Clinical trial NCT03437044
Conditions: Diabetes Mellitus, Type 2 Coronary Artery Disease
Keywords: diabetes mellitus percutaneous coronary intervention ticagrelor clopidogrel coronary artery disease
Sponsor: University of Florida
Start date: 2018-03-14; Completion date: 2020-06-27
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To date there is very little PD and pharmacokinetic (PK) data on the ticagrelor 60 mg bid dosing regimen. In particular, there is no prospective PK/PD study on this dosing regimen in patients with DM who are known to have impaired response to clopidogrel therapy. Since DM patients frequently require elective PCI due to chronic progression of CAD (and not solely because of an acute thrombotic complication), and clopidogrel remains the guideline recommended P2Y12 inhibiting therapy for these patients, understanding the PD effects of the ticagrelor 60 mg bid regimen in this setting is an unmet clinical need. This is also in light of the ongoing THEMIS trial which is specifically evaluating the impact of the ticagrelor 60 mg bid dosing regimen in type 2 DM patients without a prior major CV event.

Detailed description:
Patients with diabetes mellitus (DM) are characterized by platelet hyperreactivity and reduced pharmacodynamic (PD) effects to several oral antiplatelet agents, including clopidogrel. In addition to the hyperreactive platelet phenotype, impaired drug metabolism as well as increased platelet turnover rates may contributed to impaired clopidogrel-induced antiplatelet effects in DM patients. These observations may contribute to the higher ischemic event rates, including stent thrombosis, observed in DM patients compared with non-DM patients treated with clopidogrel.

Ticagrelor is characterized by more prompt, potent and predictable antiplatelet effects compared with clopidogrel and lower ischemic events in patients with an acute coronary syndrome (ACS) on a background of aspirin therapy. In patients who experienced a prior (1-3 years) myocardial infarction (MI), compared with placebo, ticagrelor 60 mg bid on a background of aspirin therapy also reduced long-term ischemic events, with a mortality benefit observed in DM patients.

To date the PD effects of ticagrelor versus clopidogrel in DM largely derive from post-hoc assessments or in stabilized patients (e.g. \>30 days after PCI), and have not been prospectively evaluated in the context of elective PCI procedures. Moreover, PD studies with the ticagrelor 60 mg bid regimen are limited. Therefore, the aim of this investigation will be to compare the PD effects of a ticagrelor 60 mg bid versus clopidogrel 75 mg od MD regimen in DM patients without a prior major CV event undergoing elective PCI.

Arms: arm 1: 180 mg loading dose (LD) followed by a 60 mg bid maintenance (MD) starting 12 h (± 1 h) after the LD arm 2: 600 mg LD followed by a 75 mg od MD starting 24 hours (± 1 h) after the LD
Interventions: intervention 1: Ticagrelor intervention 2: Clopidogrel
Intervention descriptions: intervention 1: After providing written informed consent and following diagnostic angiography, patients meeting study entry criteria undergoing PCI will be randomly assigned in a 1:1 ratio to treatment with either ticagrelor or clopidogrel. Randomized treatment will be maintained for 30±3 days. intervention 2: After providing written informed consent and following diagnostic angiography, patients meeting study entry criteria undergoing PCI will be randomly assigned in a 1:1 ratio to treatment with either ticagrelor or clopidogrel. Randomized treatment will be maintained for 30±3 days.

Protocol documents:
Prot_SAP_000.pdf: 
Official Title:  A Randomized Comparison of Platelet Inhibition Using a Low Maintenance Dose Ticagrelor 
Regimen Versus Standard Dose Clopidogrel in Diabetes Mellitus Patients Without Prior Major 
Cardiovascular Events Undergoing Elective Percutaneous Coronary Intervention: The OPTIMUS 
(Optimizing Antiplatelet Therapy in Diabetes Mellitus)‐6 Study   
 
NCT:  NCT03437044 
 
Document Date: January 4, 2018 
 
 
 
 
 


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A Randomized Comparison of Platelet Inhibition Using a Low Maintenance Dose 
Ticagrelor Regimen versus Standard Dose Clopidogrel in Diabetes Mellitus Patients 
without Prior Major Cardiovascular Events Undergoing Elective Percutaneous Coronary 
Intervention: The OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus)-6 
Study 
 
 
 
 
 
 
 
Dominick J Angiolillo, MD, PhD, FACC, FESC, FSCAI 
Professor of Medicine  
Director of Cardiovascular Research 
Division of Cardiology 
University of Florida College of Medicine - Jacksonville 
655 West 8th Street 
Jacksonville, FL – 32209 
Tel: 904-2443933, Fax: 904-2443102 
dominick.angiolillo@jax.ufl.edu 


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BACKGROUND AND SIGNIFICANCE 
Patients with diabetes mellitus (DM) are characterized by platelet hyperreactivity (1,2). 
Several mechanisms, including hyperglycemia, insulin resistance, associated metabolic 
conditions and other cellular abnormalities, are involved in the hyperreactive platelet phenotype 
(1,2). All these metabolic and cellular defects result in intensified platelet adhesion, activation, 
aggregation and platelet-derived thrombin generation (1,2). Importantly, patients with DM have 
shown to have reduced pharmacodynamic (PD) effects to several oral antiplatelet agents, 
including clopidogrel (1-3). In addition to the hyperreactive platelet phenotype, impaired drug 
metabolism as well as increased platelet turnover rates may contributed to impaired clopidogrel-
induced antiplatelet effects in DM patients (3-5). These observations may contribute to the 
higher ischemic event rates, including stent thrombosis, observed in DM patients compared with 
non-DM patients treated with clopidogrel (1,2,6). However, clopidogrel remains the most widely 
used oral P2Y12 receptor inhibitor and is the only agent in this class approved for use in patients 
with stable coronary artery disease (CAD) undergoing percutaneous coronary interventions (PCI) 
(7,8). These findings underscore the need to identify strategies associated with more effective 
platelet inhibition in DM patients undergoing PCI. 
Ticagrelor is a first in class cyclopentyl triazolo-pyrimidine (CPTP) characterized by 
more prompt, potent and predictable antiplatelet effects compared with clopidogrel (9). In 
patients with an acute coronary syndrome (ACS) on a background of aspirin therapy, compared 
with clopidogrel 75 mg once-daily (od), a 90 mg twice-daily (bid) ticagrelor maintenance dose 
(MD) regimen was associated with lower one-year ischemic event rates, including cardiovascular 
mortality (10). Consistent findings were observed in patients with DM (11).  In patients who 
experienced a prior (1-3 years) myocardial infarction (MI), compared with placebo, ticagrelor 60 


