Comparison of Pharmacodynamic Effects of Tirofiban vs. Cangrelor in N-STEMI Patients Undergoing Percutaneous Coronary Intervention
Conditions: Non-ST Elevation Myocardial Infarction (NSTEMI)
Sponsor: Inova Health Care Services

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 1 of 17                                
 
 
 
 
 
Comparison of Pharmacodynamic Effects of Tirofiban vs. Cangrelor in  
NSTEMI Patients Undergoing Percutaneous Coronary Intervention 
 
   
 
Principal Investigator: Paul A. Gurbel, M.D. 
 
 
 
 
 
 
Funding Source: Medicure Pharma, Inc. 
 
 
 
 
Site of Investigation: Inova Fairfax Hospital,  
Falls Church, VA and Inova Heart and Vascular Institute 
 
 
 
 
 
 
Contact Information:  
Paul A. Gurbel, M.D. 
Inova Center for Thrombosis Research and Drug Development  
Inova Heart and Vascular Institute 
3300 Gallows Road 
Falls Church, VA 22042 
Phone: 10-367-2590 Fax: 410-367-2596  
Email: paul.gurbel@inova.org 
 
 
 
 
 
Date of Protocol:  29 January 2018 
 
 
 
 
 
 

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 2 of 17                                
 
 
Synopsis 
 
Title: Comparison of Pharmacodynamic Effects of Tirofiban vs. Cangrelor in NSTEMI Patients 
Undergoing Percutaneous Coronary Intervention 
 
Short Title:  Tirofiban vs. Cangrelor in NSTEMI 
 
Rationale: Immediate potent inhibition of platelet function is critical for the prevention of 
periprocedural ischemic event occurrences in high risk N-ST segment elevation myocardial 
infraction (NSTEMI) patients undergoing percutaneous coronary intervention (PCI). Currently, 
dual antiplatelet therapy with aspirin and an oral P2Y12 receptor blocker (with loading doses) is 
widely used for PCI.1 However, immediate, potent and reversible inhibition of platelet 
aggregation is not possible even with the newer oral agents, prasugrel and ticagrelor. Therefore, 
an intravenously administered GPIIb/IIIa receptor inhibitor (tirofiban) or P2Y12 receptor blocker 
(cangrelor) with fast onset and offset of actions will provide more desired antiplatelet effects in 
the setting of PCI. Cangrelor provides effective inhibition of only ADP-mediated upstream 
platelet activation and aggregation pathways via selective inhibition of the P2Y12 receptor 
whereas a GPIIb/IIIa inhibitor such as tirofiban, will provide effective platelet inhibition by 
inhibiting the final common pathway of platelet aggregation stimulated by multiple agonists such 
as collagen, thrombin receptor activator peptide (TRAP), arachidonic acid (AA) and adenosine 
diphosphate (ADP).  The latter may translate in to superior clinical benefits compared to 
cangrelor therapy.2,3  
 
Objectives:  
Primary Objective: Assessment of platelet aggregation in response to thrombin receptor 
activator peptide (TRAP) at baseline and serially following tirofiban or cangrelor infusion.  
 
Secondary objectives:  
1) Assessment of platelet aggregation in response to ADP and collagen at baseline and serially  
    following tirofiban or cangrelor infusion.  
2) Assessment of ADP-induced and thrombin induced platelet-fibrin clot strength by  
    thrombelastography (TEG6S) 
3) Assessment of thrombin generation kinetics by Calibrated Automated Thrombogram (CAT).  
 
4) Real time evaluation of shear-induced thrombus formation using novel RUO T-TAS® plus  
    system.  
5) Assessment of High sensitivity troponin and CK-MB. 
 
Study Type: This is a single center open label, randomized, observational study.  
 
Study Design: Prospective, single center, observational study. NSTEMI patients undergoing 
PCI: 30 patients each will be treated with tirofiban or cangrelor (total n=60). The study is 
modelled after CLEAR PLATELETS study.4 
 
 
 
 

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 3 of 17                                
 
 
Study Methodology: This investigation will be conducted in NSTEMI patients undergoing PCI 
at IHVI Fairfax hospital. Platelet activation and aggregation, clot characteristics, thrombin 
generation kinetics, real time thrombus formation, and high sensitivity troponin/CK-MB will be  
assessed at the baseline, and 10 minutes, 30 minutes post-start of the infusion and 30 minutes, 1 
hour, 2 hour, 4-6 hour and 12-24 hour following  the end of infusion of tirofiban or cangrelor 
(study flow diagram).  
 
Patients: Sixty patients with NSTEMI undergoing PCI. 
 
