Triple vs. Dual Therapy

NCT ID: NCT02080858

Last Updated: 2015-04-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-05-31
• Study Completion Date: 2015-02-28

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 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

Conditions

Atrial Fibrillation; Acute Coronary Syndrome

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

Ticagrelor + Apixaban + ASA

Intervention Type: DRUG

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

Group Type: ACTIVE_COMPARATOR

Ticagrelor + Apixaban

Intervention Type: DRUG

Interventions

Ticagrelor + Apixaban + ASA

Intervention Type: DRUG

Ticagrelor + Apixaban

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

Medical University of Vienna

OTHER

Sponsor Role: lead

Responsible Party

Michael Wolzt, Prof. MD

Prof. MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Medical University of Vienna, Department of Clinical Pharmacology

Vienna, Vienna, Austria

Countries

Austria

Other Identifiers

TVDAT-1.0

Identifier Type: -

Identifier Source: org_study_id