| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with atrial fibrillation (AF) and indication to chronic oral anticoagulation after transcatheter aortic valve implantation (TAVI) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with atrial fibrillation (AF) after transcatheter aortic valve implantation (a catheter based procedure where a new valve is placed in the location of the old and narrowed aortic valve) |
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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 | 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 |
2.1.1. Co-Primary Objectives
•To assess the effect of Edoxaban versus vitamin K antagonist (VKA) on net adverse clinical events (NACE), i.e., the composite of all-cause death, myocardial infarction (MI), ischemic stroke, systemic thromboembolism (SEE), valve thrombosis, and major bleeding (International Society on Thrombosis and Haemostasis [ISTH] definition).
•To assess the effect of Edoxaban versus VKA on major bleeding (ISTH definition).
|
|
| E.2.2 | Secondary objectives of the trial |
To compare Edoxaban with VKA with regards below efficacy endpoints:
•NACE defined as the composite of all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and major and minor bleeding per TIMI definitions
•NACE defined as the composite of all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and major bleeding (Bleeding Academic Research Consortium [BARC] 3 or 5 definition)
•NACE defined as composite of all-cause death, MI, ischemic stroke, SEE, valve thrombosis and major & moderate bleeding [GUSTO] definition
•Major Adverse Cardiac Events (MACE) defined as composite of all cause death (excluding adjudicated non cardiac death), MI or repeat coronary revascularization of target lesion
•MACCE defined as composite of all cause death (excluding adjudicated non-cardiac death), MI, stroke, (ischemic, hemorrhagic / undetermined or repeat coronary revascularization of target lesion
•Cardiovascular mortality
For full list, refer to Protocol |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must satisfy all of the following criteria to be included in the study:
1. Successful TAVI via transvascular access routes such as to the femoral, carotid, axillary and subclavian arteries. Other access routes need prior approval per a majority vote from 3 members of the Executive Committee (both Global Lead Investigators and the Daiichi Sankyo Medical Lead or his/her designee). success is defined as:
a. Correct positioning of a single prosthetic heart valve into the proper anatomical location
b. Presence of all 3 conditions post TAVI
I. Mean aortic valve gradient <20 mm Hg
ii. Peak transvalvular velocity <3.0 m/s
iii. Aortic valve regurgitation of 2 or less
c. No clinically overt stroke
d. No uncontrolled bleeding at time of randomization
2. Indication for chronic OAC
a) Documented pre-existing atrial fibrillation (AF)
b) New onset AF (eg. > 30 seconds documented by ECG recording)
3. Provision of signed informed consent
4. Age ≥18 years
|
|
| E.4 | Principal exclusion criteria |
1. Conditions with a high risk of bleeding
o This may include but is not limited to: active peptic ulcer with upper gastrointestinal bleeding within last 90 days prior to randomization, malignancy at high risk of bleeding, major intraspinal or intracerebral vascular abnormalities, recent unresolved brain or spinal injury, or spinal surgery (recent = within the last 90 days prior to randomization), any intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, or clinically relevant vascular aneurysms.
2. Other known bleeding diatheses
3. Conditions that make it difficult for the subject to swallow the study medication
4. Serious unresolved periprocedural complications
5. Any contraindications to EITHER Edoxaban OR VKA per local label; this includes hypersensitivity to the active ingredient or to any of the excipients, or any components of the study medications
6. Concomitant treatment with other antithrombotic agents, (ASA > 100 mg/day, fibrinolytic therapy, or chronic (> 4 days/week) use of nonsteroidal antiinflammatory drugs (NSAIDs)); however, NSAID patches are permitted.
7. Requirement for dual-antiplatelet therapy (DAPT) at randomization that will be indicated for more than 3 months beyond the first OAC dose.
8. Treatment with other investigational (i.e., non-approved) drugs or devices within 30 days before enrollment or planned use of investigational drugs or devices during the study
For full list of Exclusion criteria: Refer to Protocol, section: 4.2 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint:
• NACE, ie, the composite of all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and major bleeding (ISTH definition)
Primary safety endpoint:
• Major bleeding (ISTH definition)
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
First occurrence of any component.
|
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
• NACE defined as the composite of all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and major bleeding (TIMI definition)
• NACE defined as the composite of all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and major bleeding ([BARC 3 or 5 definition)
• NACE defined as the composite of all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and major and moderate bleeding (GUSTO definition)
• Major Adverse Cardiac Events (MACE), defined as the composite of allcause death (excluding adjudicated non-cardiac death), MI, or repeat coronary revasularization of the target lesion
• Major Adverse Cardiac and Cerebrovascular Events (MACCE), defined as the composite of all-cause death (excluding adjudicated non-cardiac death), MI, stroke (ischemic, hemorrhagic, or undetermined), or repeat coronary revascularization of the target lesion
• Cardiovascular mortality
• Stroke (ischemic, hemorrhagic, or undetermined)
• Stroke (ischemic)
• Stroke (hemorrhagic)
• Stroke (undetermined)
• Fatal stroke (ischemic, hemorrhagic, or undetermined)
• Non-fatal stroke (ischemic, hemorrhagic, or undetermined)
• SEE
• Myocardial Infarction
• Valve thrombosis
Secondary Safety Endpoints
• Bleeding defined as TIMI major or minor, BARC 3 or 5 and GUSTO (moderate or severe)
• Bleeding defined as ISTH major and CRNM, TIMI major / minor bleeds or requiring medical attention, BARC 2, 3 or 5 and GUSTO moderate or severe
• Bleeding defined as ISTH CRNM, TIMI minor or requiring medical attention, BARC 2 and GUSTO moderate
• All bleeding that are not ISTH major, CRNM; TIMI minmal; BARC 1 non actionable and GUSTO mild
• Any bleeding
• Intracranial hemorrhage
• Life-threatening bleeding
• Fatal bleeding (fulfilling the ISTH major bleeding definition)
• Non-fatal major bleeding (ISTH definition)
• All-cause mortality
• Cardiovascular mortality
• Safety parameters such as (serious) adverse events, laboratory parameters, ECG and vital signs
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|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All clinical endpoints will be 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 | 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 147 |
| 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 |
| France |
| Germany |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Poland |
| Spain |
| Switzerland |
| 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
|
| As an event driven study, the subjects will continue on treatment until the study is stopped (the end of study) due to 320 adjudicated events (from approximately 2500 subject years) will have been reached, or they permanently discontinue from the study (for any reason). Subjects enrolled late in the study may be terminated from the study after a minimum of 6 months on treatment. Subjects will also have a post treatment Follow-up Visit 30 days (± 7 days) after the EOT Visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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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