Statistical Methodology: Sample size (n=60 patients) is based on the CLEAR PLATELETS 
study.4 Categorical variables will be compared using 2 test or the Fisher exact test as 
appropriate whereas continuous variables will be assessed using the Student unpaired t- or 
Mann-Whitney U test, and ANOVA test after checking for normal distribution. The 
pharmacodynamic effect of different regimens will be compared using a linear mixed model. 
Each model will include treatment, time, an interaction between treatment and time, and the 
baseline pharmacodynamic parameter as covariate. Analyses will be performed with SPSS 
software (SPSS, Inc., Chicago, IL) and p<0.05 will be considered significant.  
 
 
Study Flow Diagram 
 
 
 
 
 
 

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 4 of 17                                
 
 
1 
INTRODUCTION 
1.1 
Specific Aims 
To measure platelet activation and aggregation, clot characteristics, thrombin generation 
kinetics, real time thrombus formation at the baseline, and 10 minutes, 30 minutes post-start 
of the infusion and 30 minutes, 1 hour, 2 hour, 4-6 hour and 12-24 hour after the end of the 
infusion of tirofiban or cangrelor, and high sensitivity troponin and CK-MB at the baseline,  
2 hour, 4-6 hour and 12-24 hour after the end of the infusion of tirofiban or cangrelor.  
 
1) Platelet aggregation:  
    ADP-, collagen-, and TRAP -induced platelet aggregation by light transmittance  
    aggregometry. 
2) Platelet activation markers: 
    P-selectin, and annexin binding by flow cytometry. 
3) Platelet-fibrin clot characteristics and ADP-induced platelet-fibrin clot strength: 
    Thrombin- and ADP-induced platelet-fibrin-clot strength, time to initial thrombin  
     generation, and functional fibrinogen by thrombelastography (TEG6S). 
4) Shear-induced platelet aggregation:  
    Shear-induced platelet aggregation by T-TAS perfusion flow chamber using novel  
    RUO T-TAS® plus system.  
5) Thrombin generation kinetics: thrombin generation kinetics by Calibrated  
    Automated Thrombogram (CAT).  
6) High Sensitivity troponin and CK-MB 
 
 
1.2 Hypothesis  
Serial evaluation of pharmacodynamic effects of tirofiban vs. cangrelor using various 
established laboratory assays will distinguish the superior pharmacodynamic benefits of 
tirofiban vs. cangrelor.  
 
1.3 
Background and Significance 
It is estimated that, approximately 70% of the >780,000 persons with ACS in the United     
States, are diagnosed with NSTEMI.1 Based on the CRUSADE (Can Rapid risk   
stratification of Unstable angina patients Suppress ADverse outcomes with Early  
implementation of the ACC/AHA Guidelines) registry and ACTION Registry®-GWTG™  
(Acute Coronary Treatment and Intervention Outcomes Network-Get With the Guidelines),  
54-58% of NSTEMIs are managed with PCI.5 Usually NSTEMI patients are older patients 
with more comorbidities, more risk for recurrent ischemic events and more incidences of 
previous MI.1 Platelets play a critical role in periprocedural ischemic event occurrences 
including MI and stent thrombosis in patients with NSTEMI. Immediate potent inhibition of 
platelet function is critical for the prevention of periprocedural ischemic event occurrences in 
high risk N-ST segment elevation myocardial infraction (NSTEMI) patients undergoing 
percutaneous coronary intervention (PCI). Management of these patients during PCI with 
optimal antiplatelet therapy is crucial since these patients may require more effective 
antiplatelet therapy to overcome increased ischemic risk but bleeding risk is also high due to 
older age.  
   
 
 

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 5 of 17                                
 
 
Currently, dual antiplatelet therapy with aspirin and an oral P2Y12 receptor blocker (with 
loading doses) are widely used for PCI. However, immediate, potent and reversible inhibition  
 
of platelet aggregation is not possible even with the newer oral agents, prasugrel and 
ticagrelor. Therefore, an intravenously administered GPIIb/IIIa receptor inhibitor (tirofiban) 
or P2Y12 receptor blocker (cangrelor) with fast onset and offset of actions will provide more 
desired antiplatelet effects in the setting of PCI. Cangrelor is a parenterally administered 
adenosine triphosphate (ATP) analog with a short half-life (3–6min), with rapid onset/offset 
of action, and dose-dependent and predictable pharmacodynamic effects. Cangrelor provides 
effective inhibition of only ADP-mediated upstream platelet activation and aggregation 
pathways via selective inhibition of the P2Y12 receptor. In the CHAMPION-PHOENIX trial, 
11,145 patients with stable coronary artery disease (CAD) or acute coronary syndrome 
(ACS) received a bolus and infusion of cangrelor or a loading dose of 600 mg or 300 mg of 
clopidogrel. Cangrelor therapy was associated with a significantly reduced primary endpoint 
occurrence of death, MI, IDR, or stent thrombosis at 48 hours [4.7 vs. 5.9 %, odds ratio 
=0.78, p=0.005). The primary safety end point of severe bleeding at 48 hours was similar 
between the treatment groups [0.16% vs. 0.11% odds ratio=1.50, p=0.44]. The rate of stent 
thrombosis was lower in the cangrelor group compared with clopidogrel group [0.8% vs. 
1.4%, odds ratio = 0.62, p=0.01]. Furthermore, the benefits associated with cangrelor were 
consistent across the subgroups of stable angina (n=1991), NSTEMI (n=2810), and STEMI 
(n=6138) (interaction, p=0.98), and whether the patient received clopidogrel 300mg LD or 
600 mg LD (interaction, p=0.61). GUSTO severe bleeding was similar between groups.6 
Based on the favorable outcome observed in the CHAMPION-PHOENIX trial, the Food and 
Drug Administration Cardiovascular and Renal Drugs Advisory Committee recommended 
the approval cangrelor as an adjunct to PCI for reducing the risk of periprocedural thrombotic 
events such as MI, stent thrombosis and IDR. 
 
