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Triple vs. Dual Therapy

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Medical University of Vienna
Sponsor:
Information provided by (Responsible Party):
Michael Wolzt, Prof. MD, Medical University of Vienna
ClinicalTrials.gov Identifier:
NCT02080858
First received: March 5, 2014
Last updated: August 4, 2014
Last verified: August 2014
  Purpose

Background:

The acute coronary syndrome (ACS) is a complication of coronary artery disease (CAD) and associated with increased mortality. Dual antiplatelet therapy of acetylsalicylic acid (ASA) with P2Y12 receptor antagonists such as clopidogrel is a cornerstone in the treatment of patients with advanced CAD. Due to delayed onset of action, intersubject variability or resistance to clopidogrel, different platelet aggregation inhibitors have been developed. Ticagrelor is a reversible P2Y12 receptor antagonist with superior efficacy compared to clopidogrel in the prevention of cardiovascular death in these patients.

Atrial fibrillation (AF) is also associated with thromboembolic events and substantial mortality. Beside vitamin K antagonists (VKA, phenprocoumon) for stroke prevention in patients with AF, the direct factor Xa inhibitor apixaban has recently received approval for prophylactic treatment of patients with non-valvular AF.

However, there is a lack of efficacy or safety data for the combined impact of antithrombotic drugs in patients requiring arterial and venous thromboembolic prophylaxis due to their underlying co-morbidities. One trial suggests treatment with VKA + clopidogrel without ASA as equal effective as antithrombotic triple therapy (with ASA) in this population. However, the effect in combination with novel oral anticoagulants has not been investigated so far.

Study objectives:

To evaluate the effect of ticagrelor + apixaban in combination with or without ASA at steady state on markers of coagulation activation and on thrombus size in an ex vivo perfusion chamber experiment. Additionally, plasma samples will be analysed for PK-data (ticagrelor & apixaban concentrations)

Study design:

A single-centre, prospective, sequential, controlled, analyst-blinded study in two groups. Subjects will receive ticagrelor + apixaban in combination with (study A) or without (study B) ASA. All IMPs will be administered at doses indicated for stroke prevention in AF (lower dose: 2.5mg due to ethical concerns) or ACS. Markers on thrombin generation and platelet activation will be studied in venous blood where coagulation is in resting state and in shed blood where the clotting system is activated in the microvasculature in vivo: prothrombin fragment 1+2 (F1+2), thrombin-anti-thrombin (TAT), β-thromboglobulin (β-TG). Additionally, inhibition of factor Xa activity and concentrations of ticagrelor and apixaban will be assessed in venous blood. Further, thrombus size of clots formed in an ex vivo perfusion chamber will be determined by measurement of D-Dimer and p-Selectin levels.

Study population A total of 40 healthy, non-smoking and drug-free male volunteers will be enrolled (study A and B; n = 20 per group).

Main outcome variables:

  • β-TG in shed blood

Additional outcome variables:

  • F1+2 and TAT in shed blood
  • fibrin formation (D-Dimer) and platelet deposition (p-Selectin) in an ex vivo perfusion chamber model of thrombosis
  • β-TG, F1+2, TAT & inhibition of factor Xa in venous blood
  • PT, aPTT and ACT in venous blood
  • ticagrelor & apixaban plasma concentrations
  • shed blood volume

Condition Intervention Phase
Atrial Fibrillation
Acute Coronary Syndrome
Drug: Ticagrelor + Apixaban + ASA
Drug: Ticagrelor + Apixaban
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: The Effect of Ticagrelor and Apixaban With or Without Acetylsalicylic Acid on Markers of Coagulation Activation at the Site of Thrombus Formation in Vivo in Healthy Male Subjects and in an ex Vivo Perfusion Chamber Model at High and Low Shear Rate

Resource links provided by NLM:


Further study details as provided by Medical University of Vienna:

Primary Outcome Measures:
  • β-thromboglobulin (β-TG) [ Time Frame: Changes in shed blood from baseline, at 3 hours, at trough and peak steady state conditions ] [ Designated as safety issue: No ]
    Of primary interest is the difference in shed blood β-TG "3h post-dose at steady state (peak)" or "pre-dose at steady state (trough)" and Baseline during triple therapy vs. dual therapy.


