E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Atrial Fibrillation |
fibrillazione atriale |
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E.1.1.1 | Medical condition in easily understood language |
Atrial Fibrillation |
fibrillazione atriale |
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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 | 10053468 |
E.1.2 | Term | Anticoagulant therapy |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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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 | 10003658 |
E.1.2 | Term | Atrial fibrillation |
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 |
To evaluate that the oral FXIa inhibitor BAY 2433334 when compared to apixaban leads to a lower incidence of bleeding in participants with AF |
Confrontare la sicurezza dell’inibitore del FXIa orale BAY 2433334 verso apixaban in pazienti affetti da fibrillazione atriale
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E.2.2 | Secondary objectives of the trial |
Not applicable |
non applicabile |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Participant must be 45 years of age or older at the time of signing the informed consent. 2. Participant with AF documented by ECG evidence with • CHA2DS2-VASc score ≥ 2 if male or CHA2DS2-VASc score ≥ 3 if female • Indication for treatment with an oral anticoagulant in • any participant currently not treated with an oral anticoagulant (e.g. treatment naïve) or alternatively, • participant on a NOAC in case of at least one bleeding risk feature (history of a prior bleed within the last 12 months requiring medical attention and / or moderate renal dysfunction with eGFR 30-50 ml/min and / or current clinically indicated antiplatelet therapy with ASA ≤ 100 mg)
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E.3 Criteri di inclusione principali(elencare i più importanti): 1. Participant must be 45 years of age or older at the time of signing the informed consent. 2. Participant with AF documented by ECG evidence with • CHA2DS2-VASc score ≥ 2 if male or CHA2DS2-VASc score ≥ 3 if female • Indication for treatment with an oral anticoagulant in • any participant currently not treated with an oral anticoagulant (e.g. treatment naïve) or alternatively, • participant on a NOAC in case of at least one bleeding risk feature (history of a prior bleed within the last 12 months requiring medical attention and / or moderate renal dysfunction with eGFR 30-50 ml/min and / or current clinically indicated antiplatelet therapy with ASA ≤ 100 mg)
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E.4 | Principal exclusion criteria |
1. Mechanical heart valve prosthesis 2. Any degree of rheumatic mitral stenosis or moderate-to-severe, non-rheumatic mitral stenosis 3. Atrial fibrillation due to a reversible cause, participants in sinus rhythm after successful ablation, or plan for cardioversion or ablation during study conduct 4. Stroke within the last 30 days of screening 5. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg) at randomization 6. Active bleeding; known bleeding disorder 7. Known significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or hepatic insufficiency classified as Child-Pugh B or C, or ALT/AST > 2.5 x the upper limit of normal, measured between screening and randomization 8. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, calculated by Modification of Diet in Renal Disease (MDRD) formula, determined between screening and randomization 9. Major surgery during the last 30 days or planned major surgery or intervention within study period (e.g. carotid endarterectomy, coronary artery bypass grafting) 10. Known allergy, intolerance or hypersensitivity to either of the study interventions (active substance or excipients) 11. Any contraindication for the use of an anticoagulant or listed in the local labeling for apixaban 12. Requirement for chronic anticoagulation (for a different indication than AF e.g. mechanical heart valve or cardiac thrombus) or antiplatelet therapy (up to 100 mg ASA is allowed). Anticipated need for chronic (more than 4 weeks) therapy with NSAIDs 13. Treated with a Vitamin K antagonist in the 30 days prior to screening 14. Concomitant use of any of the following therapies within 14 days (or at least five half-lives of the active substance whatever is longer) before randomization and first study intervention administration: • Strong inhibitors of cytochrome P450 isoenzyme 3A4 (CYP3A4) e.g. human immunodeficiency virus protease inhibitors, systemically used azole-antimycotic agents, clarithromycin or telithromycin • Strong inducers of CYP3A4, e.g. phenytoin, carbamazepine, phenobarbital, rifampicin or St. John’s wort. 15. Women of childbearing potential (women are considered of childbearing potential if they are not surgically sterile or postmenopausal, defined as amenorrhea for > 12 months). Male participants not willing to use condoms when sexually active with a woman of childbearing potential |
1. Mechanical heart valve prosthesis 2. Any degree of rheumatic mitral stenosis or moderate-to-severe, nonrheumatic mitral stenosis rhythm after successful ablation, or plan for cardioversion or ablation during study conduct 3. Atrial fibrillation due to a reversible cause, participants in sinus 4. Stroke within the last 30 days of screening 5. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg) at randomization 6. Active bleeding; known bleeding disorder 7. Known significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or hepatic insufficiency classified as Child-Pugh B or C, or ALT/AST > 2.5 x the upper limit of normal, measured between screening and randomization 8. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, calculated by Modification of Diet in Renal Disease (MDRD) formula, determined between screening and randomization 9. Major surgery during the last 30 days or planned major surgery or intervention within study period (e.g. carotid endarterectomy, coronary artery bypass grafting) 10. Known allergy, intolerance or hypersensitivity to either of the study interventions (active substance or excipients) 11. Any contraindication for the use of an anticoagulant or listed in the local labeling for apixaban 12. Requirement for chronic anticoagulation (for a different indication than AF e.g. mechanical heart valve or cardiac thrombus) or antiplatelet therapy (up to 100 mg ASA is allowed). Anticipated need for chronic (more than 4 weeks) therapy with NSAIDs 13. Treated with a Vitamin K antagonist in the 30 days prior to screening 14. Concomitant use of any of the following therapies within 14 days (or at least five half-lives of the active substance whatever is longer) before randomization and first study intervention administration: • Strong inhibitors of cytochrome P450 isoenzyme 3A4 (CYP3A4) e.g. human immunodeficiency virus protease inhibitors, systemically used azole-antimycotic agents, clarithromycin or telithromycin • Strong inducers of CYP3A4, e.g. phenytoin, carbamazepine, phenobarbital, rifampicin or St. John's wort. 15. Women of childbearing potential (women are considered of childbearing potential if they are not surgically sterile or postmenopausal, defined as amenorrhea for > 12 months). Male participants not willing to use condoms when sexually active with a woman of childbearing potential
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E.5 End points |
E.5.1 | Primary end point(s) |
Composite of ISTH major and clinically relevant non-major bleeding |
Endpoint primario di sicurezza composito di sanguinamenti maggiori e sanguinamenti non maggiori clinicamente rilevanti secondo i criteri dell’International Society on Thrombosis and Hemostasis (ISTH) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From Visit 2 (randomization visit) until Visit 7 (safety follow-up visit) |
Da Visita 2 (randomization visit) a Visita 7 (safety follow-up visit) |
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E.5.2 | Secondary end point(s) |
Secondary Safety Endpoints: • All bleeding • ISTH major bleeding • ISTH clinically relevant non-major bleeding • ISTH minor bleeding
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Endpoint secondari di sicurezza: • tutti i sanguinamenti • sanguinamenti maggiori secondo i criteri ISTH • sanguinamenti non maggiori clinicamente rilevanti secondo i criteri ISTH • sanguinamenti minori secondo i criteri ISTH
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From Visit 2 (randomization visit) until Visit 7 (safety follow-up visit) |
Da Visita 2 (randomization visit) a Visita 7 (safety follow-up visit) |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 |
Double dummy - Dose-finding |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
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 | 3 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 87 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Canada |
Czech Republic |
France |
Hungary |
Italy |
Japan |
Latvia |
Netherlands |
Spain |
Sweden |
Switzerland |
United Kingdom |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 7 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 7 |