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mg bid on a background of aspirin therapy also reduced long-term ischemic events, with a 
mortality benefit observed in DM patients (12,13). Although in these studies ticagrelor was 
associated with increased bleeding, the net benefit still favored the use of ticagrelor, particularly 
in the DM cohorts (12,13). The advantages of ticagrelor over clopidogrel in patients with DM 
may be attributed to its enhanced antiplatelet potency, its twice-daily regimen as well as the fact 
that it does not require metabolism to exert its effects. In fact, studies have shown that twice-
daily administration of oral antiplatelet agents may overcome the negative impact of high platelet 
turnover rates on platelet inhibition in DM patients (5). Moreover, hepatic enzymatic activity 
may be downregulated in DM patients and may thus affect drugs such as clopidogrel who require 
hepatic metabolism to exert their PD effects (14).  
Aspirin monotherapy is the standard of care for prevention of ischemic events in DM 
patients without a prior major cardiovascular (CV) event (15). However, these patients remain at 
high risk for CV events despite aspirin therapy (15). This has prompted the design of the 
THEMIS  (effect of Ticagrelor on Health outcomes in diabEtes Mellitus patients Intervention 
Study; NCT01991795) trial investigating whether the adjunctive use of ticagrelor 60 mg bid can 
further reduce major cardiovascular events in type 2 DM patients without a prior major CV event 
(MI or stroke). Moreover, DM patients are at risk not only for acute atherothrombotic 
complications but also for chronic CAD progression (16,17). Therefore, these patients frequently 
undergo PCI for whom clopidogrel, in adjunct to aspirin, remains the guideline recommended 
P2Y12 receptor inhibitor (8). However, to date the PD effects of ticagrelor versus clopidogrel in 
DM largely derive from post-hoc assessments or in stabilized patients (e.g. >30 days after PCI), 
and have not been prospectively evaluated in the context of elective PCI procedures (18-21). 


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Moreover, PD studies with the ticagrelor 60 mg bid regimen are limited (22,23,24). Although 
these studies have shown that ticagrelor 60 mg has a similar PD profile than ticagrelor 90 mg, 
regardless of DM status, and is associated with more potent antiplatelet effects than clopidogrel 
75 mg, there are no studies assessing the PD profiles of ticagrelor 60 mg versus clopidogrel 75 
mg in DM patients (22,23,24). Therefore, the aim of this investigation will be to compare the PD 
effects of a ticagrelor 60 mg bid versus clopidogrel 75 mg od MD regimen in DM patients 
without a prior major CV event undergoing elective PCI.    
 
STUDY RATIONALE 
To date there is very little PD and pharmacokinetic (PK) data on the ticagrelor 60 mg bid 
dosing regimen. In particular, there is no prospective PK/PD study on this dosing regimen in 
patients with DM who are known to have impaired response to clopidogrel therapy. Since DM 
patients frequently require elective PCI due to chronic progression of CAD (and not solely 
because of an acute thrombotic complication), and clopidogrel remains the guideline 
recommended P2Y12 inhibiting therapy for these patients, understanding the PD effects of the 
ticagrelor 60 mg bid regimen in this setting is an unmet clinical need. This is also in light of the 
ongoing THEMIS trial which is specifically evaluating the impact of the ticagrelor 60 mg bid 
dosing regimen in type 2 DM patients without a prior major CV event.  
 


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REASERCH PLAN 
Study design 
The proposed investigation will be a prospective, randomized, open-label, PK/PD study 
conducted in DM patients undergoing elective PCI.  Figure 1 illustrates the overall study design. 
After providing written informed consent and following diagnostic angiography, patients 
meeting study entry criteria (see inclusion and exclusion criteria below) undergoing PCI will be 
randomly assigned in a 1:1 ratio to treatment with either ticagrelor or clopidogrel. Patients 
randomized to ticagrelor will receive ticagrelor 180 mg loading dose (LD) followed by a 60 mg 
bid MD starting 12 h (± 1 h) after the LD. Patients randomized to clopidogrel will receive a 600 
mg LD followed by a 75 mg od MD starting 24 hours (± 1 h) after the LD.  Maintenance dose 
therapy will be maintained for 30±3 days. All patients will receive a 325 mg LD of aspirin prior 
to the procedure and then 81 mg daily. Afterwards, antiplatelet treatment will be left to the 
discretion of the treating physician.  
The randomized treatment will be administered in the catheterization laboratory after 
defining coronary anatomy and before starting PCI (defined as before guide wire passing the 
target coronary lesion). Blood samples for PK/PD testing will be obtained at a total of 9 time 
points: immediately before the LD, and then at 0.5 h, 2 h, 8 h, 24 h (trough and peak), and 30 
(±3) days (trough and peak) following LD; an additional sample will be collected at the end of 
PCI. The end of PCI is defined as when the guide catheter is removed from the body at the 
completion of the procedure. Access site, choice of anticoagulant (i.e., heparin or bivalirudin), 
stent type and procedural technique will be at the discretion of the physician. Staff performing 
PK/PD assessments will remain blinded to treatment assignment.   


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The study will be performed at the University of Florida Health Science Center at UF 
Health Jacksonville - Division of Cardiology. Patients will be recruited prior to undergo 
diagnostic angiography at the inpatient and outpatient facilities 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 30 days will be considered 
valid for screening purposes. If these are not available, a blood sample will be collected for the 
screening phase. 
 
 
 


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Study Population 
Specific inclusion and exclusion criteria are described below and have been considered to closely 
reflect study entry criteria of the THEMIS trial (NCT01991795). 
Inclusion criteria 
For inclusion in the study patients should fulfill the following criteria: 
1. Provision of informed consent prior to any study specific procedures 
2. Men or women ≥18 years of age 
3. Diagnosed with type 2 DM defined by ongoing glucose lowering drug (oral medications 
and / or insulin) treatment for at least 1 month 
4. Presence of CAD undergoing elective PCI*  
* Patients will need to be cardiac enzyme-negative prior to undergoing coronary angiography. 
Patient will need to be on a background of aspirin therapy (treated with a 325 mg LD prior to 
coronary angiography unless already on chronic low-dose aspirin therapy). Patients on 
maintenance clopidogrel 75 mg therapy for at least 1 week due to a prior vascular intervention 
will also be eligible. However, patients on clopidogrel, ticagrelor or prasugrel due to a prior 
acute major cardiovascular event (MI or stroke) will not be eligible.  
 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. Previous MI (with the exception of definite non-type 1 MI [eg, due to coronary 
revascularization procedure, profound hypotension, hypertensive emergency, tachycardia, 
or profound anemia]) 


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2. Previous stroke (transient ischemic attack [TIA] is not included in the stroke definition) 
3. Use of an intravenous antiplatelet therapy (i.e., cangrelor or GPI) during PCI 
4. On treatment with clopidogrel, prasugrel, or ticagrelor due to a prior acute major CV 
event (MI or stroke) (on treatment with clopidogrel due to prior vascular intervention not 
secondary to a major CV event is allowed) 
5. Planned use of aspirin treatment at doses >100 mg od 
6. Anticipated concomitant oral or intravenous therapy with strong cytochrome P450 3A4 
(CYP3A4) inhibitors or CYP3A4 substrates with narrow therapeutic indices that cannot 
be stopped for the course of the study: 
− Strong inhibitors: ketoconazole, itraconazole, voriconazole, telithromycin, 
clarithromycin (but not erythromycin or azithromycin), nefazadone, ritonavir, 
saquinavir, nelfinavir, indinavir, atanazavir 
− CYP3A4 substrates with narrow therapeutic index: quinidine, simvastatin at doses 
>40 mg daily or lovastatin at doses >40 mg daily 
7. Need for chronic oral anticoagulant therapy or chronic low-molecular-weight heparin (at 
venous thrombosis treatment not prophylaxis doses) 
8. Patients with known bleeding diathesis or coagulation disorder 
9. History of previous intracerebral bleed at any time, gastrointestinal (GI) bleed within the 
past 6 months prior to randomization, or major surgery within 30 days prior to 
randomization 
10. Active pathological bleeding 
11. Hypersensitivity to ticagrelor and clopidogrel or any of the excipients 


