 


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13. Pregnant females [women of childbearing age must use reliable birth control (i.e. oral 
contraceptives) while participating in the study]. 
 
Research Design  
The proposed investigation will be a prospective, randomized, parallel-design, open label, 
PD study conducted in a real world clinical setting of post-MI patients. Patients will be required to 
be on DAPT for at least 2 weeks before randomization. Although vorapaxar is approved for use 
irrespective of the timing of the MI, the rationale for including patients after 2 weeks is that, given 
the negative results of the clinical trial with vorapaxar in the acute phase of ACS, it may be 
reasonable to wait until patients have been stabilized after their index MI [18]. The rationale for the 
exclusion of elderly patients (aged >75 years) and patients with a low body weight (<60 kg) is that 
prasugrel is generally not recommended in these patient populations [1,2]. 
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. Although the study has an open-label design, laboratory personnel 
performing PD testing will be blinded to treatment assignment. 
Patients on DAPT with aspirin and prasugrel/ticagrelor as part of their standard of care for at 
least 2 weeks and who are meeting study entry criteria will be randomly assigned in a 1:1:1 fashion 
to one of the following 3 treatment regimens: 1) DAPT (aspirin and prasugrel/ticagrelor) plus 


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vorapaxar 2.5mg od; 2) prasugrel/ticagrelor plus vorapaxar 2.5mg od; 3) continue DAPT with 
aspirin and prasugrel/ticagrelor. Randomized treatment will be administered for 30 ± 3 days; 
prasugrel and ticagrelor will be administered at their standard maintenance dose (10mg od and 
90mg bid, respectively). Randomization will be stratified according to type of P2Y12 inhibitor, in 
order to include at least 35% of patients on prasugrel. The rationale for predicting a higher number 
of randomized patients on ticagrelor derives from the more broad clinical indications of ticagrelor 
compared with prasugrel. Patient who entered the study before being on DAPT for 2 weeks will be 
required to complete 2 weeks of DAPT with aspirin and prasugrel/ticagrelor before randomization. 
Blood sampling for PD testing will be conducted at 3 time-points: a) baseline (while patients 
will be on standard DAPT prior to initiating randomized treatment); b) after 7-10 days of 
randomized study treatment; c) after 30 ± 3days of randomized study treatment. At each time point, 
blood will be collected before the morning dose of prasugrel/ticagrelor and vorapaxar, in order to 
measure trough levels of platelet inhibition. During study treatment in-hospital major adverse 
cardiac events (death, MI, stroke, and urgent revascularization procedures) and serious adverse 
events (bleeding and other adverse events) will be collected. Bleeding will be defined by the BARC 
(Bleeding Academic Research Consortium) definition [19]. 
After study completion, patients will resume antiplatelet treatment regimen at the discretion 
of the treating physician. A flow diagram of the study design is illustrated below. 


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Laboratory assessments 
Peripheral venous blood samples (20 mL) 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 indicated above in the study design 
section. Various PD assays will be performed as described below. Given the potential interplay 
between PAR-1 and P2Y12 mediated signaling, assessments specific for both pathways will be 
conducted [11]: 


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1. Light transmittance aggregometry (LTA) 
2. Thrombelastograph Coagulation Analyzer TEG 6s Series system (CORA® system) 
3. Whole blood vasodilator-stimulated phosphoprotein (VASP) 
4. Serum thromboxane B2 
 
Description of laboratory assays 
1) Light transmittance aggregometry (LTA): Platelet aggregation will be performed using LTA 
according to standard protocols. Blood will be collected in citrated (3.8%) 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 [20,21]. Platelet 
agonists will include AA (1 mM), collagen (3µg/ml), ADP (5 and 20 µM), TRAP (15 μM), and a 
combination of 2 µg/ml collagen-related peptide + 5 µM ADP + 15 µM TRAP (CAT). The reagent 
cocktail CAT will allow to assess the overall platelet response to a combination of agonists that 
leads to activation of multiple platelet pathways. 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. 
2) TEG 6s Series system (CORA® system): the TEG 6s system (Haemonetics Corporation, 
Braintree, MA, USA) will be used according to manufacture instructions [22]. In brief, the CORA® 


