| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stroke and thromboembolism prevention in patients with non-valvular atrial fibrillation (NVAF) undergoing planned electrical cardioversion. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Prevention of development of clots in patients with an abnormal heartbeat condition called atrial fibrillation undergoing cardioversion; a procedure that converts the abnormal heartbeat to normal. |
|
| 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 | 18.1 |
| 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 |
|
| 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 |
Primary Efficacy Objective:
Compare the incidences of the composite endpoints of stroke, systemic embolic event (SEE), myocardial infarction (MI) and cardiovascular (CV) mortality between the edoxaban group and the enoxaparin/warfarin group from randomization to end of follow up (FU).
Primary Safety Objective:
Compare the incidence of the composite endpoints of major and clinically-relevant non-major (CRNM) bleeding between the edoxaban group and the enoxaparin/warfarin group from the first administration of study drug to end of treatment + 3 days. |
|
| E.2.2 | Secondary objectives of the trial |
| Compare the incidences of the composite endpoints of stroke, systemic embolic event (SEE), myocardial infarction (MI), cardiovascular (CV) mortality and major bleedings between the edoxaban group and the enoxaparin/warfarin group from randomization to end of FU. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed ICF;
2. Male or female subjects older than the minimum legal adult age (country specific);
3. Ongoing AF lasting for at least 48 hours but ≤ 12 months;
Ongoing AF at the time of randomization should be confirmed by any electrical tracing (eg, routine 12-lead electrocardiogram (ECG), Holter monitor rhythm strip, intracardiac electrogram, or pacemaker) prior to randomization. Duration and proof of AF during the previous 12 months can be confirmed by any electrical tracing or a recording in the subject’s medical records (eg, medical chart, hospital discharge summary).
Symptomatic subjects with no known history of AF and no prior electrical tracing or recording of/about the cardiac rhythm available for the past 12 months may be randomized into the study if there is reasonable belief that the current episode of AF lasts for at least 48 hours and no longer than 12 months.
4. Subject is planned for electrical cardioversion;
Subjects with AF following a cardiac surgical procedure will be allowed in the study providing that they meet all the other inclusion criteria AND the time from the surgery to randomization is no less than 30 days. The Investigator will be responsible for assessment of risks relevant to the cardioversion procedure in such subjects. |
|
| E.4 | Principal exclusion criteria |
1. AF considered to be of a transient or reversible nature (such as in myocarditis, post-surgery [unless the duration of AF post-cardiac surgery is > 30 days, refer to inclusion criterion #4], ionic disturbances, thyrotoxicosis, pneumonia, severe anemia, etc);
2. Subjects with moderate or severe mitral stenosis, mitral valve rheumatic disease, unresected atrial myxoma, or a mechanical heart valve (subjects with bioprosthetic heart valves and/or valve repair can be included) and/or other conditions, such as PE, considered to be formal indication for conventional anticoagulation;
a. However subjects with AF and valvular heart diseases such as mitral valve prolapse, mitral valve regurgitation, and aortic valve disease are allowed in the study;
3. Subjects with a history of LAA closure (either by surgery or by a procedure);
4. Known presence of a thrombus in LAA, LA, left ventricle, aorta or intracardial mass;
5. Subjects with acute myocardial infarction (MI), stroke, acute coronary syndrome (ACS), or percutaneous coronary intervention within the previous 30 days or receiving DAPT regardless of when the event has occurred;
6. Subjects with any contraindication to anticoagulant agents;
7. Signs of bleeding or conditions associated with high risk of bleeding including major surgeries or biopsies in the last 10 days;
8. Subjects with conditions associated with high risk of bleeding such as past history of intracranial (spontaneous or traumatic), or spontaneous intraocular, spinal, retroperitoneal, or intra-articular bleeding; overt gastrointestinal (GI) bleeding or active ulcer within the previous year; recent severe trauma, major surgery, or deep organ biopsy within the previous 10 days; active infective endocarditis; uncontrolled
hypertension (blood pressure [BP] above 170/100 mmHg); or hemorrhagic disorder including known or suspected hereditary or acquired bleeding or coagulation disorder;
9. Subjects receiving dual antiplatelet therapy (eg, aspirin plus thienopyridine such as clopidogrel, prasugrel or ticagrelor) or anticipated to receive such therapy;
10. Subjects receiving prohibited concomitant medications (fibrinolytics, non-study anticoagulants other than those used as a bridge to/from study drug), chronic oral or parenteral Non-Aspirin/Non-Steroidal Anti- Inflammatory Drugs (NSAID) use for ≥ 4 days/week;
11. Subjects receiving chronic cyclosporine therapy;
12. Subjects with active liver disease or persistent (confirmed by repeat assessments at least a week apart) elevation of liver enzymes/bilirubin:
ALT or AST ≥ 3 x ULN;
TBL ≥ 2 x ULN (however, subjects whose elevated TBL is due to known
Gilbert's syndrome may be included in the study);
13. Subjects with renal failure (end stage renal disease, calculated CrCL < 15 mL/min);
14. Subjects with hemoglobin < 10 g/dL or platelet count < 100000 cells/mcL or white blood cell count < 3000 cells/mcL;
15. Subjects with pre-planned invasive procedures (other than routine endoscopy) or surgeries in which bleeding is anticipated during the study period;
16. Subjects who received any investigational drug or device within 30 days prior to randomization, or plan to receive such investigational therapy during the study period;
17. Women of childbearing potential without proper contraceptive measures, and women who are pregnant or breast feeding Note: Childbearing potential without proper contraceptive measures (i.e., a method of contraception with a failure rate < 1 % during the course of the study (including the observational period). These methods
of contraception according to the note for guidance on non-clinical safety studies for the conduct of human trials for pharmaceuticals (CPMP/ICH/286/95, modification) include consistent and correct use of hormone containing implants and injectables, combined oral contraceptives, hormone containing intrauterine devices, surgical sterilization, sexual abstinence, and vasectomy for the male partner);
18. Subjects with the following diagnoses or situations:
Active cancer undergoing chemotherapy, radiation or major surgery
within the next 3 months;
Significant active concurrent medical illness or infection;
Life expectancy < 6 months;
19. Subjects who are unlikely to comply with the protocol (eg, uncooperative attitude, inability to return for subsequent visits, and/or otherwise considered by the Investigator to be unlikely to complete the study);
20. Subjects with a known drug or alcohol dependence within the past 12 months as judged by the Investigator;
21. Subjects with any condition that, in the opinion of the Investigator, would place the subject at increased risk of harm if he/she participated in the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint
• Stroke, SEE, MI and CV mortality
Primary safety endpoint
• Major or CRNM bleedings
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
TEE-Guided Stratum: Day -3 (randomisation) to Day 58 (discontinuation visit/follow up)
Non-TEE-Guided Stratum: Day -21 (randomisation) to Day 58 (discontinuation visit/follow up) |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoint
• All-cause mortality
Secondary safety endpoints
• All bleedings
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
TEE-Guided Stratum: Day -3 (randomisation) to Day 58 (discontinuation visit/follow up)
Non-TEE-Guided Stratum: Day -21 (randomisation) to Day 58 (discontinuation visit/follow up) |
|
| 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 | No |
| 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 | Yes |
| 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 |
|
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 24 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 199 |
| 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 |
| Bulgaria |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Sweden |
| Ukraine |
| United Kingdom |
| United States |
|
| 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
|
| Last subject last follow up. |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 7 |
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