| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Subjects undergoing catheter ablation of non-valvular
atrial fibrillation |
|
| E.1.1.1 | Medical condition in easily understood language |
Subjects undergoing catheter ablation of non-valvular
atrial fibrillation |
|
| 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 | 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:
To compare descriptively the incidence of the composite of all-cause death, stroke (ischemic, hemorrhagic, or undetermined) and Major Bleeding (International Society on Thrombosis and Hemostasis [ISTH] definition) in the edoxaban group against the vitamin K antagonist (VKA) group in subjects undergoing catheter ablation of atrial fibrillation (AF) in the period from the end of the catheter ablation procedure to Day 90/end-of-treatment (EOT).
Primary safety objective:
To compare descriptively the incidence of Major Bleeding (ISTH definition) in the edoxaban group against the VKA group in the period from date of first intake of study medication to Day 90/EOT. |
|
| E.2.2 | Secondary objectives of the trial |
-Composite of all-cause death, stroke (ischemic, hemorrhagic, or undetermined, according to alternative definition (see Protocol Section 7.4.2) and Major Bleeding [ISTH]
-Composite of stroke , SEE, CV mortality
-Composite of stroke, SEE, and all-cause mortality
-Composite of stroke and TIA
-Stroke
-SEE
-TIA
-Fatal stroke
-Non-fatal stroke
-Disabling stroke
-Non-disabling stroke
-Major Bleeding, Bleeding Academic Research Consortium [BARC] (2 or higher))
-Major and Clinically Relevant Non-Major (CRNM) Bleeding
-CRNM Bleeding
-Minor Bleeding
-Any Bleeding
-Intracranial hemorrhage (ICH)
-Life-threatening bleeding
-Fatal Major Bleeding
-Non-fatal Major Bleeding
-Fatal Major Bleeding (defined by TIMI, BARC [2 or higher])
-Non-fatal Major Bleeding (defined by TIMI, BARC [2 or higher])
-AEs, SAEs, laboratory parameters, electrocardiogram and vital signs
-Relevant Health Economics Outcome Research
-Cardiac and anticoagulation markers |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female at least 18 years of age with documented history of paroxysmal (lasting ≤7 days), persistent (lasting >7 days but ≤12 months) or long-standing [long-lasting] persistent (>12 months) non-valvular AF. Duration of AF can be confirmed by any electrical tracing or a recording in the subject’s medical records (e.g., medical chart, hospital discharge summary).
2. Subject is eligible and is scheduled for either radiofrequency (RF) or cryoballoon catheter ablation (both first and repeated procedure included).
3. Signed ICF.
|
|
| E.4 | Principal exclusion criteria |
1.AF considered to be of a transient or reversible nature (such as in myocarditis, post-surgery, ionic disturbances, thyrotoxicosis, pneumonia, severe anemia etc.)
2.Subject post stroke, or with a systemic thromboembolic event within the past 6 months prior to randomization
3.Subject has a thrombus in the left atrial appendage, left atrium, left ventricle, or aorta, or an intracardial mass
4.Subject had a myocardial infarction (MI) within the 2 months prior to randomization or coronary artery bypass graft surgery within 3 months prior to the randomization
5.Subject has signs of bleeding,history of clinically-relevant bleeding according to ISTH,or conditions associated with high risk of bleeding such as past history of intracranial ,or spontaneous intraocular, spinal, retroperitoneal, or intra-articular bleeding; overt gastrointestinal bleeding or active ulcer within the previous year; recent severe trauma, major surgery, or deep organ biopsy; 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 in the last 12 months prior to randomization
6.Subjects with mechanical heart valves, subjects with moderate to severe mitral stenosis and subjects who have new implantation of a bioprosthetic heart valve, with or without AF
7.Subjects with a history of LAA occlusion/exclusion
8.Subjects with any contraindication for edoxaban, VKA,low molecular weight heparin,heparin therapy,including known allergies, hypersensitivity, or intolerance to any component of these drugs or its excipients
9.Subjects receiving dual antiplatelet therapy (DAPT, i.e., aspirin and P2Y12 antagonist) or planned to receive DAPT during the study
10.Unfractionated heparin,low molecular weight heparins, heparin derivatives (fondaparinux, etc.), and oral anticoagulants (warfarin, dabigatran etexilate, rivaroxaban, apixaban etc.)should not be used concomitantly to study medication.Any bridging with LMWH around the CA procedure is prohibited.During the CA procedure,UFH will be used according to standard of care to achieve ACT of 300 to 400 sec.Subjects who require chronic use of medicines affecting hemostasis such as higher doses of aspirin(ASA up to 100 mg per day allowed) or chronic oral or parenteral intake of non-aspirin non-steroidal anti inflammatory drugs (NSAID) on ≥4 days/week
11.Subjects with active liver disease or persistent elevation of liver enzymes/bilirubin:
―Alanine transaminase or aspartate transaminase ≥2 times the upper limit of normal
