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

March 5, 2014
August 4, 2014
May 2014
October 2014   (final data collection date for primary outcome measure)
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.
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)" - "pre-dose at steady state (trough)" during triple therapy vs. dual therapy.
Complete list of historical versions of study NCT02080858 on ClinicalTrials.gov Archive Site
  • 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.
  • 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)" - "pre-dose at steady state (trough)" 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)" - "pre-dose at steady state (trough)" 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)" - "pre-dose at steady state (trough)" 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)" - "pre-dose at steady state (trough)" during triple therapy vs. dual therapy.
Not Provided
Not Provided
 
Triple vs. Dual Therapy
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

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
Not Provided
Interventional
Phase 1
Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Atrial Fibrillation
  • Acute Coronary Syndrome
  • Drug: Ticagrelor + Apixaban + ASA
  • Drug: Ticagrelor + Apixaban
  • 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
    Intervention: 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
    Intervention: Drug: Ticagrelor + Apixaban
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
40
December 2014
October 2014   (final data collection date for primary outcome measure)

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
Male
18 Years to 40 Years
Yes
Austria
 
NCT02080858
TVDAT-1.0
Yes
Michael Wolzt, Prof. MD, Medical University of Vienna
Medical University of Vienna
Not Provided
Not Provided
Medical University of Vienna
August 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP