The Effect of Clopidogrel and Ticagrelor With and Without Acetylsalicylic Acid (ASA) on Hemostatic System Activation at the Site of Plug Formation in Vivo in Man

Study Overview
=================
Brief Summary
-----------------
Background: Coronary heart disease is the most common cause of death in industrialized countries. Revascularisation by percutaneous coronary angioplasty or thrombolysis is the main principle for treatment of the acute coronary syndrome. To inhibit platelet activity patients are routinely given acetylsalicylic acid (ASA) and clopidogrel, a second-generation thienopyridine. Recently, ticagrelor, a novel cyclopentyl-triazolo-pyrimidine with several pharmacological advantages, has demonstrated greater efficacy but a higher bleeding risk than clopidogrel. Coronary thrombus formation is a complex process and the antithrombotic mechanisms of platelet function inhibitors are incompletely understood. Studies in venous blood or in vitro do not truly reflect the in vivo circumstances as they often do not take into account flow conditions or the interaction between endothelium, blood cells and coagulation factors. Results from animal models may not be relevant for the prothrombotic mechanisms in humans. We have developed a technique that allows investigating hemostatic system activation directly at the site of thrombus formation in vivo in humans. Aim: to compare the inhibitory effects of clopidogrel and ticagrelor (with and without concomitant ASA) on hemostatic system activation under circumstances close to the in vivo situation. Design, patients and interventions: prospective, randomized, double-blind, placebo controlled parallel-group study with a 2x2 factorial design including 112 healthy volunteers who will be randomised to 4 treatment arms: ticagrelor or clopidogrel + placebo, ticagrelor or clopidogrel + ASA. Outcome variables: Indicators of platelet and coagulation activation [ß-thromboglobulin and thromboxane B2 as well as prothrombin fragment F1+2 and D-Dimer, respectively] will be measured before and at several time points during a 8 day period in venous blood and in blood emerging from a standardized injury of the microvasculature to determine bleeding time (shed blood). Statistical considerations: Sample size calculation is based on the percent change in the main outcome variable β-TG in shed blood from baseline to 2 hours after treatment start. Statistical analysis is based on the full analysis set, including all randomized subjects who received at least the starting dose of the study medication and for whom blood collections at baseline and at 2 hours after treatment start have been performed.

Official Title
-----------------
The Effect of Clopidogrel and Ticagrelor With and Without Acetylsalicylic Acid (ASA) on Hemostatic System Activation at the Site of Plug Formation in Vivo in Man

Conditions
-----------------
Acute Coronary Syndrome

Intervention / Treatment
-----------------
* Drug: Clopidogrel
* Drug: Ticagrelor
* Drug: ASA
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: young, healthy males Exclusion Criteria: history of bleeding any medication known intolerance to study drug(s)

Ages Eligible for Study
-----------------
Minimum Age: 19 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Clopidogrel + ASA<br> | Drug: Clopidogrel<br>* 1x Loading dose 600 mg 6x maintenance dose 150 mg<br>Drug: ASA<br>* 7x 100mg acetylsalicylic acid (clopidogrel arm) 1x 300 mg acetylsalicylic acid (ticagrelor arm)<br>|
| Placebo Comparator: Clopidogrel + Placebo<br> | Drug: Clopidogrel<br>* 1x Loading dose 600 mg 6x maintenance dose 150 mg<br>Drug: Placebo<br>* 7x 300mg acetylsalicylic acid placebo<br>|
| Active Comparator: Ticagrelor + ASA<br> | Drug: Ticagrelor<br>* 1x Loading dose: 180 mg 6x Maintenance dose: 90 mg bid<br>Drug: ASA<br>* 7x 100mg acetylsalicylic acid (clopidogrel arm) 1x 300 mg acetylsalicylic acid (ticagrelor arm)<br>|
| Placebo Comparator: Ticagrelor + Placebo<br> | Drug: Ticagrelor<br>* 1x Loading dose: 180 mg 6x Maintenance dose: 90 mg bid<br>Drug: Placebo<br>* 7x 300mg acetylsalicylic acid placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ß-Thromboglobulin in shed blood 2h after first study drug intake |  | 2 hours after first study drug intake | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ACS, Acute coronary syndrome