―Total bilirubin (TBL) ≥1.5 times the ULN (subjects whose elevated TBL is due to known Gilbert’s syndrome may be included in the study)
―Hepatic disease associated with coagulopathy and clinically relevant bleeding risk
12.Subjects with kidney failure (creatinine clearance<15 mL/min)
13.Subjects with hemoglobin <10 g/dL or platelet count <100,000 cells/µL or white blood cell count <3000 cells/µL
14.Subjects with pre-planned invasive diagnostic or therapeutic procedures/interventions (other than endoscopy) during the study period in which bleeding is anticipated
15.Participation in any other interventional trial (subjects who received any investigational drug or device within 30 days prior to randomization,or plan to receive such therapy during the study period)
16.Previous randomization in this study
17.Female subjects of childbearing potential without using highly effective contraception.Females taking oral contraceptives should have been on therapy for at least three months.Adequate contraceptives include:Combined (estrogen and progestogen containing) oral, intravaginal or transdermal hormonal contraception associated with inhibition of ovulation;progestogen-only oral, injectable or implantable hormonal contraception associated with inhibition of ovulation;intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner;sexual abstinence
18.Pregnant or breast-feeding subjects
19.Subjects with the following diagnoses or situations:
-Active cancer undergoing chemotherapy, radiation or major surgery within the next 5 months
-Significant active/uncontrolled concurrent medical illness
-Life expectancy <6 months
20.Subjects who are unlikely to comply with the protocol (e.g., uncooperative attitude, inability to return for subsequent visits, and/or otherwise considered by the Investigator to be unlikely to complete the study)
21.Subjects with a known drug or alcohol dependence within the past 12 months prior to randomization as judged by the Investigator
22.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
23.Planned procedure using laser catheter ablation or other forms of catheter ablation different from RF or cryoballoon, microwaves, hot balloon, etc) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Composite of all-cause death, stroke (ischemic, hemorrhagic, or undetermined), and Major Bleeding (ISTH definition), analyzed as time to first occurrence of any component.
Major Bleeding (ISTH definition), analyzed as time to first occurrence of Major Bleeding. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| All adjudicated endpoints are analyzed as time to first occurrence of any of its components |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
• Composite of all-cause death, stroke (ischemic, hemorrhagic, or undetermined, according to alternative definition (see Protocol Section 7.4.2 for details) and Major Bleeding (ISTH definition)
• Composite of stroke (ischemic, hemorrhagic, or undetermined) SEE, and CV mortality
• Composite of stroke (ischemic, hemorrhagic, or undetermined) SEE, and all-cause mortality
• Composite of stroke (ischemic, hemorrhagic, or undetermined) and TIA
• Stroke (ischemic, hemorrhagic, or undetermined)
• Stroke (ischemic)
• Stroke (hemorrhagic)
• Stroke (undetermined)
• SEE
• TIA
• Fatal stroke (ischemic, hemorrhagic, or undetermined)
• Non-fatal stroke (ischemic, hemorrhagic, or undetermined)
• Disabling stroke (ischemic, hemorrhagic, or undetermined)
• Non-disabling stroke (ischemic, hemorrhagic, or undetermined)
Safety:
• Major Bleeding (defined by TIMI, BARC (2 or higher))
• Major and Clinically Relevant Non-Major (CRNM) Bleeding (ISTH definition)
• CRNM Bleeding (ISTH definition)
• Minor Bleeding (ISTH definition)
• Any Bleeding
• ICH
• Life-threatening bleeding
• Fatal Major Bleeding (ISTH definition)
• Non-fatal Major Bleeding (ISTH definition)
• Fatal Major Bleeding (defined by TIMI, BARC [2 or higher])
• Non-fatal Major Bleeding (defined by TIMI, BARC [2 or higher])
• Safety parameters such as AEs, SAEs, laboratory parameters, ECG and vital signs.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All adjudicated endpoints are analyzed as time to first occurrence of any of its components |
|
| 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 | No |
| 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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 |
| Belgium |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Netherlands |
| Poland |
| Spain |
| Taiwan |
| United Kingdom |
|
| 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
|
| All randomized subjects will have a contact planned 30-35 days after the EOT visit, to collect data on targeted concomitant medications, SAEs, and other AESI. The final contact is the post-treatment follow-up visit scheduled at 30-35 days after the EOT visit. The study is deemed completed as soon as the final contact of the last subject is performed in all centers and in all participating countries. |
|
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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