| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Coronary Syndrome and Non-valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention |
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| E.1.1.1 | Medical condition in easily understood language |
| Acute Coronary Syndrome and Non-valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10051592 |
| E.1.2 | Term | Acute coronary syndrome |
| E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
New off-label regimen of reduced ticagrelor dose in patients with AF and ACS. The most valuable scientific points of the project supporters in the first-ever trial of the historic off-label P2Y12 inhibitor (ticagrelor) as part of dual antiplatelet therapy in patients with AF and ACS, and the evaluation of the dose of ticagrelor in ACS. The three innovative aspects are: a new treatment regimen with a reduced dose of ticagrelor in ACS, an option to subscribe to the Polish market for a two-component tablet containing ticagrelor and dabigatran, and the potential production of two-component tablets, prices of different ticagrelor and dabigatran emissions, depending on the individual risk and bleeding in the patient. In case of success, the proposed study is a clinical question about the so far unknown optimal treatment strategy for AF and ACS.
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female patients aged ≥18 years’
2. Patients with new-onset or pre-existing non-valvular AF That have been receiving at least two doses of dabigatran before randomization or were treatment naïve prior to PCI. AF may be paroxysmal, persistent or permanent, but must not be secondary to a reversible disorder such as MI, pulmonary embolism, recent surgery, pericarditis or thyrotoxicosis unless long-term treatment with an OAC is anticipated.
3. Patients presenting with ACS that had undergone a successful PCI (either drug-eluting stent (DES) implantation or plain old balloon angioplasty (POBA)) within the previous 120 hours (in case of the multistage PCI during primary hospitalization the time should be counted from the last stage). ACS may be ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), or unstable angina (UA). Successful treatment with PCI is defined as achievement of <30% residual diameter stenosis of the target lesion assessed by visual inspection or quantitative coronary angiography and no in-hospital major adverse cardiac events (AMI or repeat coronary revascularisation of the target lesion). For ACS patients with ST-segment elevation, persistent ST-segment elevation of at least 0.1 mV in at least two contiguous leads or a new left bundle-branch block should be present [27]. For ACS patients without ST-segment elevation, at least two of the following three criteria should be met: (i) ST-segment changes on electrocardiography, indicating ischemia; a positive test of a biomarker, indicating myocardial necrosis; or one of several risk factors (age ≥60 years; previous myocardial infarction or coronary artery bypass grafting; coronary artery disease with stenosis of ≥50% in at least two vessels; previous ischemic stroke, transient ischemic attack, carotid stenosis of at least 50%, or cerebral revascularization; diabetes mellitus; peripheral arterial disease; chronic renal dysfunction, defined as a creatinine clearance of <60 ml per minute per 1.73 m2 of body surface area) [40].
4. The patient must be able to give informed consent in accordance with ICH GCP guidelines and local legislation and/or regulations.
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| E.4 | Principal exclusion criteria |
1. Mechanical or biological heart valve prosthesis;
2. PCI with bare-metal stent insertion;
3. Unsuccessful PCI (>30% residual stenosis of the target lesion);
4. Cardiogenic shock during current hospitalization;
5. Adverse bleeding or ischaemic event during current hospitalization;
6. Anaemia (haemoglobin <10 g/dL) or thrombocytopenia (platelet count <100 x109/L) at screening,
7. Severe renal impairment (creatinine clearance <30mL/min (estimated CrCl calculated by Cockcroft-Gault equation) at screening;
8. Active liver disease at screening: persistently elevated alanine aminotransferase (ALT) or aspartate transaminase (AST) levels >3 times the upper limit of normal (ULN);
9. Use of fibrinolytic agents within 24 hours of screening;
10. Gastrointestinal bleeding within 1 month prior to screening unless, in the opinion of the Investigator, the cause has been permanently eliminated (e.g., by surgery);
11. Major bleeding episode (reduction in the haemoglobin level of at least 2 g/dL, transfusion of at least two units of blood, or symptomatic bleeding in a critical area or organ), including life-threatening bleeding episode (symptomatic intracranial bleeding, bleeding with a decrease in the haemoglobin level of at least 5 g/dL or bleeding requiring transfusion of at least 4 units of blood or inotropic agents or necessitating surgery) within 1 month prior to screening;
12. Stroke within 1 month prior to screening;
13. Major surgery within 1 month prior to screening;
14. Malignancy or radiation therapy within 6 months prior to screening unless, in the opinion of the Investigator, the estimated life expectancy is greater than 36 months;
15. History of intraocular, spinal, retroperitoneal, or traumatic intra-articular bleeding unless the causative factor has been permanently eliminated or repaired;
16. Haemorrhagic disorder or bleeding diathesis (e.g. von Willebrand disease, haemophilia A or B or other hereditary bleeding disorder, history of spontaneous intra-articular bleeding, history of prolonged bleeding after surgery/intervention);
17. Past an organ transplant or patient on the waiting list for organ transplant;
18. Need for continued treatment with systemic ketoconazole, itraconazole, posaconazole, cyclosporine, tacrolimus, dronedarone, rifampicin, phenytoin, carbamazepine, St. John’s Wort or any cytotoxic/myelosuppressive therapy.
19. Need for continued treatment with non-steroidal anti-inflammatory drugs (NSAIDs);
20. Pre-menopausal women (last menstruation ≤1 year prior to screening) who:
o Are pregnant or breastfeeding or
o Are not surgically sterile or
o Are of childbearing potential and not practicing two acceptable methods of birth control, or do not plan to continue practicing an acceptable method of birth control throughout the trial. Acceptable methods of birth control are oral or parenteral (patch, injection, implant) hormonal contraception, which has been used continuously for at least one month prior to the first dose of study medication, intrauterine device or intrauterine system, double-barrier method of contraception (condom and occlusive cap or condom and spermicidal agent), male sterilization and complete sexual abstinence (if acceptable by local authorities). Periodic abstinence is not an acceptable method of contraception.
21. Known allergy to dabigatran, ticagrelor, clopidogrel, aspirin, or to the excipients used for the tables of the drugs;
22. Contraindications, in the Investigator’s opinion to dabigatran, ticagrelor, clopidogrel, or aspirin;
23. Participation in another trial with an investigational drug or device within the past 30 days preceding the screening visit (patients participating in an observational study only will not be excluded);
24. Patients who are not willing or able to comply with the protocol requirements or considered unreliable by the Investigator concerning the requirements for follow-up during the study and/or compliance with study drug administration, who have a life expectancy less than the expected duration of the trial due to concomitant disease, or who have any condition which in the opinion of the Investigator, would not allow safe participation in the study (e.g., drug addiction, alcohol abuse).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary study endpoint is the first major or clinically relevant non-major bleeding event, as defined by the International Society on Thrombosis and Haemostasis (ISTH), in a time-to-event analysis. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 months after starting treatment |
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| E.5.2 | Secondary end point(s) |
| The main secondary endpoint is a composite efficacy endpoint of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization (PCI or coronary artery bypass grafting). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 12 months after starting treatment |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Prospective randomized open blinded end-point (PROBE) study |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 14 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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A Steering Committee, consisting of representatives from every partner site participating in the trial (Medical University of Gdańsk, Medical University of Warsaw,
Collegium Medicum Bydgoszcz, Prof. Christian Templin, MD, PhD, University Heart Centre, Department of Cardiology, University Hospital Zurich, Zurich, Switzerland)
and external international experts (Eliano Navarese, MD, PhD, Mater Dei Hospital Bari, Italy) |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 29 |
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