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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 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 arachidonic acid (AA) platelet 
agonists 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 assay uses AA and ADP agonists to generate test results that reflect the inhibiting 
effects of antiplatelet agents such as TxA2 Inhibitors (e.g., aspirin) and ADP P2Y12 inhibitors (e.g., 
ticagrelor). Since thrombin (present in blood samples) is the primary and most potent activator of 
platelets, its activity must be inhibited with heparin so that the platelet activating effects of ADP and 


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AA can be measured. Since thrombin has been rendered inactive by heparin, activatorF is used to 
replace thrombin’s role in the conversion of fibrinogen to fibrin and Factor XIII to Factor XIIIa. 
Thus, with this cross-linked fibrin network as the foundation, additional clot strength due to 
platelet-fibrin bonding related to ADP and AA platelet receptor activation can be measured. 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 activatorF test provides the contribution of fibrin to 
the overall strength of the clot.  This test value is used in the calculation of aggregation/inhibition 
for MA ADP and MA AA. The AA and ADP test provide measures of MA, percent inhibition and 
percent aggregation. 
3) Whole blood vasodilator-stimulated phosphoprotein (VASP): VASP phosphorylation (VASP-P) 
is a marker of P2Y12 receptor reactivity. VASP will be assessed according to standard protocol 
using labeled monoclonal antibodies by flow cytometry with the Platelet VASP-FCM kit (Biocytex 
Inc., Marseille, France) as previously described [23]. 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 PGE1-stimulated platelets reduces PGE1-induced VASP-P 
levels. If P2Y12 receptors are successfully inhibited by inhibitors, addition of ADP will not reduce 
the PGE1-stimulated VASP-P levels. The platelet reactivity ratio (PRI) will be calculated after 
measuring VASP-P levels after stimulation with PGE1 (MFI PGE1) and also PGE1 + ADP (MFI 


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PGE1 + ADP). The P2Y12 reactivity ratio = ([MFI PGE1] – [MFI PGE1 + ADP]/[MFI PGE1]) x 
100%. 
4) Serum thromboxane B2: The concentration of serum thromboxane B2 (TXB2) will be measured 
by using the TXB2 EIA kit (Cayman Chemical Company, Ann Arbor, MI) according to the 
instructions of the manufacturer, as previously described [24]. Briefly, samples will be diluted with 
EIA buffer 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 1000 pg/mL and 7.8 pg/mL using EIA buffer 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. 
 
Study endpoints and sample size calculation 
The primary end point of our study is the comparison of CAT-induced MPA between DAPT 
and DAPT plus vorapaxar after 30 ± 3 days of treatment. We hypothesize that adjunctive vorapaxar 
will result into a significant reduction of platelet aggregation. Assuming a 10% absolute reduction 
in CAT-induced MPA with a common standard deviation of 13%, 37 patients per group will be 
needed to detect a significant difference between DAPT and DAPT plus vorapaxar with a 90% 
power and 2-sided alpha=0.05. Considering a possible 30-35% rate of invalid results due to 
hemolysis or drop-out and the three arms of treatment up to 146 patients will need to be 
randomized. Since there are no preliminary data in this particular setting, the sample size of our 
study was calculated based on previous data of vorapaxar in addition to DAPT with aspirin and 
clopidogrel [21]. This approach is in agreement with recommendations for pilot investigations [25]. 


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Our secondary outcome will be the comparison of CAT-induced MPA between vorapaxar in 
addition to a new generation P2Y12 receptor inhibitor (prasugrel or ticagrelor) and vorapaxar in 
addition to standard DAPT (aspirin and prasugrel/ticagrelor). We hypothesize that stopping aspirin 
will not lead to significant differences in CAT-induced MPA after 30 ± 3 days of treatment. 
Other objectives will include the comparisons among the 3 groups of all PD parameters 
measured by multiple assays at every time point, as well as intragroup comparisons of PD 
parameters in order to evaluate the variability over time of vorapaxar PD effects, as well as how PD 
measures will be affected by aspirin withdrawal.  
 
