Atrial FibrillationPhase 4NCT01812200
Antithrombotic Triple Therapy in Humans
A Phase 4 study testing Dabigatran, Ticagrelor, ASA, Rivaroxaban, Ticagrelor, ASA and Phenprocoumon, Ticagrelor, ASA in people with Atrial Fibrillation and Acute Coronary Syndrome, run by Medical University of Vienna at 1 site in Austria.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 40 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Atrial Fibrillation, Acute Coronary Syndrome
- What is being tested?
- Dabigatran, Ticagrelor, ASA, Rivaroxaban, Ticagrelor, ASA and Phenprocoumon, Ticagrelor, ASA
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 60 participants
- Where
- 1 siteAustria
- Study dates
- Oct 2012to Jul 2013
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Who cannot join
- 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)
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- 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
Trial locations and contacts
1 site in 1 country.
Austria1 site
Medical University of Vienna; Department of Clinical Pharmacology
Vienna, 1090
About this study
Official title: 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.
Read more
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.
- Conditions
- Atrial Fibrillation, Acute Coronary Syndrome
- Being tested
- Dabigatran, Ticagrelor, ASA, Rivaroxaban, Ticagrelor, ASA, Phenprocoumon, Ticagrelor, ASA
- Medical subject headings
- Atrial Fibrillation, Acute Coronary Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Dabigatran, Ticagrelor, ASADrug
Rivaroxaban, Ticagrelor, ASADrug
Phenprocoumon, Ticagrelor, ASADrug
| Study group | Role | What they receive |
|---|---|---|
| Dabigatran, Ticagrelor, ASA | Active comparator | Dabigatran 150mg td Ticagrelor 90 mg td ASA 100 mg od for 5 days Receives: Drug: Dabigatran, Ticagrelor, ASA |
| Rivaroxaban, Ticagrelor, ASA | Active comparator | Rivaroxaban 20 mg od Ticagrelor 90 mg td ASA 100 mg od for 5 days Receives: Drug: Rivaroxaban, Ticagrelor, ASA |
| Phenprocoumon, Ticagrelor, ASA | Active comparator | 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 Receives: Drug: Phenprocoumon, Ticagrelor, ASA |
What is being measured
The primary outcome is the main question the study is designed to answer.
Changes of β-TG, F1+2 and TAT in shed blood
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
Measured: Changes from baseline at 3 hours and 5 days after intervention
Secondary outcomes (1)
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
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
Measured: 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)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Mar 2013 (estimated)
- Study startOct 2012
- Primary completionMay 2013
- Study completionJul 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Atrial FibrillationStudies of the same condition, open and under way.
- More trials run by Medical University of ViennaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 60 participants (actual)
Sponsor and investigators
- Lead sponsor
- Medical University of Vienna
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Michael Wolzt, Prof. MD, Medical University of Vienna
- Investigators
- Michael Wolzt, Prof. MD, Principal investigator, Department of Clinical Pharmacology, Medical University of Vienna
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01812200
- Sponsor's protocol ID
- ATTT-1.0
- Status last verified
- Mar 2014
- First submitted
- 9 Mar 2013
- Last updated
- 6 Mar 2014
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Weisshaar S, Litschauer B, Gouya G, Mayer P, Smerda L, Kapiotis S, Kyrle PA, Eichinger S, Wolzt M. Antithrombotic triple therapy and coagulation activation at the site of thrombus formation: a randomized trial in healthy subjects. J Thromb Haemost. 2014 Nov;12(11):1850-60. doi: 10.1111/jth.12726. Epub 2014 Oct 16.
PubMed 25211369
Study at a glance
From the registry record, last updated by the sponsor on 6 Mar 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT01812200
- Acronym / sponsor ID
- ATTT-1.0
- Conditions
- Atrial Fibrillation, Acute Coronary Syndrome
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 60 participants (actual)
- Lead sponsor
- Medical University of ViennaUniversity, hospital or other
- Study start
- Oct 2012
- Primary completion
- May 2013 (actual)
- Study completion
- Jul 2013 (actual)
- First posted
- 18 Mar 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Dabigatran, Ticagrelor, ASA | Active comparator | Drug: Dabigatran, Ticagrelor, ASADabigatran 150mg td Ticagrelor 90 mg td ASA 100 mg od for 5 days |
| Rivaroxaban, Ticagrelor, ASA | Active comparator | Drug: Rivaroxaban, Ticagrelor, ASARivaroxaban 20 mg od Ticagrelor 90 mg td ASA 100 mg od for 5 days |
| Phenprocoumon, Ticagrelor, ASA | Active comparator | Drug: Phenprocoumon, Ticagrelor, ASAPhenprocoumon 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 |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (13 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Dabigatran, Ticagrelor, ASA | Drug | Dabigatran, Ticagrelor, ASA |
| Rivaroxaban, Ticagrelor, ASA | Drug | Rivaroxaban, Ticagrelor, ASA |
| Phenprocoumon, Ticagrelor, ASA | Drug | Phenprocoumon, Ticagrelor, ASA |
Primary outcome
Changes of β-TG, F1+2 and TAT in shed blood
Time frame: Changes from baseline at 3 hours and 5 days after intervention
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
1 secondary outcome
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)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Mar 2014.
- Derived from this study: PubMed 25211369Weisshaar S, Litschauer B, Gouya G, Mayer P, Smerda L, Kapiotis S, Kyrle PA, Eichinger S, Wolzt M. Antithrombotic triple therapy and coagulation activation at the site of thrombus formation: a randomized trial in healthy subjects. J Thromb Haemost. 2014 Nov;12(11):1850-60. doi: 10.1111/jth.12726. Epub 2014 Oct 16.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michael Wolzt, Prof. MD principal investigator
Department of Clinical Pharmacology, Medical University of Vienna
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Dabigatran, Ticagrelor, ASA, Rivaroxaban, Ticagrelor, ASA and Phenprocoumon, Ticagrelor, ASA in people with Atrial Fibrillation and Acute Coronary Syndrome, run by Medical University of Vienna at 1 site in Austria.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Mar 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Austria. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the 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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01812200, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Mar 2014.