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12. Increased risk of bradycardic events (eg, known sick sinus syndrome, second or third 
degree AV block or previous documented syncope suspected to be due to bradycardia) 
unless treated with a pacemaker 
13. Known severe liver disease (eg, ascites and/or clinical signs of coagulopathy) 
14. Renal failure requiring dialysis 
15. Known platelet count <80x106/mL 
16. Known hemoglobin <9 g/dL 
17. Women of child-bearing potential (ie, those who are not chemically or surgically 
sterilized or who are not post-menopause) who are not willing to use a medically 
accepted method of contraception that is considered reliable in the judgment of the 
investigator OR who have a positive pregnancy test at enrolment or randomization OR 
women who are breast-feeding. If a subject becomes pregnant during the course of the 
study the investigational product should be discontinued immediately [the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) will be followed up and documented even if the subject 
was discontinued from the study]. 
18. Inability of the patient to understand and/or comply with study procedures and/or follow 
up, in the opinion of the investigator, OR any conditions that, in the opinion of the 
investigator, may render the patient unable to complete the study 
19. Life expectancy of less than 1 month based on investigator’s judgement 
20. Participation in another clinical study with an investigational (defined as non-FDA 
approved) product within 28 days prior to enrolment  
21. Previous randomization in the present study 


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Blood sampling and PK/PD Assessments  
Blood samples for screening procedures if needed will be obtained via antecubital vein 
puncture using a 21-gauge needle. Blood samples for PK/PD testing at baseline (before the LD), 
at 0.5 h, and at the end of the PCI will be collected from the arterial access site sheet; blood 
samples for the 2 h, 8 h, 24 h (trough and peak), and 30±3 days (trough and peak) time points 
will be collected via antecubital vein puncture using a 21-gauge needle. The last dose intake of 
study drug will be 12±2 h and 24±2 h prior to blood sampling in order to guarantee assessment 
of trough level of platelet inhibition for ticagrelor and clopidogrel, respectively, while peak 
levels of platelet inhibition will be assessed by obtaining blood samples 2 h after MD 
administration (22). The first few mL of blood will be discharged in order to avoid spontaneous 
platelet activation. Whole blood samples will be collected into 3.2% 9NC Coagulation Sodium 
Citrate, 2mL (Vacuette, Kremsmünster, Austria) and 3.2% Buffered Sodium Citrate, 4.5mL (BD, 
Franklin Lakes, NJ, USA)  tubes as appropriate for the specific assays being conducted.  
PD assessments 
A total of 3 different PD assays will be used for this study: 
1) VerifyNow (VN) PRU: The VN System is a turbidimetric based optical detection system 
which measures platelet induced aggregation as an increase in light transmittance (Accumetrics, 
San Diego, CA) and will be utilized according to manufacturer’s instructions, as previously 
described (3). The assay is based on microbead agglutination and uses specific reagents for the 
pathways of interest. The VN-PRU assay, by combining ADP+PGE1, measures changes in 
platelet function specific to P2Y12 receptor inhibitors. The assay is based upon the ability of 
activated platelets to bind fibrinogen. Fibrinogen-coated microparticles aggregate in proportion 


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to the number of GP IIb/IIIa receptors expressed. Light transmittance increases as activated 
platelets bind and aggregate fibrinogen-coated beads. The instrument measures this change in 
optical signal and reports results in P2Y12 Reaction Units (PRU). 
2) Whole blood vasodilator-stimulated phosphoprotein (VASP): VASP phosphorylation 
(VASP-P) is a marker of P2Y12 receptor signaling. VASP will be assessed the ELISA VASP-P 
kit (Biocytex Inc., Marseille, France) as previously described (25). After a first step of parallel 
whole blood sample activation with PGE1 and PGE1+ADP, platelets from the sample are lysed, 
allowing released VASP to be captured by an anti-human VASP antibody, which is coated in the 
microtiter plate. Then, a peroxidase-coupled anti-human VASP-P antibody binds to 
phosphorylated serine 239 antigenic determinant of VASP. The bound enzyme peroxidase is 
then revealed by its activity on TMB substrate over a predetermined time. After stopping the 
reaction, absorbance at 450 nm is directly related to the concentration of VASP-P contained in 
the sample.PGE1 increases VASP-P levels by stimulation of adenylate cyclase. Binding of ADP 
to P2Y12 leads to Gi-coupled inhibition of adenylate cyclase. Therefore, the addition of ADP to 
PGE1-stimulated platelets reduces PGE1-induced VASP-P levels. If P2Y12 receptors are 
successfully inhibited, addition of ADP will not reduce the PGE1-stimulated VASP-P levels. The 
platelet reactivity index (PRI) will be calculated after measuring VASP-P levels. 
3) Light transmittance aggregometry (LTA): Platelet aggregation will be performed using LTA 
according to standard protocols. 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 (3). Platelet agonists will include arachidonic acid (AA; 1 
mM), collagen (3µg/ml) and ADP (5 and 20 µM) and TRAP (15 μM). PRP will be obtained as a 


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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) and late platelet aggregation (LPA) in light transmittance from baseline using 
PPP as a reference.  
 
PK assessments 
PK assessments will include determination of plasma concentration of clopidogrel active 
metabolite, ticagrelor and its active metabolite (AR-C124910XX), as previously described 
(3,26). Time for the maximum plasma concentration (Tmax), maximum observed plasma 
concentration (Cmax) and the area under the plasma concentration vs. time curve from time 0 to 
the last measurable concentration (AUC0-t) will be calculated.  
 
Other laboratory assessments 
Blood samples will also be collected to assess the following parameters: a) HbA1c at baseline; b) 
reticulated platelets at baseline and 30 days; c) troponin levels at baseline, and 6 h and 24 h post 
PCI. 
 
 
 


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Study endpoints, sample size calculation and statistical analysis 
The primary endpoint of our study will be platelet reactivity, measured as PRU level 
using VN, of ticagrelor versus clopidogrel MD at 30 days after PCI, immediately pre-dosing 
dosing (trough levels). Based on previous studies (22,24,27), assuming a standard deviation of 
55 and 100 PRU for ticagrelor and clopidogrel, respectively, a sample size of 34 patients (17 per 
treatment group) will be needed to detect an absolute difference of 95 PRU between ticagrelor 
and clopidogrel (corresponding to means of 170 versus 75)  with a 90% power and a 2-tailed 
alpha value of 0.05. Assuming a potential 25% in data attrition due to patient drop-out (e.g., due 
to side effects, unplanned use of parenteral antiplatelet therapies after randomization or 
withdrawal of consent) or invalid PD samples (e.g, due to hemolysis or technical reasons), a 
sample size of approximately 42 patients is expected to be randomized. 
Conformity to the normal distribution will be evaluated for continuous variables with the 
Shapiro-Wilk test. For baseline characteristics, continuous variables will be expressed as mean 
(standard deviation [SD]) and categorical variables as frequencies and percentages. Chi-squared 
test or Fisher’s exact test will be used where appropriate to compare categorical variables 
between 2 groups.  
The PD population will include all patients with PD data and without a major protocol 
deviation thought to affect significantly the PD of ticagrelor or clopidogrel. The PD population 
will be used for analysis of all primary and secondary PD variables. Erroneously treated patients 
(eg, those randomized to one treatment but actually given the other) will be accounted for based 
on the actual treatment received.  