Statistical analysis plan  
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 between categorical 
variables will be performed using two-tailed Fisher’s exact test or the Pearson's chi-square test. 
Student´s t test, Mann-Whitney U-test and Wilcoxon test will be used to compare continuous 
variables when appropriate. An analysis of covariance (ANCOVA) method with a general linear 
model, using baseline variables significantly different between groups as covariates, will be used to 
evaluate the overall difference between groups and all between-groups comparisons, in line with 
other PD studies [23]. Analysis of variance (ANOVA) will be used to evaluate intragroup 
comparisons. A 2-tailed p value of < 0.05 is considered to indicate a statistically significant 
difference for all the analyses performed. Statistical analysis will be performed by our group using 
SPSS v22.0 software (SPSS Inc. Chicago, IL).  


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Publication Strategy/Additional Information  
Study subjects will be identified first (months 1-24): we expect to enroll approximately 5-6 
subjects monthly and complete enrollment in 24 months (total: 126 subjects enrolled). Months 25-
26 will be implied for statistical analysis and months 27-28 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 straight 
forward prospective study and is based on well-established methods. However, since there is limited 
experience with vorapaxar to define 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 [25]. 
 
Possible Discomforts and Risk 
In clinical trials, the most common clinical side effects of vorapaxar were anemia (5%), 
depression (2.4%) and rash (2.2%) [14, 18]. The most important adverse effect associated with the 
use of vorapaxar is bleeding. The risk of TIMI clinically significant bleeding with vorapaxar is 
15.8% and 11.1% with placebo (HR 1.46; 95% CI, 1.36-1.57, p<0.001); the risk of TIMI non-
CABG-related major bleeding with vorapaxar is 2.8% and 1.8% with placebo (HR 1.46; 95% CI, 
1.22-1.75, p<0.001); the risk of intracranial bleeding (intracerebral, subdural or epidural) with 
vorapaxar is 1% vs 0.5% with placebo (HR 1.94; 95% CI 1.39-2.70; p <0.001) [14]. However, such 


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bleeding prevalence occurred in the setting of long-term (3 years) trial, while our study is limited to 
only approximately 30 days of vorapaxar therapy. We have also excluded from the study patients at 
increased risk of bleeding complications [12-14]. Moreover, the use of vorapaxar in this study is 
limited to the intended for use population at low risk of bleeding. All clinical events described 
above, if they were to occur, as well as death, myocardial infarction, stroke, and urgent 
revascularization procedure with PCI or coronary artery bypass grafting will be recorded. Bleeding 
data will be collected using BARC definitions [20]. Clinical events will be evaluated by a local 
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 (major bleeding – defined as life-threatening: 
fatal, symptomatic intracranial hemorrhage, leading to a drop in hemoglobin of at least 5 g/dL, 
significant hypotension requiring intravenous inotropes, requiring surgical intervention, or requiring 
transfusion of 4 or more units of blood; non–life-threatening: substantially disabling, intraocular 
bleeding leading to vision loss, or requiring at least 2 units of blood; thrombocytopenia <50,000 ) 
the local committee will meet and antiplatelet treatment management will be managed according to 
physician recommendation. 
 
Definition of Adverse Events 
An adverse event is any unintended or undesirable experience that occurs during the course 
of the clinical investigation whether or not it is considered to be therapy related.  This includes any 
newly occurring event or previous condition that has increased in severity or frequency since the 
initiation of study treatment.  Adverse events will be followed until resolution while the patient 


Protocol version: June 30, 2018 
NCT02545933 
 
19 
 
remains on-study.  Once the patient is removed from study, events thought to be related to the study 
therapy will be followed until resolution or until the patient starts a new treatment regimen. 
Serious Adverse Events (SAE): An adverse event occurring while on study and considered 
related (reasonable possibility that the study treatment caused the adverse experience) to the study 
treatment that results in any of the following outcomes: 
- Death 
- A life-threatening adverse experience. 
- A persistent or significant disability, incapacity, or is a congenital anomaly, or birth  
defect. 
- Requires inpatient hospitalization, or prolongation of existing hospitalization. 
The definition of serious adverse event also includes ‘important medical event’.  Medical 
and scientific judgment should be exercised in deciding whether expedited reporting is 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 patient and/or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the definition above.  These 
should also usually be considered serious.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization; or development of drug dependency or drug abuse. 
 