Secondary Outcome Measures:
  • Prothrombin fragment F1+2 (F1+2) [ Time Frame: Changes in shed blood from baseline, at 3 hours, at trough and peak steady state conditions ] [ Designated as safety issue: No ]
    Of primary interest is the difference in shed blood F1+2 "3h post-dose at steady state (peak)" or "pre-dose at steady state (trough)" and Baseline during triple therapy vs. dual therapy.

  • Thrombin-Anti-Thrombin (TAT) [ Time Frame: Changes in shed blood from baseline, at 3 hours, at trough and peak steady state conditions ] [ Designated as safety issue: No ]
    Of primary interest is the difference of TAT in shed blood "3h post-dose at steady state (peak)" or "pre-dose at steady state (trough)" and Baseline during triple therapy vs. dual therapy.

  • D-dimer [ Time Frame: Changes from baseline, at 3 hours, at trough and peak steady state conditions ] [ Designated as safety issue: No ]
    Changes on fibrin formation in an ex vivo perfusion chamber model of thrombosis at high and low shear rate. Of primary interest is the difference in D-Dimer "3h post-dose at steady state (peak)" or "pre-dose at steady state (trough)" and Baseline during triple therapy vs. dual therapy.

  • P-selectin [ Time Frame: Changes from baseline, at 3 hours, at trough and peak steady state conditions ] [ Designated as safety issue: No ]
    Changes on platelet deposition in an ex vivo perfusion chamber model of thrombosis at high and low shear rate. Of primary interest is the difference in D-Dimer "3h post-dose at steady state (peak)" or "pre-dose at steady state (trough)" and Baseline during triple therapy vs. dual therapy.


Estimated Enrollment: 40
Study Start Date: May 2014
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ticagrelor + Apixaban + ASA
180 mg Ticagrelor loading dose + apixaban 2.5 mg bid + 300 mg ASA loading dose (day 1) followed by ticagrelor 90 mg bid + apixaban 2.5 mg + 100 mg ASA od to reach steady state conditions within 4.5 days
Drug: Ticagrelor + Apixaban + ASA
Active Comparator: Ticagrelor + Apixaban
180mg ticagrelor loading dose + apixaban 2.5 mg bid (day 1) followed by ticagrelor 90 mg bid + apixaban 2.5 mg to reach steady state conditions within 4.5 days
Drug: Ticagrelor + Apixaban

  Eligibility

Ages Eligible for Study:   18 Years to 40 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

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 behaviour

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. peridontitis, haemorrhoids, acute gastritis, peptic ulcer, intestinal ulcer)
  • Known sensitivity to common causes of bleeding (e.g. nasal)
  • History of thromboembolism
  • Anaemia (defined as haemoglobin levels < LLN)
  • Impaired liver function (AST, ALT, GGT >2 x ULN, Bilirubin >1.5 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 test agents
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02080858

Locations
Austria
Medical University of Vienna, Department of Clinical Pharmacology Recruiting
Vienna, Austria, 1090
Contact: Michael Wolzt, Prof. MD    +43 1 40400 ext 29810    michael.wolzt@meduniwien.ac.at   
Principal Investigator: Michael Wolzt, Prof. MD         
Sub-Investigator: Stefan Weisshaar, MD         
Sponsors and Collaborators
Medical University of Vienna
  More Information

No publications provided

Responsible Party: Michael Wolzt, Prof. MD, Prof. MD, Medical University of Vienna
ClinicalTrials.gov Identifier: NCT02080858     History of Changes
Other Study ID Numbers: TVDAT-1.0
Study First Received: March 5, 2014
Last Updated: August 4, 2014
Health Authority: Austria: Agency for Health and Food Safety

Keywords provided by Medical University of Vienna:
Apixaban
Ticagrelor
ASA
shed blood
perfusion chamber

Additional relevant MeSH terms:
Acute Coronary Syndrome
Atrial Fibrillation
Angina Pectoris
Arrhythmias, Cardiac
Cardiovascular Diseases
Chest Pain
Heart Diseases
Myocardial Ischemia
Pain
Pathologic Processes
Signs and Symptoms
Vascular Diseases
Ticagrelor
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Purinergic Agents
Purinergic Antagonists
Purinergic P2 Receptor Antagonists
Purinergic P2Y Receptor Antagonists

ClinicalTrials.gov processed this record on November 24, 2014