A GPIIb/IIIa inhibitor such as tirofiban, will provide effective platelet inhibition by 
inhibiting the final common pathway of platelet aggregation stimulated by multiple agonists 
such as collagen, TRAP, and ADP. The latter may translate in to superior clinical benefits 
compared to cangrelor therapy.  
 
2 
STUDY DESIGN AND SUBJECT SELECTION  
2.1 
Study Type 
This is a single center open label, randomized, observational study. 
 
2.2 
Setting 
The study will be done at Inova Fairfax Hospital in an inpatient setting. Screening will take 
place at the emergency room (ER), coronary angiography preparation room, or coronary 
angiography suite. Study procedures after obtaining consent will occur at the emergency 
room and IHVI (coronary angiography suite, coronary angiography recovery room, intensive 
care coronary care unit, and coronary care step-down units). 
 
2.3 
Duration of Study 
Subject participation will be until date of discharge.   
 
 

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 6 of 17                                
 
 
2.4. Number of Subjects and Randomization procedure 
Sixty patients with NSTEMI undergoing PCI will be randomized to receive 1:1 tirofiban or 
cangrelor. Allocation of study treatment will be performed via a web-based interactive 
randomization system, based on a computer-generated random sequence with a random block 
size. 
 
2.5. Study Population 
2.5.1. Population Characteristics  
2.5.1.1. Gender and racial and ethnic origin of subjects 
The study’s intended population is inclusive of both genders (males and females), and 
all racial and ethnic groups and subgroups.   
 
2.5.1.2. 
Age of Subjects 
Subject enrollment will be comprised of subjects >18 years of age.  
 
2.5.2 Vulnerable Population 
Children, pregnant women, institutionalized persons, and persons with decisional 
incapacity will be not be enrolled in this study.  
 
2.6. Recruitment 
Recruitment will occur at the Inova Fairfax Hospital. The expected length of the recruitment 
period is 24 months. If the study conduct (e.g. recruitment rate; drop-out rate; data quality; 
protocol compliance) does not suggest a proper completion of the trial within the reasonable 
time frame as agreed upon, the recruitment period may be extended to reach the desired 
sample size. 
 
2.7.  Inclusion Criteria 
The study will include subjects with non-ST elevation myocardial infraction (NSTEMI). 
Subjects may be enrolled if they appropriately fulfill all inclusion criteria. 
 
1. NSTEMI meeting the following criteria: 
a) Patients 18 years of age or older with one or more of the following symptoms:  
-new ST-segment depression or transient elevation of at least 1 mm 
-elevations in troponin I, troponin T, or creatine kinase MB levels above ULN  
b) Eligible for ticagrelor, cangrelor, aspirin, UFH, and GP IIb/IIIa inhibitor 
treatment. 
c) Admitted at cardiac catheterization laboratory hospital or associated facility. 
d) Competent mental condition to provide informed consent. 
 
2.8. Exclusion Criteria 
             Subjects will be excluded from study participation if any of the exclusion criteria is met. 
1. Unstable angina with negative troponin, STEMI 
2. Cardiogenic shock 
3. Refractory ventricular arrhythmias 
4. New York Heart Association class IV congestive heart failure 
5. Cardiac arrest within 1 week of study entry 

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 7 of 17                                
 
6. History of hemorrhagic or ischemic stroke, TIA, sub-arachnoid hemorrhage or 
intracranial neoplasm, arteriovenous malformation, or aneurysm 
7. Fibrinolytic therapy within 48 hours of study entry 
8. Active pathological bleeding or history of bleeding diathesis 
 
