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) |
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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 |
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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 |
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).
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|
E.2.2 | Secondary objectives of the trial |
Compare Edoxaban with VKA for below efficacy endpoints
•NACE defined as composite of all-cause death, MI, ischemic stroke, SEE,
valve thrombosis&major and minor bleeding per TIMI definitions
•NACE defined as composite of all-cause death, MI, ischemic stroke, SEE,
valve thrombosis&major bleeding (BARC 3 or 5 definition)
•NACE defined as the composite of all-cause death, MI, ischemic stroke,
SEE, valve thrombosis & major and moderate bleeding (Global Utilization
of Streptokinase&Tissue Plasminogen Activator for Occluded Coronary
Arteries 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 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 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 mmHg
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 AF
b) New onset AF (e.g., > 30 seconds documented by ECG)
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 contraindication 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.
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|
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
revascularization 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 minimal; BARC 1
nonactionable;
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 |
|
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 | 6 |
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 the 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.
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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 | 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 |