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

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.

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.

Study Overview

• Status: Completed
• Conditions: Ischemia
• Intervention / Treatment: Drug: Ticagrelor; Drug: Clopidogrel

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medical University of Vienna, Department of Clinical Pharmacology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ticagrelor; Loading dose of 180 mg on day one, followed by a regular intake (90 mg twice daily) for 14 days	Drug: Ticagrelor; 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).; Other Names: Brilique
Active Comparator: Clopidogrel; Loading dose of 600 mg on day one, followed by a regular intake (75 mg once daily) for 14 days	Drug: Clopidogrel; 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; Other Names: Plavix

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Michael Wolzt, Prof. MD

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: October 15, 2015
• First Submitted That Met QC Criteria: October 17, 2015
• First Posted (Estimate): October 20, 2015

Study Record Updates

• Last Update Posted (Estimate): September 20, 2016
• Last Update Submitted That Met QC Criteria: September 19, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Ischemia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Ticagrelor; Clopidogrel
• Other Study ID Numbers: FBF-Tica-Clopi