9. Severe hepatic insufficiency 
10. Current peptic ulceration 
11. Increased bleeding risk, per investigator judgment 
12. Known anemia (hematocrit<25%)/thrombocytopenia (platelet count < 
100,000mm3) 
13. Surgery within 4 weeks before study entry or planned surgery within 2 months 
after study entry 
14. Any P2Y12 receptor inhibitor or  GP IIb/IIIa inhibitor within 7 days of study 
entry  
15. Receiving warfarin or other coumadin derivatives or NOACs within the last 10 
days with an INR >1.5 secs or planned use during the hospitalization period 
16. Contraindication to the use of ticagrelor and/or aspirin 
17. Receiving or will receive oral anticoagulation or other oral antiplatelet therapy 
(except aspirin) that cannot be safely discontinued within the next 3 months 
18. Receiving daily NSAIDs or COX2 inhibitors that cannot be discontinued or 
anticipated to require >2 weeks of daily NSAIDs or COX2 inhibitors during 
study 
19. Investigational drug in last 30 days or presently enrolled in drug/device study 
20. Pregnant or lactating women 
21. Women of childbearing potential (post-menopausal women can be enrolled if 
at least 1 year of amenorrhea or surgically sterile) on oral contraceptives or 
planning a pregnancy.  
 
*Women of child-bearing potential who are not taking oral contraceptives and are not planning on 
becoming pregnant may be enrolled in the study. Safety urine pregnancy test will be done prior to and 
after the drug infusion. 
22. Condition associated with poor treatment compliance (e.g., alcoholism, mental 
illness, or drug dependence) 
23. Inability to provide written informed consent and to understand the full 
meaning of the informed consent 
 
3 
STUDY METHODS 
3.1 Standard of Care Treatments 
Subjects enrolled may be receiving a range of medical therapies as recommended by 
evidence-based guidelines. The investigator or qualified designee is responsible for verifying 
compliance in source documentation and ensuring that any other treatments delivered are 
according to the local standard of care. Standard of care treatments/parameters in the context 
of this study include: 
 
1. Aspirin: 325 mg loading dose followed by 81 mg qd. 
2. Ticagrelor: 180 mg loading dose administered in the catheterization laboratory before the  
     start of the PCI followed by 90 mg bid. 
3. Cangrelor: administered in the catheterization laboratory immediately prior to PCI- before 
guidewire is placed in the vessel (30 ug/kg bolus followed by 4ug/kg/min infusion for 2  

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 8 of 17                                
 
 
hours) 
4. Tirofiban: administered in the catheterization laboratory immediately prior to PCI- before 
guidewire is placed in the vessel 
    (25 ug/kg bolus followed by 0.15 ug/kg/min (CrCl>60ml/min) or 0.075 ug/ml/min  
    (CrCl≤60 ml/min infusion for 2 hours).  
5. Unfractionated heparin (UFH) in tirofiban arm: as needed (e.g., 2,000 to 5,000 U) to  
    achieve an ACT of 200 to 250 s. 
6. Unfractionated heparin in the cangrelor arm: as needed to achieve an ACT of 250 to 300 s  
    for HemoTec, 300 to 350 s for Hemochron  
 
Subjects who were prescribed medications by his/her main provider that are prohibited 
during the study (see section 3.2) will be excluded or exited from the study.  
 
3.2 Medications/Therapies Prohibited During the Study 
The medications/therapies prohibited during the study are warfarin, anticoagulant other than 
UFH, oral direct anticoagulants, P2Y12 receptor blockers other than ticagrelor or cangrelor, 
glycoprotein IIb/IIIa inhibitors other than tirofiban. Potential and enrolled subjects on or 
started on prohibited medications will be excluded or exited from the study. 
 
3.3 Laboratory Measurements 
Phlebotomy sites will be carefully chosen to minimize risk and platelet activation. After 
discarding the first 2-3 mL of free flowing blood, the blood collection tubes will be filled to 
capacity and gently inverted 3 to 5 times to ensure complete mixing of the anticoagulant. 
Tubes containing 3.2% trisodium citrate and hirudin will be used for flow cytometry, light 
transmittance aggregometry, thrombelastography, and shear-induced platelet aggregation. 
 
 Platelet Aggregation  
Platelet aggregation will be assessed in platelet-rich plasma using a Chronolog Lumi-
Aggregometer (model 490-4D) with the AggroLink software package after stimulation 
with 5 and 20uM ADP, 4ug/ml collagen and 15 and 20uM TRAP). 
 
 Platelet Activation  
Expressions of p-selectin, and annexin binding will be assessed by flow cytometry using 
respective antibodies at baseline, and 1 hour and 12-24 hour after the end of the infusion.       
 
 Platelet-Fibrin Clot Characteristics  
Plate-fibrin clot characteristics will be assessed by the TEG6s instrument. TEG6S is a 
microfluidic fully automated cartridge-based device that provides quantitative and qualitative 
measurements of the physical properties of a clot. We will assess thrombin- and ADP-induced 
platelet-fibrin-clot strength, time to initial thrombin generation, and functional fibrinogen 
 Shear-Induced Platelet Aggregation:  
  Shear-induced platelet aggregation by novel T-TAS® plus system.  
 
