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Antithrombotic Triple Therapy in Humans

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Michael Wolzt, Prof. MD, Medical University of Vienna
ClinicalTrials.gov Identifier:
NCT01812200
First received: March 9, 2013
Last updated: March 5, 2014
Last verified: March 2014

March 9, 2013
March 5, 2014
October 2012
May 2013   (final data collection date for primary outcome measure)
Changes of β-TG, F1+2 and TAT in shed blood [ Time Frame: Changes from baseline at 3 hours and 5 days after intervention ] [ Designated as safety issue: No ]
Changes from baseline β-TG, F1+2 and TAT concentrations in shed blood at 3 hours and 5 days (steady state condition) after study drug administration(s) will be assessed
Same as current
Complete list of historical versions of study NCT01812200 on ClinicalTrials.gov Archive Site
Changes of D-Dimer, TxB2, CD40L and p-Selectin in shed blood; β-TG, F1+2, TAT, D-Dimer, TxB2, CD40L, p-Selectin, ETP, aPTT, PT, inhibition of factor Xa, Biophen®, Hemoclot® in venous blood [ Time Frame: Changes from baseline at 3 hours and 5 days after intervention (shed blood parameters); changes from baseline at 1, 2, 3 hours and 5 days after intervention (venous blood parameters) ] [ Designated as safety issue: No ]
Changes from baseline secondary outcome parameters at (1 hour, 2 hours - if applicable), 3 hours and 5 days (steady state condition) after study drug administration(s) will be assessed
Same as current
Not Provided
Not Provided
 
Antithrombotic Triple Therapy in Humans
A Prospective, Randomized, Controlled, Analyst-blinded, Parallel Group Study to Investigate the Effect of Antithrombotic Triple Therapy With Ticagrelor and Acetylsalicylic Acid in Combination With Dabigatran or Rivaroxaban or Phenprocoumon on Markers of Coagulation Activation in Venous and Shed Blood in Healthy Male Subjects

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 rivaroxaban and the direct thrombin inhibitor dabigatran have 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.

Study objectives: To evaluate the effect of ticagrelor + ASA in combination with dabigatran, rivaroxaban or phenprocoumon at steady state on markers of coagulation activation. The effects on coagulation activation will also be studied after a single dose of dabigatran, rivaroxaban or ticagrelor and at a therapeutic INR of phenprocoumon.

Study design: A single-centre, prospective, randomized, controlled, analyst-blinded study in three parallel-groups. Subjects will receive ticagrelor + ASA in combination with dabigatran (treatment A), rivaroxaban (treatment B) or phenprocoumon (treatment C). All IMPs will be administered at doses indicated for stroke prevention in AF 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), D-Dimer, thromboxane B2 (TxB2), CD40 ligand (CD40L), p-Selectin. Further, the endogenous thrombin potential (ETP), inhibition of factor Xa activity, activated partial thromboplastin time (aPTT), prothrombin time (PT), Biophen® and Hemoclot® will be assessed in venous blood.

Study population: A total of 60 healthy, non-smoking and drug-free male volunteers will be enrolled in this trial and randomized into one of three balanced groups (treatment A, B and C; n = 20 per group).

Main outcome variables: β-TG, F1+2 and TAT in shed blood

Additional outcome variables:

  • D-Dimer, TxB2, CD40L and p-Selectin in shed blood
  • β-TG, F1+2, TAT, D-Dimer, TxB2, CD40L, p-Selectin, ETP, aPTT, PT, inhibition of factor Xa, Biophen® and Hemoclot® in venous blood

Risk/ benefit assessment:Total blood loss will be, dependent on treatment allocation, between 330 ml and 510 ml throughout the entire study period of 4 - 5 weeks. This amount of venous blood is considered to be acceptable in this healthy population. Blood sampling procedures may cause mild and transient pain. A minor haematoma may occur at the site of needle insertions. Bleeding time incisions may leave small persistent scars. Administration of the study drugs, in particular as triple combination for 5 days, results in transient hypocoagulability and may cause overt or occult bleeding. The risk is considered low in the healthy subjects under study. Continuous monitoring of safety parameters (haemoglobin, haematocrit, platelet count, coagulation) and surveillance of the overall status will be performed during study participation. Subjects will be instructed to avoid vigorous physical exercise and handling of hazardous machinery during study participation. ASA, dabigatran and rivaroxaban can cause gastrointestinal discomfort. Other side effects are rare.

The combination of these novel anticoagulants (dabigatran, rivaroxaban, ticagrelor) has not been investigated so far. Conducting this study in a healthy population limits potential bleeding risk reported from drug interactions and impaired liver or renal function, which may influence the pharmacokinetics and -dynamics of the investigational products.

This study can provide information on haemostatic system activation in vivo during triple treatment with antithrombotic drugs, which is indicated for patients with AF and ACS. The results of this study may provide dosing guidance for risk reduction of patients with ACS and AF.

Not Provided
Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
  • Atrial Fibrillation
  • Acute Coronary Syndrome
  • Drug: Dabigatran, Ticagrelor, ASA
  • Drug: Rivaroxaban, Ticagrelor, ASA
  • Drug: Phenprocoumon, Ticagrelor, ASA
  • Active Comparator: Dabigatran, Ticagrelor, ASA
    Dabigatran 150mg td Ticagrelor 90 mg td ASA 100 mg od for 5 days
    Intervention: Drug: Dabigatran, Ticagrelor, ASA
  • Active Comparator: Rivaroxaban, Ticagrelor, ASA
    Rivaroxaban 20 mg od Ticagrelor 90 mg td ASA 100 mg od for 5 days
    Intervention: Drug: Rivaroxaban, Ticagrelor, ASA
  • Active Comparator: Phenprocoumon, Ticagrelor, ASA
    Phenprocoumon X mg to reach an INR of 2-3 on day 5 of triple therapy Ticagrelor 90 mg td ASA 100 mg od for 5 days
    Intervention: Drug: Phenprocoumon, Ticagrelor, ASA
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
60
July 2013
May 2013   (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 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
  • Impaired liver function (AST, ALT, GGT >3 x ULN, 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 below 100 mmHg or 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
Contact information is only displayed when the study is recruiting subjects
Austria
 
NCT01812200
ATTT-1.0
Yes
Michael Wolzt, Prof. MD, Medical University of Vienna
Medical University of Vienna
Not Provided
Principal Investigator: Michael Wolzt, Prof. MD Department of Clinical Pharmacology, Medical University of Vienna
Medical University of Vienna
March 2014

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