Triple vs. Dual Therapy

Overview[ - collapse ][ - ]

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 parallel-groups. Subjects will receive ticagrelor + apixaban in combination with (treatment A) or without (treatment 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 in this trial (treatment 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 - ticagrelor & apixaban plasma concentrations - shed blood volume
ConditionAtrial Fibrillation
Acute Coronary Syndrome
InterventionDrug: Ticagrelor + Apixaban + ASA
Drug: Ticagrelor + Apixaban
PhasePhase 1
SponsorMedical University of Vienna
Responsible PartyMedical University of Vienna
ClinicalTrials.gov IdentifierNCT02080858
First ReceivedMarch 5, 2014
Last UpdatedMarch 5, 2014
Last verifiedMarch 2014

Tracking Information[ + expand ][ + ]

First Received DateMarch 5, 2014
Last Updated DateMarch 5, 2014
Start DateMarch 2014
Estimated Primary Completion DateDecember 2014
Current Primary Outcome Measuresβ-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.
Current 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)" - "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.

Descriptive Information[ + expand ][ + ]

Brief TitleTriple vs. Dual Therapy
Official TitleThe 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
Brief Summary
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
parallel-groups. Subjects will receive ticagrelor + apixaban in combination with (treatment
A) or without (treatment 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 in this trial (treatment 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

- ticagrelor & apixaban plasma concentrations

- shed blood volume
Detailed DescriptionNot Provided
Study TypeInterventional
Study PhasePhase 1
Study DesignAllocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Condition
  • Atrial Fibrillation
  • Acute Coronary Syndrome
InterventionDrug: Ticagrelor + Apixaban + ASA
Drug: Ticagrelor + Apixaban
Study Arm (s)
  • 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
  • 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

Recruitment Information[ + expand ][ + ]

Recruitment StatusRecruiting
Estimated Enrollment40
Estimated Completion DateDecember 2014
Estimated Primary Completion DateOctober 2014
Eligibility 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
GenderMale
Ages18 Years
Accepts Healthy VolunteersAccepts Healthy Volunteers
ContactsNot Provided
Location CountriesAustria

Administrative Information[ + expand ][ + ]

NCT Number NCT02080858
Other Study ID NumbersTVDAT-1.0
Has Data Monitoring CommitteeYes
Information Provided ByMedical University of Vienna
Study SponsorMedical University of Vienna
CollaboratorsNot Provided
Investigators Not Provided
Verification DateMarch 2014

Locations[ + expand ][ + ]

Medical University of Vienna, Department of Clinical Pharmacology
Vienna, Austria, 1090
Contact: Michael Wolzt, Prof. MD | +43 1 404002981 | michael.wolzt@meduniwien.ac.at
Principal Investigator: Michael Wolzt, Prof. MD
Recruiting