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The primary analysis of the difference between ticagrelor and clopidogrel in PRU will be 
analyzed using analysis of variance. Treatment level means and 2-sided 95% confidence 
intervals (CIs) will be estimated. Analysis of variance will also used to evaluate other intergroup 
comparisons. Repeated measures of analysis of variance, taking into account between- and 
within-subject variations, will be conducted to evaluate the impact of the 2 different treatments 
on platelet reactivity across time points. A p-value < 0.05 will be considered statistically 
significant. Statistical analysis will be performed with SPSS version 24 software (SPSS Inc.). 
Secondary endpoints will include comparisons of measures of platelet reactivity using 
VN, VASP, and LTA at all other time points [0.5 h, 8 h, 24 h (trough and peak), 30 days (trough 
and peak) following LD, and end of PCI] as well as rates of high on-treatment platelet reactivity 
(HPR). In line with recent expert consensus definitions, HPR will be defined as a PRU >208, 
VASP-PRI> 50%, maximum LTA response to 20 μM ADP > 59 %, maximum LTA response to 
5 μM ADP > 46 % (28). In addition, time for the maximum plasma concentration (Tmax), 
maximum observed plasma concentration (Cmax) and the area under the plasma concentration vs. 
time curve from time 0 to the last measurable concentration (AUC0-t) of plasma concentration of 
clopidogrel active metabolite, ticagrelor and its active metabolite (AR-C124910XX) will be 
calculated. 
All patients who received at least 1 dose of study drug will be included in the safety 
population. Safety will be evaluated by assessment of adverse events (including bleeding and 
ischemic), serious adverse events, physical examination, and vital signs. Adverse events will 
collected up to 7 days after the completion of the study. Bleeding events will be classified 
according to BARC (Bleeding Academic Research Consortium) criteria (29). Stent thrombosis 


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will be classified according to ARC (Academic Research Consortium) definitions (30). MI, 
including peri-procedural MI, will be defined according to the universal definition (31). Ischemic 
stroke will be defined as an ischemic cerebral infarction caused by an embolic or thrombotic 
occlusion of a major intracranial artery. Death will be considered cardiac in origin unless 
obvious non-cardiac causes can be identified.   
 
Possible Discomforts and Risk 
In clinical trials, the most important adverse effect associated with the use of ticagrelor 
60 mg was bleeding. The risk of major bleeding with ticagrelor 60 mg was 2.3%; the combined 
risk of intracranial hemorrhage or fatal bleeding was 0.7% (12). However, such bleeding 
prevalence occurred in the setting of long-term trial (median follow-up of 33 months) with 
bleeding events that accrued over time, while our study is limited to only 30 ± 3 days of therapy. 
Moreover, these bleeding rates occurred versus placebo, while in our investigation which is 
being conducted in patients undergoing PCI which mandates the use of a P2Y12 inhibitor, 
ticagrelor will be compared with clopidogrel, which is also associated with an increased risk of 
bleeding compared with placebo (9). Therefore, we do not anticipate that ticagrelor will 
significantly increase the risk of bleeding compared with clopidogrel. Dyspnea has been reported 
as the main non-bleeding side effect with ticagrelor and occurs in up to 15.8% of patients 
(10,12). Dyspnea has been associated with drug discontinuation in 4.6% of patients (10,12). 
Patients who discontinue ticagrelor therapy will be switched to clopidogrel. Ultimately, although 
a 60 mg dosing regimen has not been specifically tested in DM patients undergoing PCI, this 
dosing regimen has shown to be associated with more potent antiplatelet effects than clopidogrel 


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and has not been associated with any increase in thrombotic complications in elective PCI 
patients conducted in an unselected cohort of subjects, which included patients with DM (27). 
Overall, these considerations limit any safety concerns associated with the conduct of this study.  
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. Clinical events will be evaluated by a local data safety monitoring 
board (DSMB) committee, comprised of 2 faculty members (2 cardiologists), not directly 
involved in the research. In the event of a report of a serious adverse event (as defined below) the 
DSMB will meet and antiplatelet treatment management will be managed, including stopping if 
of clinical concern, according to physician recommendation. 
 
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 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 immediately life-threatening adverse experience: An adverse 
event occurring while on study that results in any of the following outcomes: 
- Death 


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- 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. Study related 
SAE will be defined as a SAE considered related (reasonable possibility that the study treatment 
caused the adverse experience) to the study treatment. 
 
Reporting of serious adverse events  
A copy of the MedWatch/AdEERs report must be faxed to AstraZeneca at the time the 
event is reported to the FDA. It is the responsibility of the investigator to compile all necessary 
information and ensure that the FDA receives a report according to the FDA reporting 
requirement timelines and to ensure that these reports are also submitted to AstraZeneca at the 
same time. 


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Serious adverse events that do not require expedited reporting need to be reported to 
AstraZeneca quarterly either as individual case reports or as line-listings. When reporting to 
AstraZeneca, a cover page should accompany the MedWatch/AdEERs form indicating the 
following: 
 
External Sponsored Research (ESR) 
 
The investigator IND number assigned by the FDA 
 
The investigator’s name and address 
 
The trial name/title and AstraZeneca ESR reference number 
Investigative site must also indicate, either in the SAE report or the cover page, the 
causality of events in relation to all study medications. 
To meet data privacy and confidentiality requirements, Adverse Event (AE) information 
(both individual case reports and listings) must be sent from the Sponsor/Sponsor-Investigator by 
secure e-mail, if secure email is not available AE information must be sent by fax.  Send SAE 
report and accompanying cover page to AstraZeneca by Email: 
AEMailboxClinicalTrialTCS@astrazeneca.com) or Fax to AstraZeneca’s designated fax line: +1 
302 886 4114). Serious adverse events that do not require expedited reporting to the FDA need 
to be reported to AstraZeneca preferably using the MedDRA coding language for serious adverse 
events.  
All SAEs have to be reported to AstraZeneca, whether or not considered causally related 
to the investigational product. All SAEs will be documented. The investigator is responsible for 
informing the IRB and/or the Regulatory Authority of the SAE as per local requirements. All 


Confidential 
Version 3 – January 4, 2018 
 
19 
 
pregnancies and outcomes of pregnancy should be reported to AstraZeneca’s designated e-mail 
or fax line (noted above) 
 
Possible benefits 
The present investigation is aimed to evaluate the PD effects of ticagrelor 60 mg bid 
compared with a standard dosing regimen of clopidogrel in DM patients with CAD undergoing 
elective PCI. 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 
 
Publication Strategy/Additional Information  
Study subjects will be identified first (months 1-12): we expect to enroll approximately 3-
4 subjects monthly and complete enrollment in 12 months (total: 42 subjects enrolled). Months 
13-14 will be implied for statistical analysis and months 15-16 for abstract or manuscript 
preparation. We intend to present data at a major scientific meeting at completion of the study. 
We anticipate no major problems with the described protocol since the approach is a 
straightforward prospective study and is based on well-established methods.  
 
 


Confidential 
Version 3 – January 4, 2018 
 
20 
 
Conflict of Interest 
Dr. Angiolillo is a consultant for Astra Zeneca, the maker of ticagrelor. 


