Comparison of TIcagrelor and Clopidogrel in Patients With Coronary Artery diseaSe and Type 2 Diabetes Mellitus (TICS-DM)

Study Overview
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Brief Summary
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Patients with type 2 diabetes mellitus (T2DM), have a high prevalence of suboptimal response to clopidogrel (up to 40%). This impaired response to antiplatelet drugs has been consistently associated with a higher risk of adverse ischemic outcomes. Different strategies have been suggested to overcome variability in response to clopidogrel and improve clinical outcomes in diabetic patients. One of these strategies is the use of newer P2Y12 inhibitors, such as ticagrelor, with more potent and consistent platelet inhibitory effects compared to clopidogrel. In summary, since patients with T2DM continue to have enhanced platelet reactivity despite the administration of commonly used dual antiplatelet therapy with aspirin and standard doses of clopidogrel, newer and more potent antiplatelet treatment strategies are warranted in this high-risk population. The purpose of the present study is to compare platelet inhibitory effects achieved with ticagrelor versus clopidogrel, both on top of aspirin therapy, in patients with type 2 DM and stable coronary artery disease.

Detailed Description
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Despite the clinical benefit associated with dual therapy consisting in aspirin and clopidogrel, there are still a considerable number of patients who continue to have atherothrombotic events. Several studies have shown a wide interindividual variability in response to clopidogrel treatment and patients with poor response have an increased risk of recurrent ischemic events. In particular, patients with type 2 diabetes mellitus (T2DM), have a high prevalence of suboptimal response to clopidogrel (up to 40%). This impaired response to antiplatelet drugs has been consistently associated with a higher risk of adverse ischemic outcomes. Different strategies have been suggested to overcome variability in response to clopidogrel and improve clinical outcomes in diabetic patients. One of these strategies is the use of newer P2Y12 inhibitors, such as ticagrelor, with more potent and consistent platelet inhibitory effects compared to clopidogrel. In summary, since patients with T2DM continue to have enhanced platelet reactivity despite the administration of commonly used dual antiplatelet therapy with aspirin and standard doses of clopidogrel, newer and more potent antiplatelet treatment strategies are warranted in this high-risk population. The purpose of the present study is to compare platelet inhibitory effects achieved with ticagrelor versus clopidogrel, both on top of aspirin therapy, in patients with type 2 DM and stable coronary artery disease (CAD). This is a multi-center prospective, open-label, two-sequence, two-period, randomized crossover study conducted in T2DM patients between the ages of 18 and 75 years with known CAD. Subjects will be randomized in a 1:1 fashion to take ticagrelor (180-mg loading dose the first day followed by 90-mg maintenance dose) or clopidogrel (600-mg loading dose the first day followed by 75-mg daily maintenance dose) for one-week on a background of aspirin therapy (100 mg daily). After a 2-4 week washout period, subjects will cross-over treatment regimen. The washout periods are included to minimize carryover effects between treatment regimens. Patient compliance will be assessed by interview and pill counting. Platelet function testing will be performed at the following time-points (repeated in the two periods of treatment): baseline, 2 and 24 hours after taking loading dose of the assigned drug, and 1 week after initiating the assigned drug. All statistical comparisons of platelet function for the primary and secondary endpoints will be conducted using linear mixed-effect models with treatment, sequence, period and treatment*period (treatment by period interaction in order to test for carryover effects) as fixed effects, subject as a random effect and baseline value of the corresponding platelet function test as a covariate. A two-tailed p value of less than 0.05 will be considered to indicate a statistically significant difference for all the analyses performed.

Official Title
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Comparison of TIcagrelor and Clopidogrel in Patients With Coronary Artery diseaSe and Type 2 Diabetes Mellitus (TICS-DM): a Randomized Pharmacodynamic Study

Conditions
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Coronary Artery Disease, Diabetes Mellitus. Type 2

Intervention / Treatment
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* Drug: Ticagrelor
* Drug: Clopidogrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent prior to any study specific procedures Age between 18 and 75 years Type 2 DM according to ADA criteria Angiographically documented CAD Chronic treatment (>1 month) with aspirin (100mg/day) Exclusion Criteria: Known allergies to aspirin, clopidogrel, or ticagrelor Blood dyscrasia Any recent acute coronary syndrome (<30 days) or hemodinamic instability Recent antiplatelet therapy (<14 days), with the exception of ASA, including: thienopyridines, cilostazol, dipiridamol, glycoprotein IIb/IIIa inhibitors Oral anticoagulation with a coumarin derivative Concomitant treatment with a potent CYP3A4 inhibitor (e.g. ketoconazole, claritromicine, nefazodone, ritonavir, atazanavir) Any active bleeding Recent history of stroke, TIA or intracranial bleeding (<6 months prior to inclusion) Platelet count <100x106/microl Severe chronic kidney disease (creatinine clearance measured with Cockcroft-Gault formula <30ml/min) Any active neoplasm Baseline ALT >2.5 times the upper limit of normality Pregnant or childbearing females

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>After providing written informed consent, eligible subjects will be randomized in a 1:1 fashion to group A or B. Ticagrelor (180-mg loading dose the first day followed by 90-mg b.i.d. maintenance dose) for one week; washout period of 2-4 weeks; crossover to clopidogrel (600-mg loading dose the first day followed by 75-mg daily maintenance dose) for one-week. | Drug: Ticagrelor<br> <br> * Other names: Brilinta;Drug: Clopidogrel<br> <br> * Other names: Plavix;|
| Experimental: Group B<br>After providing written informed consent, eligible subjects will be randomized in a 1:1 fashion to group A or B. Clopidogrel (600-mg loading dose the first day followed by 75-mg daily maintenance dose) for one-week; washout period of 2-4 weeks; crossover to ticagrelor (180-mg loading dose the first day followed by 90-mg b.i.d. maintenance dose) for one week. | Drug: Ticagrelor<br> <br> * Other names: Brilinta;Drug: Clopidogrel<br> <br> * Other names: Plavix;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Platelet reactivity | maximal platelet aggregation, measured with light transmittance aggregometry (using 20 μM ADP as agonist), achieved after 1 week of treatment with ticagrelor or clopidogrel | 7 days |