Possible benefits 


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NCT02545933 
 
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The present investigation is aimed to evaluate the PD effects of vorapaxar as an add-on 
therapy to standard antiplatelet treatment in patients with previous MI. 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 
 
None 
Conflict of Interest 
Dr. Angiolillo is a consultant for Merck, the maker of vorapaxar. 
 
 
 
 
 
 
 


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NCT02545933 
 
21 
 
References 
1. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management 
of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American 
College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am 
Coll Cardiol. 2014;64:e139-228. 
2. Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. Nat Rev 
Cardiol. 2015;12:30-47. 
3. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, et al. Variability in individual responsiveness to 
clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol. 
2007;49:1505-16. 
4. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with 
acute coronary syndromes. N Engl J Med. 2007;357:2001-15. 
5. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute 
coronary syndromes. N Engl J Med. 2009;361:1045-57. 
6. Davì G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007; 357:2482-94. 
7. Angiolillo DJ, Ueno M, Goto S. Basic principles of platelet biology and clinical implications. 
Circ J. 2010; 74:597-607. 
8. Brummel-Ziedins K, Undas A, Orfeo T, et al. Thrombin generation in acute coronary syndrome 
and stable coronary artery disease: dependence on plasma factor composition. J Thromb 
Haemost. 2008;6:104-10. 
9. Cho JR, Rollini F, Franchi F, et al. Unmet needs in the management of acute myocardial 
infarction: role of novel protease-activated receptor-1 antagonist vorapaxar. Vasc Health Risk 
Manag. 2014; 10:177-88. 
10. Angiolillo DJ, Capodanno D, Goto S. Platelet thrombin receptor antagonism and 
atherothrombosis. Eur Heart J. 2010; 31:17-28. 
11. Nylander S, Mattsson C, Ramström S, Lindahl TL. Synergistic action between inhibition of 
P2Y12/P2Y1 and P2Y12/thrombin in ADP- and thrombin-induced human platelet activation. Br 
J Pharmacol. 2004;142:1325-31. 


Protocol version: June 30, 2018 
NCT02545933 
 
22 
 
12. FDA Vorapaxar prescribing information [online] 
http://www.fda.gov/drugs/informationondrugs/ucm423935.htm Accessed on March 2015. 
13. EMA Vorapaxar prescribing information [online] 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002814/hum
an_med_001839.jsp&mid=WC0b01ac058001d124 Accessed on March 2015. 
14. Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the secondary prevention of 
atherothrombotic events. N Engl J Med. 2012; 366:1404-13. 
15. Scirica BM, Bonaca MP, Braunwald E, et al. Vorapaxar for secondary prevention of thrombotic 
events for patients with previous myocardial infarction: a prespecified subgroup analysis of the 
TRA 2°P-TIMI 50 trial. Lancet. 2012; 380:1317-24. 
16. Armstrong PC, Leadbeater PD, Chan MV, et al. In the presence of strong P2Y12 receptor 
blockade, aspirin provides little additional inhibition of platelet aggregation. J Thromb Haemost. 
2011;9:552-61. 
17. Kirkby NS, Leadbeater PD, Chan MV, et al. Antiplatelet effects of aspirin vary with level of 
P2Y₁₂ receptor blockade supplied by either ticagrelor or prasugrel. J Thromb Haemost. 
2011;9:2103-5. 
18. Tricoci P, Huang Z, Held C, et al. Thrombin-receptor antagonist vorapaxar in acute coronary 
syndromes. N Engl J Med. 2012;366:20-33. 
19. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular 
clinical trials: a consensus report from the Bleeding Academic Research Consortium. 
Circulation. 2011;123:2736-47. 
20. Angiolillo DJ, Badimon JJ, Saucedo JF, et al. A pharmacodynamic comparison of prasugrel vs. 
high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: 
results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial. Eur 
Heart J. 2011;32:838-46. 
21. Storey RF, Kotha J, Smyth SS, et al. Effects of vorapaxar on platelet reactivity and biomarker 
expression in non-ST-elevation acute coronary syndromes. The TRACER Pharmacodynamic 
Substudy. Thromb Haemost. 2014;111:883-91. 