Confidential 
Version 3 – January 4, 2018 
 
21 
 
REFERENCES 
1. Rollini F, Franchi F, Muñiz-Lozano A, Angiolillo DJ. Platelet function profiles in patients 
with diabetes mellitus. J Cardiovasc Transl Res. 2013;6:329-345. 
2. Ferreiro JL, Angiolillo DJ. Diabetes and antiplatelet therapy in acute coronary syndrome. 
Circulation. 2011;123:798-813. 
3. Angiolillo DJ, Jakubowski JA, Ferreiro JL, et al. Impaired responsiveness to the platelet 
P2Y12 receptor antagonist clopidogrel in patients with type 2 diabetes and coronary artery 
disease. J Am Coll Cardiol. 2014;64:1005-14. 
4. Erlinge D, Varenhorst C, Braun OO, et al. Patients with poor responsiveness to 
thienopyridine treatment or with diabetes have lower levels of circulating active metabolite, 
but their platelets respond normally to active metabolite added ex vivo. J Am Coll Cardiol. 
2008;52:1968-77. 
5. 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. 
6. Angiolillo DJ, Bernardo E, Sabaté M, et al. Impact of platelet reactivity on cardiovascular 
outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll 
Cardiol. 2007;50:1541-7. 
7. Sherwood MW, Wiviott SD, Peng SA, et al. Early clopidogrel versus prasugrel use among 
contemporary STEMI and NSTEMI patients in the US: insights from the National 
Cardiovascular Data Registry. J Am Heart Assoc. 2014;3:e000849. 


Confidential 
Version 3 – January 4, 2018 
 
22 
 
8. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on 
Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report 
of the American College of Cardiology/American Heart Association Task Force on Clinical 
Practice Guidelines. Circulation. 2016;134:e123-55. 
9. Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. Nat Rev 
Cardiol. 2015;12:30-47. 
10. 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. 
11. James S, Angiolillo DJ, Cornel JH, et al. Ticagrelor vs. clopidogrel in patients with acute 
coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient 
Outcomes (PLATO) trial. Eur Heart J. 2010;31:3006-16. 
12. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior 
myocardial infarction. N Engl J Med. 2015;372:1791-800. 
13. Bhatt DL, Bonaca MP, Bansilal S, et al. Reduction in Ischemic Events With Ticagrelor in 
Diabetic Patients With Prior Myocardial Infarction in PEGASUS-TIMI 54. J Am Coll 
Cardiol. 2016;67:2732-40. 
14. Harrison SA. Liver disease in patients with diabetes mellitus. J Clin Gastroenterol. 
2006;40:68-76. 
15. Capodanno D, Angiolillo DJ. Aspirin for Primary Cardiovascular Risk Prevention and 
Beyond in Diabetes Mellitus. Circulation. 2016;134:1579-1594. 


Confidential 
Version 3 – January 4, 2018 
 
23 
 
16. Nicholls SJ, Tuzcu EM, Kalidindi S, et al. Effect of diabetes on progression of coronary 
atherosclerosis and arterial remodeling: a pooled analysis of 5 intravascular ultrasound trials. 
J Am Coll Cardiol. 2008;52:255-62. 
17. Nakanishi R, Ceponiene I, Osawa K, et al. Plaque progression assessed by a novel semi-
automated quantitative plaque software on coronary computed tomography angiography 
between diabetes and non-diabetes patients: A propensity-score matching study. 
Atherosclerosis. 2016;255:73-79. 
18. Sweeny JM, Angiolillo DJ, Franchi F, et al. Impact of Diabetes Mellitus on the 
Pharmacodynamic Effects of Ticagrelor Versus Clopidogrel in Troponin-Negative Acute 
Coronary Syndrome Patients Undergoing Ad Hoc Percutaneous Coronary Intervention. J Am 
Heart Assoc. 2017;6(4). 
19. Clavijo LC, Maya J, Carlson G, et al. Platelet inhibition with ticagrelor versus clopidogrel in 
Hispanic patients with stable coronary artery disease with or without diabetes mellitus. 
Cardiovasc Revasc Med. 2015;16:450-4. 
20. Zafar MU, Zafar M, Baber U, et al. Antithrombotic potency of ticagrelor versus clopidogrel 
in type-2 diabetic patients with cardiovascular disease. Thromb Haemost. 2017;117:1981-
1988. 
21. Mangiacapra F, Panaioli E, Colaiori I, et al. Clopidogrel Versus Ticagrelor for Antiplatelet 
Maintenance in Diabetic Patients Treated With Percutaneous Coronary Intervention: Results 
of the CLOTILDIA Study (Clopidogrel High Dose Versus Ticagrelor for Antiplatelet 
Maintenance in Diabetic Patients). Circulation. 2016;134:835-7. 


Confidential 
Version 3 – January 4, 2018 
 
24 
 
22. Storey RF, Angiolillo DJ, Bonaca MP, et al. Platelet Inhibition With Ticagrelor 60 mg 
Versus 90 mg Twice Daily in the PEGASUS-TIMI 54 Trial. J Am Coll Cardiol. 
2016;67:1145-54. 
23. Thomas MR, Angiolillo DJ, Bonaca MP, et al. Consistent platelet inhibition with ticagrelor 
60 mg twice-daily following myocardial infarction regardless of diabetes status. Thromb 
Haemost. 2017;117:940-947. 
24. Alexopoulos D, Despotopoulos S, Xanthopoulou I, Davlouros P. Low-Dose Ticagrelor 
Versus Clopidogrel in Patients With Prior Myocardial Infarction. J Am Coll Cardiol. 
2017;70:2091-2092. 
25. Bonello L, Laine M, Camoin-Jau L, et al. Onset of optimal P2Y12-ADP receptor blockade 
after ticagrelor and prasugrel intake in Non-ST elevation acute coronary syndrome. Thromb 
Haemost. 2015;114:702-7. 
26. Teng R, Butler K. Pharmacokinetics, pharmacodynamics, tolerability and safety of single 
ascending doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in 
healthy subjects. Eur J Clin Pharmacol 2010;66:487-96. 
27. Orme RC, Parker WAE, Thomas MR, et al. Study of Ticagrelor Compared With Clopidogrel 
in Elective PCI (STEEL PCI). American Heart Association Scientific Session 2017. 
28. Tantry US, Bonello L, Aradi D, et al. Consensus and update on the definition of on-treatment 
platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am 
Coll Cardiol. 2013;62:2261-73. 


Confidential 
Version 3 – January 4, 2018 
 
25 
 
29. 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. 
30. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case 
for standardized definitions. Circulation. 2007;115:2344-51. 
31. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J 
Am Coll Cardiol. 2012;60:1581-98. 
 

ICF_001.pdf: 
Official Title:  A Randomized Comparison of Platelet Inhibition Using a Low Maintenance Dose Ticagrelor 
Regimen Versus Standard Dose Clopidogrel in Diabetes Mellitus Patients Without Prior Major 
Cardiovascular Events Undergoing Elective Percutaneous Coronary Intervention: The OPTIMUS 
(Optimizing Antiplatelet Therapy in Diabetes Mellitus)‐6 Study   
 
NCT:  NCT03437044 
 
Document Date: February 15, 2018 
 
 
 
 
 


 
APPROVED 
 
Feb 15, 2018 
 
WIRB 
 
 
 
Research Subject Information and Consent Form (ICF) for use in the US, 
1(13) 
 
 
TITLE: 
A Randomized Comparison of Platelet Inhibition Using a Low 
Maintenance Dose Ticagrelor Regimen versus Standard Dose 
Clopidogrel in Diabetes Mellitus Patients without Prior Major 
Cardiovascular Events Undergoing Elective Percutaneous 
Coronary Intervention: The OPTIMUS (Optimizing Antiplatelet 
Therapy in Diabetes Mellitus)-6 Study 
 
PROTOCOL NO.: 
optvi_version3 
 
WIRB® Protocol #20180124 
 
SPONSOR: 
University of Florida 
 
FUNDING: 
AstraZeneca 
 
INVESTIGATOR: 
Dominick J. Angiolillo, M.D., Ph.D. 
 