 Thrombin Generation Kinetics:  
Time to peak thrombin generation, peak thrombin generation, and total thrombin 
 

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 9 of 17                                
 
 
generation kinetics will be assessed by Calibrated Automated Thrombogram (CAT). These 
parameters will be assessed at baseline and 10 minutes post-start of the infusion. 
 High Sensitivity Troponin and CK-MB:  
High sensitivity troponin and CK-MB will be assessed at baseline, and 2 hour, 4-6 hour and 
12-24 hour after the end of the infusion. 
 
3.4 Primary and Secondary endpoints  
3.4.1 Primary Endpoint 
Relative difference in 20 uM TRAP-induced platelet aggregation between cangrelor and  
tirofiban therapy at 30 minutes post-start of the infusion.  
 
3.4.2 Secondary Endpoints 
 Relative differences in 15 and 20 µM TRAP- induced platelet aggregation by light 
transmittance aggregometry between cangrelor and tirofiban therapy at all post-
infusion time points except stated above.  
 Relative differences in ADP and collagen-induced platelet aggregation by  
light transmittance aggregometry between cangrelor and tirofiban therapy at all post-
infusion time points. 
   Relative differences in P-selectin, and annexin binding between cangrelor and 
tirofiban therapy at 1 h and 12-24h after the end of the infusion. 
  Relative differences in thrombin- and ADP-induced platelet-fibrin-clot strength,      
        time to initial thrombin generation, and functional fibrinogen between cangrelor and  
        tirofiban therapy at all post-infusion time points.  
 Relative differences in shear-induced platelet aggregation between cangrelor and  
        tirofiban therapy at all post-infusion time points.  
 Relative differences in time to peak thrombin generation, peak thrombin generation  
       and total thrombin generation between cangrelor and tirofiban therapy at 10 minutes  
       post-infusion time point. 
 Relative differences in peak high sensitivity troponin and CK-MB between cangrelor 
and tirofiban therapy will be assessed at 2 hour, 4-6 hour and 12-24 hour post-
infusion time points. 
 
3.4.3 Clinical Endpoints 
         Patients will be followed for clinical outcomes. All AEs and SAEs will be collected from 
randomization through 48 hours (+24 hours) after randomization. If there is a delay 
between time of randomization and start of study drug, AEs will be collected from time of 
randomization through 48 hours (+24) after study drug initiation. If a subject is discharged 
from the hospital prior to the 48 hour (+24 hour) assessment time-frame, subjects will 
receive a telephone call to review AEs and SAEs.  
 
        3.4.4.     Adverse Events 
         Patients will be carefully monitored for AEs by the investigator during the designated study 
         period. AEs and the treatment provided during the study should be recorded in the patient‘s 
         treatment record and eCRF. Those events that are serious in nature will be reported to 
Medicure in an expedited manner. Patients experiencing AEs will be followed clinically 
until their health has returned to baseline status or until all parameters have returned to 

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 10 of 17                              
 
normal or have otherwise been explained. The investigator will provide or arrange 
appropriate supportive care for the patient if necessary. 
 
        Adverse Event 
An AE is defined as any untoward medical occurrence in a patient administered a 
medicinal product and which does not necessarily have to have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of 
amedicinal product, whether or not considered related to the medicinal product. 
 
        Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that: 
Results in death,  
       Is life-threatening, i.e., the subject was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred . 
 
Results in persistent or significant disability/incapacity, 
Requires in-patient hospitalization or prolongs hospitalization, 
Is a congenital anomaly/birth defect, or 
Is another medically significant event that, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above  
 
Severity is an estimate or measure of the intensity of an AE, while the criteria for serious  
AEs are indications of adverse patient outcomes for regulatory reporting purposes. A severe    
AE need not necessarily be considered serious and a serious AE need not be considered 
severe. For example, nausea that persists for several hours may be considered severe nausea, 
but not an SAE. On the other hand, an MI that may be considered minor could also be an 
SAE if it prolonged hospitalization. 
 
        3.4.5. Bleeding 
       Bleeding will be assessed by the BARC scale. Bleeding will be assessed from the time of     
       randomization through 48 hours after study drug initiation. 
 
       BARC criteria: 
 Type 0: no evidence of bleeding. 
 Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled 
performance of studies, hospitalization, or treatment by a healthcare professional. 
Examples include, but are not limited to, bruising, hematoma, nosebleeds, or 
hemorrhoidal bleeding for which the patient does not seek medical attention. Type 1 
bleeding may include episodes that lead to discontinuation of medications by the patient 
because of bleeding without visiting a healthcare provider. 
 Type 2: any clinically overt sign of hemorrhage (eg, more bleeding than would be 
expected for a clinical circumstance, including bleeding found by imaging alone) that is 
actionable but does not meet criteria for type 3, type 4 (CABG-related), or type 5 (fatal 
bleeding) BARC bleeding. The bleeding must require diagnostic studies, hospitalization, 
or treatment by a healthcare professional. In particular, the bleeding must meet at least  
 

