The Effect of Ticagrelor or Clopidogrel on Endothelial Function During Acute and Chronic Treatment

Study Overview
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Brief Summary
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To investigate if treatment with ticagrelor can mitigate the transient loss of endothelium-dependent vasodilatation of the resistance vasculature following a short period of ischemia, compared with clopidogrel at standard clinical doses. The effect of ticagrelor or clopidogrel will be studied after a loading dose and after a two weeks period of regular intake on FBF in response to the vasodilators acetylcholine or nitroglycerin before and 10 min after a 20 min forearm ischemia, respectively.

Detailed Description
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Ischemia-reperfusion (IR) causes tissue injury. Preclinical animal data suggest that ticagrelor but not clopidogrel protects against IR injury due to inhibition of cellular adenosine uptake and NO-synthase stimulation. It is unclear if this action is part of the beneficial clinical effect of ticagrelor in patients with a history of acute coronary syndrome. The preventive action of ticagrelor on IR injury may also be of interest for the peripheral vasculature, where IR injury is known to result in endothelial dysfunction. This study aims to investigate if treatment with ticagrelor can mitigate the transient loss of endothelium-dependent vasodilatation of the resistance vasculature following a short period of ischemia, compared with clopidogrel at standard clinical doses. We will study the effect of ticagrelor or clopidogrel after a loading dose and after a two weeks period of regular intake on forearm blood flow (FBF) reactivity in response to the vasodilators acetylcholine (ACh; endothelium-dependent agonist) or nitroglycerin (GTN; endothelium-independent vasodilator) before and 10 min after a 20 min forearm ischemia, respectively

Official Title
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The Effect of an Acute Dose of Ticagrelor or Clopidogrel and of Treatment for 14 Days on Ischemia-reperfusion Induced Endothelial Dysfunction of the Forearm Vasculature in Healthy Male Subjects.

Conditions
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Ischemia

Intervention / Treatment
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* Drug: Ticagrelor
* Drug: Clopidogrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male subjects; 18 - 40 years of age Body mass index between 18 and 27 kg/m2 Written informed consent Normal findings in medical & bleeding history Non-smoking Exclusion Criteria: Regular intake of any medication including OTC drugs and herbals within 2 weeks before IMP administration Known coagulation disorders (e.g. haemophilia, von Willebrand´s disease) Known disorders with increased bleeding risk (e.g. peridontosis, haemorrhoids, acute gastritis, peptic ulcer, intestinal ulcer) Known sensitivity to common causes of bleeding (e.g. nasal) History of thromboembolism History of occlusive vascular diseases History of vascular anomalies Impaired liver function (AST, ALT, gGT, bilirubin >2 x ULN) Impaired renal function (serum creatinine > 1.3 mg/dl) Any other relevant deviation from the normal range in clinical chemistry, haematology or urine analysis HIV-1/2-Ab, HbsAg or HCV-Ab positive serology Systolic blood pressure above 145 mmHg, diastolic blood pressure above 95 mmHg Known allergy against any test agent under study Regular daily consumption of more than on litre of xanthine-containing beverages or more than 40g alcohol Participation in another clinical trial during the preceding 3 weeks

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ticagrelor<br>Loading dose of 180 mg on day one, followed by a regular intake (90 mg twice daily) for 14 days | Drug: Ticagrelor<br>* Subjects will receive an oral loading dose of 180 mg ticagrelor on study day 1 followed by a maintenance dose of 90 mg twice daily for 14 days (until study day 15).<br>* Other names: Brilique;|
| Active Comparator: Clopidogrel<br>Loading dose of 600 mg on day one, followed by a regular intake (75 mg once daily) for 14 days | Drug: Clopidogrel<br>* Subjects will receive a loading dose of 600 mg clopidogrel on the first study day followed by a maintenance dose of 75 mg once daily for 14 days<br>* Other names: Plavix;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC) of Forearm blood flow (FBF) measurements of Acetylcholin (ACh) induced vasodilatation | To test the effect of ticagrelor or clopidogrel on ACh-induced vasodilatation of the forearm resistance vasculature as assessed by FBF measurement before and 10 min after a 20 min forearm ischemia. | Change of the AUC before and 10 min after forearm ischemia | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC) of Forearm blood flow (FBF) measurements of Glyceroltrinitrate (GTN) induced vasodilatation | To test the effect of ticagrelor or clopidogrel on GTN-induced vasodilatation of the forearm resistance vasculature as assessed by FBF measurement before and 10 min after a 20 min forearm ischemia. | Change of AUC before and 10 min after forearm ischemia | 
| (Expected) Peak plasma concentration of ticagrelor or clopidogrel |  | 2.5 h after IMP intake |