655 W 8th St 
 
Jacksonville, Florida 32209 
 
United States 
 
SITE: 
University of Florida Health Science Center / Jacksonville 
 
655 W. 8th St 
 
Jacksonville, Florida 32209 
 
United States 
 
STUDY-RELATED 
PHONE NUMBERS: 
Dominick J. Angiolillo, M.D., Ph.D. 
 
904-244-3378 
 
904-244-0411 (24 hours) 
 
 
Name of person seeking your consent: 
 
 
Place of employment & position: 
 
 
Name of Participant (“Study Subject”) 
 
 
 
 
RESEARCH SUBJECT INFORMATION AND CONSENT FORM 
AND 
AUTHORIZATION TO USE AND DISCLOSE HEALTH 
INFORMATION  


 
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WIRB 
 
 
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Introduction 
 
You are being asked to take part in a research study.  Before you decide if you want to take part, 
it is important for you to understand the following: 
 
 Why the research is being done 
 How your information will be used 
 What the study will involve, and 
 The possible benefits, risks and discomforts to you. 
 
Please take time to read the following information carefully and discuss it with your family 
doctor, if you wish.  If you are in any other study receiving another study drug, you cannot take 
part in this study.  If you do not sign this consent form, you cannot take part in this study. 
 
Information about this study is made available on public websites around the world in 
accordance with AstraZeneca public commitment to transparency of the clinical research and 
with applicable law. 
 
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. 
 
Information on AstraZeneca-sponsored, new and ongoing clinical studies and results from these 
studies are also provided on http://www.astrazenecaclinicaltrials.com/. 
 
Your study doctor is a researcher for this study.  As a researcher, he is interested both in your 
health and how this study is carried out.  The study doctor is receiving funding from AstraZeneca 
(the company paying for the study or ‘the study sponsor’) to carry out this study.  You do not 
have to take part in any research study offered by any doctor.  Whether or not you choose to take 
part in this study, you will still receive the medical care you already have been receiving.  You 
may ask for a second opinion about your care at any time.  You can get this opinion from a 
doctor who is not connected with this study. 
 
The Western Institutional Review Board® (WIRB®) has approved the information in this consent 
document and has given approval for the study doctor to do the study.  The Western Institutional 
Review Board® (WIRB®) is a group of people who perform independent review of research.  
This does not mean that WIRB has approved your participation in the study.  You must think 
about the information in this consent document for yourself.  You must then decide if you want 
to be in the study. 
 
Read this information carefully and please ask the study doctor or the study staff if you 
have any questions. 
 
Why is this research being done? 
 
You are being asked to participate in a research study. The purpose of this consent form is to 
give you information about the study including its purpose, procedures, benefits, and risks.  You 
should take part in the study only if you want to do so.  You may refuse to take part in or 
withdraw from the study at any time without penalty or loss of benefits to which you are 
otherwise entitled. 
 


 
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You are being asked to take part in this research study because you have diabetes and you are 
undergoing diagnostic angiography to define whether you have blockages in the arteries of the 
heart (known as coronary artery disease) that may require treatment with a balloon and a stent 
(also known as Percutaneous Coronary Intervention or PCI). If you undergo PCI, you will be 
asked to take either ticagrelor (BRILINTATM) or clopidogrel during this study.  Ticagrelor and 
clopidogrel are routinely used in patients undergoing PCI, the choice of which is at the discretion 
of the treating physician. However, if you participate in this study, you will be randomly 
assigned (like a flip of a coin) to receive ticagrelor or clopidogrel. 
 
The primary purpose of this study is to measure how sticky your platelets are at different time 
points after receiving ticagrelor or clopidogrel.  This is the part of the research study that is under 
investigation.  In particular, platelets are a type of blood cells.  When you have a cut or break in 
your skin, platelets have an important job of traveling to the area and forming a clot or scab to 
stop the bleeding. The stickier your platelets are, the greater your chances of having heart 
attacks, strokes, or clots in your stents. Platelets from patients with diabetes tend to stick together 
more, increasing the risk of having further heart attacks or strokes. To prevent these, there are 
antiplatelet drugs (blood thinners) to keep your platelets from sticking together. Clopidogrel and 
ticagrelor are among the most common blood thinners used in the treatment of patients with 
coronary artery disease and are both approved by the U.S. Food and Drug Administration (FDA) 
for patients with unstable angina and acute coronary syndrome. However, it has been shown that 
platelets from patients with diabetes treated with clopidogrel still continue to stick together more 
than they should. On the contrary, ticagrelor is more effective for at least the first twelve months 
following acute coronary syndrome in preventing platelets from sticking together. Two 
maintenance doses of ticagrelor have been approved by the FDA. A higher dose (90 mg 
twice/day) is commonly used during the first year in patients undergoing PCI because of a heart 
attack, while a lower dose (60 mg twice/day) is commonly used once patients with heart attacks 
are more stable, in particular one year following when patients experienced a heart attack. In 
these more stable patients it is has been shown that the two doses of ticagrelor have very similar 
effects in preventing platelets from sticking together. Therefore, it has been suggested that the 
lower dose may be of potential value in stable patients (e.g., who never had a heart attack) with 
diabetes who undergo PCI. Preliminary studies, which have also included patients with diabetes, 
have already supported the feasibility of doing this and have also shown the lower dose of 
ticagrelor to be more effective than clopidogrel in preventing platelets from sticking together. In 
this study the goal is to investigate the effects of the low dose ticagrelor with standard dose 
clopidogrel exclusively in stable patients with diabetes undergoing PCI. Their use in this study is 
investigational. 
 
How many people are expected to take part in this research study? 
 
The study will include about 50 randomized subjects. Half of the subjects (25) will receive 
clopidogrel and the other half (25) will receive ticagrelor. 
 
How long will you be in this research study? 
 
You will be participating in the study for up to 33 days. 
 


 
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What will be done as part of your normal clinical care (even if you did not participate in 
this research study)? 
 
You will undergo a diagnostic coronary angiography and receive a PCI if necessary.  If you 
undergo PCI, you will receive a blood thinner (commonly clopidogrel or ticagrelor) in addition 
to aspirin. You will also receive an initial dose of aspirin (loading dose) that will be higher than 
the maintenance dose, if this has not been done, or if you are not already on aspirin every day, 
followed by a daily maintenance dose of aspirin 81mg. The loading dose of aspirin administered 
is 325 mg. 
 
What will be done only because you are in this research study? 
 
Once you have signed this consent form, you will be assigned a unique number to help protect 
your identity and personal health information.  By participating in this study, you are agreeing to 
allow the study sponsor, its representatives, and the study manager to collect information about 
your health and treatment.  Information about you will be reported directly from your study 
doctor to the research study personnel. 
 