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 11 of 17                              
 
 
one of the following criteria: First, it requires intervention, defined as a healthcare 
professional–guided medical treatment or percutaneous intervention to stop or treat 
bleeding, including temporarily or permanently discontinuing a medication or study drug. 
Examples include, but are not limited to, coiling, compression, use of reversal agents (eg, 
vitamin K, protamine), local injections to reduce oozing, or a temporary/permanent 
cessation of antiplatelet, antithrombin, or fibrinolytic therapy. Second, the bleeding leads 
to hospitalization or an increased level of care, defined as leading to or prolonging  
hospitalization or transfer to a hospital unit capable of providing a higher level of care. Or 
third, the bleeding prompts evaluation, defined as leading to an unscheduled visit to a 
healthcare professional resulting in diagnostic testing (laboratory or imaging). Examples 
include, but are not limited to, hematocrit testing, hemoccult testing, endoscopy, 
colonoscopy, computed tomography scanning, or urinalysis. A visit or phone call to a 
healthcare professional during which neither testing nor treatment is undertaken does not 
constitute type 2 bleeding. 
 
 Type 3: clinical, laboratory, and/or imaging evidence of bleeding with specific healthcare 
provider responses, as listed below: 
  
 Bleeding Academic Research Consortium type 3a bleeding  
Any transfusion with overt bleeding 
 
            Overt bleeding plus hemoglobin drop ≥3 to <5 g/dL (provided hemoglobin drop is related   
            to bleeding). Hemoglobin drop should be corrected for intracurrent transfusion in which  
            1 U packed red blood cells or 1 U whole blood would be expected to increase  
            hemoglobin by 1 g/dL. 
 
 Bleeding Academic Research Consortium type 3b bleeding  
             Overt bleeding plus hemoglobin drop ≥5 g/dL (provided hemoglobin drop is related to  
             bleed). Hemoglobin drop should be corrected for intracurrent transfusion in which 1 U  
             packed red blood cells or 1 U whole blood would be expected to increase hemoglobin by  
            1 g/dL. 
 
            Cardiac tamponade 
            Bleeding requiring surgical intervention for control (excluding dental/nasal/  
            skin/hemorrhoid) 
            Bleeding requiring intravenous vasoactive drugs 
 
 Bleeding Academic Research Consortium type 3c bleeding  
             Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation;  
             does include intraspinal); subcategories confirmed by autopsy, imaging, or lumbar  
             puncture.  
            Intraocular bleed compromising vision 
 
 Type 4: Coronary Artery Bypass Graft–related bleeding  
             Perioperative intracranial bleeding within 48 hours 
             Reoperation after closure of sternotomy for the purpose of controlling bleeding 
 

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 12 of 17                              
 
              
 Transfusion of ≥5 U whole blood or packed red blood cells within a 48-hour period (only  
             allogenic transfusions are considered transfusions for CABG-related bleeds) 
             Chest tube output ≥2 L within a 24-hour period 
 
 Type 5: Fatal bleeding  
             Fatal bleeding is bleeding that directly causes death with no other explainable cause.    
             BARC fatal bleeding is categorized as either definite or probable as follows: 
 
- 
Probable fatal bleeding (type 5a) is bleeding that is clinically suspicious as the cause 
of death, but the bleeding is not directly observed and there is no autopsy or 
confirmatory imaging. 
- 
Definite fatal bleeding (type 5b) is bleeding that is directly observed (by either 
clinical specimen [blood, emesis, stool, etc] or imaging) or confirmed on autopsy. 
- 
The site of fatal bleeding is specified as intracranial, gastrointestinal, retroperitoneal, 
pulmonary, pericardial, genitourinary, or other. 
- 
Bleeding Academic Research Consortium fatal bleeding is meant to capture deaths 
that are directly due to bleeding with no other cause. The time interval from the  
bleeding event to the death should be considered with respect to likely causality, but 
there is no specific time limit proposed. Bleeding that is contributory but not directly 
causal to death is not classified as fatal bleeding but may be categorized as other 
forms of bleeding. Bleeding that leads to cessation of antithrombotic or other 
therapies may be contributory but again would not be classified as fatal bleeding. 
Bleeding associated with trauma or with surgery may be fatal, depending on whether 
it was determined to be directly causal or not. 
 
Examples of potential scenarios consistent with BARC fatal bleeding include the 
following: (1) A patient who receives a fibrinolytic agent for a small inferior MI 
loses consciousness and dies; autopsy shows an intracranial hemorrhage with mass 
effect: definite fatal bleed, intracranial; (2) a patient who receives a fibrinolytic agent 
for a large anterior MI loses consciousness and develops cardiac arrest; clinical 
examination immediately earlier showed a dilated left pupil: probable fatal bleed, 
intracranial; (3) a post-PCI patient on dual antiplatelet therapy who has a witnessed 
large gastrointestinal bleed becomes hypotensive and dies: definite fatal bleed, 
gastrointestinal; and (4) a patient develops a gastrointestinal bleed that is successfully 
cauterized; 3 days later, the gastroenterologist stops dual antiplatelet therapy and the 
patient has a fatal MI: not a fatal bleed. 
 