Protocol version: June 30, 2018 
NCT02545933 
 
23 
 
22. FDA TEG 6s Series system indications for use and 510(k) summary [online] 
www.accessdata.fda.gov/cdrh_docs/pdf14/k140893.pdf Accessed on April 2015 
23. Rollini F, Franchi F, Tello-Montoliu A, et al. Pharmacodynamic effects of cangrelor on platelet 
P2Y12 receptor-mediated signaling in prasugrel-treated patients. JACC Cardiovasc Interv. 
2014;7:426-34. 
24. Capodanno D, Patel A, Dharmashankar K, et al. Pharmacodynamic effects of different aspirin 
dosing regimens in type 2 diabetes mellitus patients with coronary artery disease. Circ 
Cardiovasc Interv. 2011;4:180-7. 
25. Lancaster GA, Dodd S, Williamson PR. Design and analysis of pilot studies: recommendations 
for good practice. J Eval Clin Pract. 2004; 10:307-12. 
 
 

ICF_001.pdf: 
 
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University of Florida – Jacksonville 
SUBJECT INFORMATION AND CONSENT FORM 
 
 
TITLE: 
Adjunctive Vorapaxar Therapy in Patients with Prior Myocardial 
Infarction Treated with New Generation P2Y12 Receptor Inhibitors 
Prasugrel and Ticagrelor (VORA-PRATIC): A Prospective, 
Randomized, Pharmacodynamic Study. 
 
PROTOCOL NO.: 
VORA-PRATIC 
 
WIRB® Protocol #20152115 
 
SPONSOR: 
Dominick J. Angiolillo, MD, PhD 
 
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 
 
904-244-3378 
 
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.  
 
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. 
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WHY IS THIS RESEARCH STUDY BEING DONE? 
You are being asked to participate in this study because you had a heart attack and because of 
this you are taking a blood thinning medication called prasugrel or ticagrelor, commercially 
known as Effient® or Ticagrelor®, in addition to a baby aspirin. 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. To prevent a heart attack, there are 
antiplatelet drugs (blood thinners) to keep your platelets from sticking together. These 
antiplatelet drugs include clopidogrel (Plavix®), prasugrel (Effient®) and ticagrelor (Brilinta®), 
and must be used, in addition to baby aspirin, in the treatment of patients who have heart disease 
like you. Moreover, there is a new blood thinner medication, called vorapaxar (Zontivity®), 
which has a different mechanism than Plavix®, Effient® and Brilinta®. It appears that, when 
added to one of them, it may be able to reduce the clot formation. In fact, in a large study of 
patients who experienced a heart attack, Zontivity® in addition to standard antiplatelet drugs, has 
shown to reduce the risk of future heart attacks, although there were more bleedings. Recent 
studies have shown that in patients treated with a potent blood thinner such as Brilinta® or 
Effient®, the role of aspirin in keeping platelets from sticking together, is minor.  However, it is 
unknown if when adding Zontivity® to patients treated with either Brilinta® or Effient®, if 
stopping aspirin is as effective on blocking platelets compared with patients treated  with aspirin 
plus either Brilinta® or Effient®. 
 
The purpose of this study is to evaluate the effect of Zontivity® in addition to either Brilinta® or 
Effient® with and without aspirin. Subjects participating in this study will be randomized (like a 
flip of a coin) either to receive Zontivity® in addition to their standard blood thinning medication 
with or without aspirin or to continue their therapy without any change. Afterwards you will 
receive your standard-of-care therapy.   
 
The clinical setting and the dose in which Zontivity® is being used in this research has been 
approved by the Food and Drug Administration (FDA). 
 
HOW MANY PEOPLE ARE EXPECTED TO TAKE PART IN THIS RESEARCH 
STUDY? 
Up to 146 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 33 days.  
 
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. 
 