If you agree to participate in this study, your medical records will be reviewed and your 
information will be recorded onto case report forms for scientific, medical, and other research 
purposes.  Depending on your study doctor’s/institution’s requirements, copies of the study 
forms may be included in your medical record.  Your study doctor will use this information 
about you to complete this research. 
 
Study Visits 
 
The first visit with your study doctor, also known as the Screening Visit, will start with your 
study doctor and/or the study staff explaining the study to you.  During this visit, you will 
receive a copy of this Research Subject Information Consent-Authorization Form, and you will 
be allowed to ask your study doctor any questions that you might have.  You are welcome to take 
this form home to think about whether or not you want to participate.  If you decide to participate 
in this study, you will need to sign this form at your study doctor’s office.  Your study doctor or 
an authorized study representative will sign this form as well.  You will receive a signed copy of 
this form. 
 
Once you have signed this form, your study doctor will perform a physical exam as well as check 
things like your heart rate, respiration rate, blood pressure, and body temperature.  Your study 
doctor will also take a blood sample from you (about one half tablespoon of blood) to test for 
routine blood levels.  If you are a woman, you may need to take a pregnancy blood test.  Your 
study doctor may ask you some questions about your health during your exam, including asking 
you about your health history and any medications you are taking. 
 
If you meet the requirements to be in the study, you will need to see your study doctor again to 
begin your treatment.  This is known as the Randomization/First Dose visit and will occur at 
the time of coronary angiography. You will be randomly assigned to take either ticagrelor or 
clopidogrel, along with aspirin. If you are randomized to receive clopidogrel, you will receive a 
600 mg loading dose followed by 75 mg daily dose and your daily 81 mg aspirin.  If you are 
randomized to receive ticagrelor, you will receive a 180 mg loading dose followed by a 60 mg 
twice a day dose and your 81 mg aspirin. You will take the first dose of study drug in the 


 
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WIRB 
 
 
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catheterization laboratory after the diagnostic angiography procedure is performed. After the 
diagnostic angiography procedure is over and it has been determined that a PCI is necessary as 
your standard of care, you will take either 180 mg of ticagrelor or 600 mg clopidogrel.  If you are 
assigned to ticagrelor, you will start taking 60 mg of ticagrelor twice daily starting 12 hours after 
the first dose.  If you are assigned to clopidogrel, you will start taking 75 mg of clopidogrel once 
daily starting 24 hours after the first dose. 
 
You will be taking the assigned study medication for up to 33 days. You will need to provide 
blood samples on the first two days.  This may happen more than once per day, depending on the 
study visit day.  You will have blood samples taken up to 8 hours after the first dose 
administration. You will be asked to come to our clinical site after 30±3 days from your PCI in 
the morning, before your morning dose of clopidogrel or ticagrelor, to re-assess how sticky your 
platelets are. After this blood draw, the study will be over and you will resume your standard of 
care therapy as instructed by your treating physician. 
 
During your study participation, blood samples will be taken from you at different times: 
 
 Before angiography (screening): 
o A total of 15 mL of blood (about 1 tablespoon) may be collected at the screening 
visit 
 
 After angiography/randomization: 
o 30 ml of blood ( about 2 tablespoons) will be drawn from you before you take 
your study drug for the day to measure your platelet response to the study drug 
o 30 ml of blood (about 2 tablespoons) will be drawn from you 0.5 hours after you 
take the study drug  to measure your platelet response to the study drug 
o 30 ml of blood (about 2 tablespoons) will be drawn from you at the end of the PCI 
procedure to measure your platelet response to the study drug 
o 30 ml of blood (about 2 tablespoons) will be drawn from you 2 hours after the 
PCI procedure to measure your platelet response to the study drug 
o 30 ml of blood (about 2 tablespoons) will be drawn from you 8 hours after the 
PCI procedure  to measure your platelet response to the study drug 
o 30 ml of blood (about 2 tablespoons) will be drawn from you 24 hours after the 
PCI procedure  to measure your platelet response to the study drug before taking 
your dose of medication 
o 30 ml of blood (about 2 tablespoons) will be drawn from you 24 hours after the 
PCI procedure  to measure your platelet response to the study drug 2 hours after 
taking your dose of medication 
o 30 ml of blood (about 2 tablespoons) will be drawn from you at 30 days after the 
PCI procedure to measure your platelet response to the study drug before taking 
your morning dose of medication 
o 30 of blood (about 2 tablespoons) will be drawn from you at 30 days after the PCI 
procedure  to measure your platelet response to the study drug 2 hours after taking 
your dose of medication 
 


 
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You must also be willing to do the following: 
 
 Attend the scheduled visits 
 Take the study drug(s) as directed, and 
 Tell the study staff about any other medicines that you are taking. 
 
What are the possible discomforts and risks? 
 
Either study drug may cause some side effects.  You may experience none, some or all of those 
listed below. 
 
The risks and discomforts associated with the collection of a blood sample from a vein include 
faintness, inflammation of the vein, pain, bruising, or bleeding at the site where the needle enters 
the vein.  There is also a slight possibility of infection. 
 
Percentage of subjects reporting adverse events not associated with bleeding at least 3% or more 
in each group 
 
 
Ticagrelor (9235 patients) Clopidogrel (9186 patients) 
 Dyspnea (shortness of breath) 
13.8 
7.8 
 Headache 
6.5 
5.8 
 Cough 
4.9 
4.6 
 Atrial fibrillation 
4.2 
4.6 
 Mild to moderate diarrhea 
3.7 
3.3 
 Nausea 
4.3 
3.8 
 Hypotension (low blood pressure) 
3.2 
3.3 
 Hypertension 
3.8 
4.0 
 Dizziness 
4.5 
3.9 
 Non-cardiac chest pain 
3.7 
3.3 
 Back Pain 
3.6 
3.3 
 Fatigue 
3.2 
3.2 
 Cardiac (heart) chest pain 
3.1 
3.5 
 
General Risk of Bleeding 
 
 Medications that restrict platelet function including aspirin, ticagrelor and clopidogrel 
increase the risk of bleeding.  Ticagrelor increased the overall risk of bleeding slightly 
more than clopidogrel. 
 
The study drug used in this study may involve other risks that are not known at this time, 
including possible life-threatening reactions. 
 
The most important non-medical risk involved in a research study such as this is loss of 
confidentiality; however, the study will strive to conform to all applicable privacy and 
confidentiality laws. 
 


 
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New Information 
 
Your study doctor may receive new information about the study drug.  If the study doctor 
believes it may affect your decision to take part in the study, you will be told.  If this changes 
your decision to take part in the study, please talk with your study doctor about your decision. 
 
Women Of Child-Bearing Potential 
 
There might be unknown risks to the unborn baby if you are or if you become pregnant during 
the study.  Due to these risks, you must not take part in this study if you are pregnant, plan to 
become pregnant during the research study period, or are breast-feeding a baby.  Women must be 
post-menopausal or surgically sterile or have a negative serum pregnancy test and use reliable 
birth-control strategies during the study. 
 
If you are a woman: 
 
 By signing this consent form, you confirm to the best of your knowledge that you are not 
pregnant now and you do not intend to become pregnant during this study. 
 
 A serum pregnancy test will be done to check for pregnancy before you take part in this 
study. 
 