 
3.5 Consent 
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB -approved informed consent. If the subject is capable of 
doing so, he/she will indicate assent by personally signing and dating the written informed 
consent document.  Informed consent must be obtained before conducting any study-specific 
procedures (i.e., all of the procedures described in the protocol). The process of obtaining 
informed consent will be documented in the subject source documents. 
 
 

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 13 of 17                              
 
 
4 STATISTICAL CONSIDERATIONS/DATA ANALYSIS  
 
4.1 Sample Size   
This is an observational study. Based on CLEAR PLATELETS Study, we think 30 patients 
in each group are sufficient.  
 
4.2 Statistical Calculations  
Sample size (n=60 patients) is based on the CLEAR PLATELETS study. Categorical 
variables will be compared using 2 test or the Fisher exact test as appropriate whereas 
continuous variables will be assessed using the Student unpaired t or Mann-Whitney U test, 
and ANOVA test after checking for normal distribution. The pharmacodynamic effect of 
different regimens will be compared using a linear mixed model taking into account the 
within-subject correlation and a first-order autoregressive error structure. Each model will 
include treatment, time, an interaction between treatment and time, and the baseline 
pharmacodynamic parameter as covariate. Analyses will be performed with SPSS software 
(SPSS, Inc., Chicago, IL) and p<0.05 will be considered significant.  
 
5 SCHEDULE OF PROCEDURES 
    The study comprises of 2 periods: Baseline/pre-study drug infusion and post-start of study    
    drug infusion. Data analysis is summed up by timepoints: baseline/pre-study drug infusion, 10 
    minutes and 30 minutes post-start of the infusion and 30 minutes, 1 hour, 2 hour, 4-6 hour,  
    and 12-24 hours post-end of study drug infusion.   
 
5.1 Timing of Assessments 
 
5.1.1 Baseline/Pre-study drug infusion 
Subjects will be pre-screened to ensure that the subject is eligible for the study. During the 
baseline visit, the following will be completed and documented in the Case Report Forms 
(CRF): 
 Obtain written informed consent 
 Complete inclusion/exclusion criteria 
 Obtain demographic information (i.e. date of birth, gender, and race) 
 Record medical history (including medical, surgical, and smoking history) 
 Record concomitant medications  
 Obtain height and weight 
 Obtain and record pre-intervention vital signs  
 Obtain urine specimen for pregnancy test, if applicable 
 Obtain blood specimen for platelet activation, aggregation, and biomarkers, clot 
strength and clot characteristics prior to study drug infusion (baseline) 
 
5.1.2 Post-start of study drug infusion 
Subjects are expected to be seen as an inpatient during the study. Time-points for this 
period include 10 minutes and 30 minutes post-start of the infusion and 30 minutes, 1 hour, 
2 hour, 4-6 hour, and 12-24 hour post-end of study drug infusion (a 10% window at each 
time point is acceptable). During these time points, blood specimens for platelet activation, 
aggregation, clot characteristics, and biomarkers, will be obtained. If applicable, urine  
 

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 14 of 17                              
 
 
specimen for pregnancy test will be obtained at 12-24 hours post-end of drug infusion. 
Continued eligibility, changes in concomitant medications, and subject status will be 
collected. 
  
6 DATA MANAGEMENT 
6.1 Data Storage and Management 
Designated study site staff will record data required by the protocol into the CRFs and enter 
it into the electronic database. Authorized research staff will review the CRFs for 
completeness and accuracy and make any necessary corrections to the data entered into the 
electronic database. Information about study subjects will be kept confidential and managed 
according to the requirements of the Health Insurance Portability and Accountability Act of 
1996 (HIPAA).  Each subject screened and enrolled will be assigned a subject identification 
number (ID) and a list of subjects with their corresponding subject ID will be maintained 
separately from collected data. Physical CRFs will be stored in the research site in a locked 
office and electronic subject data will be locked in a password protected file on a secure 
internet server, accessed only by authorized research staff.   
 
6.2 Records Retention  
The Investigator will maintain the records of final CRFs (CDROM copies), worksheets, 
paper source documents, and all other study-specific documentation in accordance with ICH 
Guidelines. Essential documents should be retained until at least three (3) years after the 
investigation is formally discontinued. 
 
6.3 Confidentiality 
Subject information will be kept confidential as according to HIPAA requirements. Subject 
data will be stored and managed as outlined in section 6.1. All data records will be stored on 
site until 2 years after the investigation is formally discontinued. Paper records will be 
shredded and recycled. Records stored on a computer hard drive will be erased using a 
commercial software application designed to remove all data from the storage device.   
 