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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 antiplatelet medication. If you are found to be 
pregnant, you will not be randomized and your participation in this study will end.  
 
Other study related procedures will include a physical. 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, for a total of 1 blood draw per visit.  
 
Approximately 20 cc (approximately one tablespoon) of blood will be collected from you at each 
visit by inserting a needle directly into your vein or from a catheter in your vein. 
 
Baseline platelet function tests will be done (while you are taking your standard therapy) to see 
how sticky your platelets are. After this, you will be randomized (chosen, like the flip of a coin) 
to one of the 3 groups, you will have an equal chance of being in each group: (1) add Zontivity® 
to your current blood thinner therapy (which is either Effient® or Brilinta®) combined with 
aspirin; or (2) add Zontivity® to your standard blood thinner therapy (which is either Effient® or 
Brilinta®) stopping aspirin; or (3) continue with your standard blood thinner therapy (which is 
either Effient® or Brilinta®) combined with aspirin. 
 
After 7-10 days you will be asked to come to our clinical site in the morning 24±4 hours after last 
dose if you are taking Effient® or 12±2 hours after the last dose if you are taking Brilinta®. Blood 
draw will be performed. After this first phase you will continue the allocated combination of 
treatment and after approximately 20 days you will be asked to come to our clinical site for the 
last blood draw. It will be performed in the morning 24±4 hours after last dose if you are taking 
Effient® or 12±2 hours after the last dose if you are taking Brilinta®. After this, the study will be 
over and you will resume your standard of care therapy.   
 
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. 
ii. 
The most common side effects of Zontivity® are: anemia, depression, rash and 
bleeding that may be minor or life-threatening or fatal. 
iii. 
Loss of confidentiality.   
 
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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.  
 
Additional Risks: 
Among the three groups of subjects, there may be differences in the incidence of adverse cardiac 
events (MACE). 
 
While bleeding is listed as a risk of vorapaxar (study drug), there may be differences in bleeding 
risks among the three groups. 
 
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 may or may 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 learn more about the effects of 
administering vorapaxar (Zontivity®) 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 has received consulting fees from Aralez, the maker of vorapaxar, in the past 12 
months.  Please feel free to ask any further questions you might 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. You will also receive other 
study medications (e.g. prasugrel or ticagrelor) at no cost to you limited to the duration of the 
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 $15.00 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. If the payments total $600 or more or you are a nonresident alien, payment 
will be processed through the University of Florida Accounts Payable department and 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 sponsor and 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. You will be responsible for any 
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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) 244-3378 
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.  You can also have access to Zontivity outside of 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-
244-3378 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, or 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. 
 
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.  
 
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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 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 patients with coronary artery 
disease and diabetes, with or without kidney disease 
 to evaluate a possible new use for the study drug   
 to determine the causes or effects of the study condition 
 
Once this information is collected, it becomes part of the research record for this study. 
 
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  
 
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Your PHI may be shared with: 
 
 The study sponsor Dominick J. Angiolillo, MD, PhD and Merk Company. 
 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 
 
Every attempt will be made to protect your right to privacy within legal limits.  However, records 
associated with your participation in the study, including medical histories (case histories) which 
may identify you, and this informed consent signed by you, will be made available for inspection 
by the Western Institutional Review Board® (WIRB®), Merk company or designee (including any 
persons or companies which are contracted by Merk company to have access to the research 
information during and after the study, such as the monitor(s) and auditor(s)), the US Food and 
Drug Administration (FDA), and state and other local authorities.  Because of the need to release 
information to these parties, absolute confidentiality cannot be guaranteed.  In addition, the 
results of treatment and laboratory data may be published for scientific purposes, but your 
identity will not be disclosed. By signing a written informed consent form, you are authorizing 
such access. 
 
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. 
 
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You have the right to review and copy your protected health information. However, we can make 
this available only after the study is finished. 
 
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 904-244-3378 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 IRB in Jacksonville at (904) 244-9478. 
NCT02545933


 
APPROVED 
 
AS MODIFIED 
 
Jul 05, 2018 
 
WIRB 
 
 
10
 
WIRB is a group of people who perform independent review of research.  
 
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 
NCT02545933