 If at any time during this study you think you might be pregnant, or later learn that you 
were pregnant during the study, you must contact the study doctor immediately for 
further instructions about your participation in this study and follow-up. 
 
What are the possible benefits to you? 
 
It is possible that either one of these treatments will help you; however, this cannot be 
guaranteed. The intent of this study is to better understand how ticagrelor and clopidogrel work 
in people with diabetes who are undergoing PCI immediately after having an angiogram. 
 
How could others possibly benefit from this research study? 
 
The information we get from this study may help us to better understand how patients with 
diabetes respond to these drugs after a PCI. 
 
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. 
 
What other choices do you have if you do not want to be in this research study? 
 
You do not have to take part in this study to be treated for your heart disease.  There are other 
approved treatments available for this condition.  You might be able to get the Ticagrelor or 
Clopidogrel without being in the study.  Your family doctor or the study doctor can explain the 
other treatments that are available. 
 


 
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What if you are injured because of the research study? 
 
If you are injured as a direct result of your participation in this study, the sponsor will pay for all 
reasonable and necessary medical expenses required to treat your injury, so long as: 
 
1. The injury occurs during your participation in the study. 
2. The injury results directly from the study drug or study-required procedures [that you 
would not have received as part of your routine medical care] 
 
The sponsor and the Principal Investigator will determine whether your injury is related to your 
participation in this study. 
 
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 Angiolillo, MD, PhD at 904-244-0411 if you 
experience an injury or have questions about any discomforts that you experience while 
participating in this study. 
 
Will you be paid for taking part in this research study? 
 
You will be paid a total of $50 in a Visa debit card for your complete participation in the study. 
 
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. 
 
If you choose to take part in this study, will it cost you anything? 
 
The study drug will be provided at no cost to you while you are participating in this study. 
 


 
APPROVED 
 
Feb 15, 2018 
 
WIRB 
 
 
9(13) 
The Sponsor will pay for the medical services that you receive as part of your participation in 
this study which are described in the section of the consent form headed by the question “What 
Will Be Done Only Because You Are In This Research Study”. This may include some medical 
services that you would have received if you were not in this study.  All other medical services 
will be billed to you or your insurance company.  You will be responsible for paying any 
deductible, co-insurance, or co-payments for those services, and for any non-covered or out-of-
network services. Some insurance companies may not cover costs associated with research 
studies.  Please contact your insurance company for additional information. 
 
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, MD, PhD at 
904-244-3933 or 904-244-0411 (24 hours).  He will tell you how to stop your participation 
safely. 
 
How is my Health Information Collected, Used, and Disclosed (Shared)? 
 
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR RESEARCH 
PURPOSES 
 
If you agree to participate in this study, the study doctor will create, collect, and use private 
information about you and your health. This information is called protected health information or 
PHI.  In order to do this, the study doctor needs your authorization.  The following section 
describes what PHI will be collected, used and shared, how it will be collected, used, and shared, 
who will collect, use or share it, who will have access to it, how it will be secured, and what your 
rights are to revoke this authorization. 
 
Your protected health information may be collected, used, and shared with others to determine if 
you can participate in the study, and then as part of your participation in the study.  This 
information can be gathered from you or your past, current or future health records, from 
procedures such as physical examinations, x-rays, blood or urine tests or from other procedures 
or tests.  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 


 
APPROVED 
 
Feb 15, 2018 
 
WIRB 
 
 
10(13) 
number, social security number, or any other photographs, numbers, codes, or so forth that link 
you to the information in the limited data set.  If limited data sets are created and used, 
agreements between the parties creating and receiving the limited data set are required in order to 
protect your identity and confidentiality and privacy. 
 
Your PHI may be collected, used, and shared with others to make sure you can participate in the 
research, throughout your participation in the research, and to evaluate the results of the research 
study.  More specifically, your PHI may be collected, used, and shared with others for the 
following study-related purpose(s): 
 
 to determine the effectiveness of the study drug in treating Coronary Artery Disease 
 to evaluate a possible new use for the study drug 
 to determine the causes or effects of the study condition Coronary Artery Disease 
 
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 
 
Your PHI may be shared with: 
 
 the study sponsor Dominick J. Angiolillo, MD, PhD and AstraZeneca LP 
 United States and foreign governmental agencies who are responsible for overseeing 
research, such as the Food and Drug Administration, the Department of Health and 
Human Services, and the Office of Human Research Protections 
 Government agencies who are responsible for overseeing public health concerns such as 
the Centers for Disease Control and federal, state and local health departments 
 Western Institutional Review Board 
 Your insurance company for purposes of obtaining payment 
 
Otherwise, your research records will not be released without your permission unless required by 
law or a court order. It is possible that once this information is shared with authorized persons, it 
could be shared by the persons or agencies who receive it and it would no longer be protected by 
the federal medical privacy law. 
 
Your PHI will be used and shared with others until 25 years after the study ends. 
 
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. 
 


 
APPROVED 
 
Feb 15, 2018 
 
WIRB 
 
 
11(13) 
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.  If you revoke your authorization, you can no longer 
participate in this research study. 
 
Who would you call if you have any questions? 
 
You have the right to ask questions about this study at any time and are encouraged to do so. 
 
Contact Dominick J. Angiolillo, M.D., Ph.D. at 904-244-3933 or 904-244-0411 (24 hours) for any 
of the following reasons: 
 
 if you have any questions about your participation in this study, 
 if at any time you feel you have had a research-related injury or a reaction to the study drug, 
or 
 if you have questions, concerns or complaints about the research 
 
If you have any questions about your rights as a research subject, or if you have questions, 
concerns or complaints regarding this research study, 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 
 
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. 
 
or 
 
The University of Florida in Jacksonville at (904) 244-9478. 
 
Can you be withdrawn from this research study? 
 
You have the right to withdraw from this study at any time and still receive the same standard of 
care. There are no consequences if you decide to withdraw except you cannot be in the study 
anymore. 
 


 
APPROVED 
 
Feb 15, 2018 
 
WIRB 
 
 
12(13) 
The study doctor or sponsor may choose to end your participation in this study without your 
consent at any time for any of the following reasons: 
 
 You are unable to continue in the study 
 
 You do not follow the instructions of the study doctor 
 
 You experience an injury related to the study 
 
 It is in your best interest 
 
 You do not consent to continue in the study after being told of changes in the research 
that may affect you 
 
 For any other reason. 
 
If you stop taking part in the study completely, it is recommended that you go through study 
withdrawal procedures that the Study Doctor considers necessary for your safety.  No further 
study related contacts or data collection will then occur except as described in this informed 
consent. 
 
If you have an Adverse Event at your final study visit or withdrawal visit then your study doctor 
may wish to contact you and ask you about this, until it has completely resolved.  The sponsoring 
company may also ask the study doctor for this information. 


 
APPROVED 
 
Feb 15, 2018 
 
WIRB 
 
 
13(13) 
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 information and consent form, I have not given up any of the legal rights that I 
otherwise would have as a subject in a research study. 
 
I authorize the collection, use and disclosure of my health information in accordance with this 
form, including transfer to countries outside of the United States. 
 
 
 
 
 
 
Signature of Subject 
Date of Signature 
 
 
 
 
Printed Name of Subject 
 
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: 
 
 
 
 
 
 
Signature of person conducting informed consent discussion 
Date of signature