7 DATA SAFETY MONITORING PLAN 
7.1 The principal investigator holds ultimate responsibility for the oversight and execution of 
the data and safety monitoring plan. This research site will be fully committed in the 
ongoing review and refinement of the trial’s processes to assure subject safety, data 
validity and integrity, and regulatory compliance. 
7.2 The principal investigator and an independent medical monitor will review the safety 
data, assure protocol compliance, and conduct safety reviews to protect each subject’s 
safety and welfare in this clinical investigation. The review process will be initiated after 
enrolling the first 10 subjects and every 10 subjects thereafter. The principal investigator 
will evaluate whether the study should continue unchanged, require modification, or 
closed the enrollment.   
7.3 Case report forms (CRF) will be completed to capture protocol data. Two study 
coordinators on site will do separate CRF audits to assure data is accurate and complete 
and to assure adherence to study protocol. This will allow for identification of protocol 
deviations and areas in which practice can be improved. Audits will be done on all paper 
CRFs, which include the subject’s informed consent form, ICF notes, subject eligibility,  
 

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 15 of 17                              
 
medical records, concomitant medication list, laboratory results, study procedures, visit 
notes, investigator notes, and adverse event forms. Proper filing of required regulatory 
documentation and subject CRFs, correct transcription of data, which will include 
checking for appropriate units of measure and legibility, will be monitored. 
 
8 HUMAN SUBJECTS PROTECTION (RISKS, BENEFITS, AND ALTERNATIVES) 
8.1 Risks 
8.1.1 Potential loss of privacy 
 Protected health information (PHI) will be collected during the study. The risk for breach of 
confidentiality and privacy will be minimized by shielding the subjects unlinking his or her 
identity from his or her personal health information. 
 
8.1.2 Adverse events 
All adverse events will be collected and reported. SAEs will be treated appropriately and 
managed as according to standard of care.  
 
8.1.3 Economic risk 
  No economic risk is expected. 
 
8.2 Benefits and Alternatives 
Participation in the study is entirely voluntary. The alternative is not to participate in the trial. 
Patients may benefit from the antithrombotic properties of the parenteral agents.  
 
9 SUBJECT COMPENSATION 
9.1 Costs 
The subject or their insurance company will not be billed for this study. All study related 
tests that are not considered as standard of care will be paid for by the research site.  
 
10 ADVERSE EVENT REPORTING 
10.1 
Adverse Event Reporting 
The principal investigator has the primary responsibility for SAE identification, documentation, 
grading, and assignment of attribution to the study intervention. SAEs related to study 
procedures will be collected and reported (see section 6.1.2). SAEs must be recorded in the AE 
CRF with the following information:  
 
-The intensity grade (see CTCAE v4.03 grading) 
 
-The relationship to study procedure 
 
-Attribution 
 
-Duration 
 
-Occurrence (known risks for study procedure-expected, unexpected) 
 
-Other contributing causes 
 
-Actions in response to event 
 
-Outcome 
 
-Criteria for SAE  
 
10.2 
Protocol Deviations and Violations 
The principal investigator will not deviate from the protocol without obtaining approval from 
the IRB or Ethics Committee and the sponsor. Protocol deviations that occur will be reported 
to the Inova IRB at the time of continuing review. Protocol violations that affect the subject’s 

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 16 of 17                              
 
rights and safety, and/or affects study integrity will be reported to the Inova IRB within 10 
working days of event knowledge.  
 
11 
FUNDING   
This research is funded by Medicure Pharma, Inc. There is no investigational product involved. 
Treatment assigned to the subject will be as according to main provider’s discretion as according 
to standard of care.  
 
12 
CONFLICTS OF INTEREST   
Dr. Gurbel reports personal fees from AstraZeneca, Boehringer Ingelheim, Merck, Janssen 
Pharmaceuticals, Bayer, and Haemonetics; grants from Haemonetics, Merck, Harvard Clinical 
Research Institute, National Institutes of Health, Coramed Technologies, MedImmune, a patent 
for platelet function testing; and stock options in Merck. 
 
13 
FACILITIES AND EQUIPMENT  
The research site is equipped with its own laboratory equipment, which includes state of the art 
technologies for platelet assays, centrifuges, refrigerators, and freezers for study specimen 
processing and storage.  
 
14 
OUTSIDE CONSULTANTS/COLLABORATORS  
There are no outside consultants/collaborators participating. 
 
15 
CONTRACTURAL AGREEMENTS   
   
There are no outside consultants/collaborators participating.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Tirofiban vs. Cangrelor in NSTEMI                                                                                                            ICTR; IHVI 
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CONFIDENTIAL               MEDICURE Protocol     Version 3        PI: Paul A Gurbel                           Page 17 of 17                              
 
 
16 
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