| 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) |
| Pazienti con fibrillazione atriale (FA) e indicazione per terapia anticoagulante orale (TAO) cronica dopo impianto transcatetere di valvola aortica (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) |
| Pazienti con fibrillazione atriale (FA) e indicazione per terapia anticoagulante orale (TAO) cronica dopo impianto transcatetere di valvola aortica |
|
| 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 |
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).
|
Obiettivi co-primari
¿ Valutare l¿effetto di edoxaban rispetto a un antagonista della vitamina K (Vitamin K Antagonist, VKA) sugli eventi avversi clinici netti (Net Adverse Clinical Events, NACE), ossia un endpoint composito costituito da decesso per tutte le cause, infarto del miocardio (IM), ictus ischemico, tromboembolia sistemica (Systemic Embolic Event, SEE), trombosi valvolare ed emorragia maggiore (definizione della Societ¿ internazionale di trombosi ed emostasi [International Society on Thrombosis and Haemostasis, ISTH].
¿ Valutare l¿effetto di Edoxaban rispetto a VKA sull¿emorragia maggiore (definizione ISTH).
|
|
| 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, hemorragic/undetermined) or repeat coronary revascularization of target lesion
- Cardiovasculary mortality
For full list, refer to Protocol |
Confr Edoxaban e VKA relativ ai seguenti endpoint di efficacia:
¿ NACE, definito come un endpoint composito costituito da decesso per tutte le cause, IM, ictus ischemico, SEE, trombosi valvolare ed emorragia maggiore e minore secondo le definizioni TIMI
¿ NACE, definito come endpoint composito costituito da decesso per tutte le cause, IM, ictus ischemico, SEE, trombosi valvolare ed emorragia maggiore (definizione 3 o 5 del Bleeding Academic Research Consortium [BARC])
¿ NACE, definito come endpoint composito costituito da decesso per tutte le cause, IM, ictus ischemico, SEE, trombosi valvolare ed emorragia magg. e moderata (definizione del Global Utilization of Streptokinase And Tissue Plasminogen Activator For Occluded Coronary arteries [GUSTO])
- Gravi eventi cardiaci avversi (MACE) definiti come di cause generali di morte (escl il decesso accertato per cause non cardiache) IM,ICTUS o ripet
- Gravi eventi cardiaci cerebrovascolari avversi definiti come insieme di cause gen di morte |
|
| 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 transfemoral TAVI with any approved/marketed device (other access routes may only be used if they become standard of care with a proven superior outcome and after written approval of this study’s Executive Committee); 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. Pre-existing atrial fibrillation (AF)
b. New onset AF (e.g.> 30 seconds documented by ECG recording)
3. Provision of signed informed consent
4. Age =18 years
|
Per essere inclusi nello studio, i soggetti devono soddisfare tutti i seguenti criteri:
1. Intervento di TAVI transfemorale riuscito (possono essere usate altre vie di accesso soltanto se diventano lo standard di cura, dimostrando un esito superiore comprovato e previa approvazione scritta del Comitato esecutivo di questo studio) con qualsiasi dispositivo approvato/commercializzato; l’intervento è definito riuscito in caso di:
a. Posizionamento corretto di una singola protesi valvolare cardiaca nella sede anatomica appropriata
b. Presenza di tutte e 3 le condizioni post-TAVI
i. Gradiente medio della valvola aortica < 20 mm Hg
ii. Velocità massima del flusso transvalvolare < 3,0 m/s
iii. Rigurgito della valvola aortica uguale o inferiore a 2
c. Nessun ictus clinicamente evidente
d. Nessuna emorragia incontrollata al momento della randomizzazione
2. Indicazione per TAO cronica
a. Fibrillazione atriale (FA) preesistente documentata
b. FA di nuova insorgenza (e.g. > 30 secondi documentati dal tracciato ECG)
3. Sottoscrizione del consenso informato
4. Età = 18 anni |
|
| E.4 | Principal exclusion criteria |
1. Other conditions with a high risk of bleeding
o This may include but is not limited to: active peptic ulcer or upper gastrointestinal (GI) bleeding within last 90 days prior to randomization, malignancy at high risk of bleeding, recent unresolved brain or spinal injury, spinal or ophthalmic surgery (within the last 90 days prior to randomization), any intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or major intraspinal or intracerebral vascular abnormalities.
2. Other known bleeding diatheses
3. Conditions that make it difficult for the subject to take the study medication
4. Serious unresolved periprocedural complications
5. Any contraindications to BOTH Edoxaban AND VKA per local label, ASA, and/or P2Y12 antagonists
6. Concomitant treatment with other antithrombotic agents, ASA > 100 mg/day, fibrinolytic therapy, or chronic (> 4 days/week) use of nonsteroidal antiinflammatory drugs (NSAIDs)
7. Requirement for dual-antiplatelet therapy (DAPT) at randomization that will be indicated for more than 4 weeks beyond randomization
8. Treatment with other investigational 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 |
1. Altre patologie con elevato rischio di emorragia
Sono incluse, a titolo esemplificativo e non esaustivo: ulcera peptica attiva con emorragia del tratto gastrointestinale (GI) superiore nei 3 mesi precedenti la randomizzazione, neoplasia maligna a elevato rischio di emorragia, lesione cerebrale o spinale recente o non risolta, chirurgia spinale od oftalmica recente (nei 3 mesi precedenti la randomizzazione), qualsiasi emorragia endocranica, varici esofagee note o sospette, malformazioni arterovenose, aneurismi vascolari o anomalie maggiori a livello intraspinale o intracerebrale.
2. Altra diatesi emorragica nota
3. Patologie che rendano difficile l'assunzione del farmaco dello studiio da parte del soggetto
4. Gravi complicanze periprocedurali irrisolte
5. controindicazioni sia a edoxaban che a VKA per etichetta locale, ASA, e/o agli antagonisti di P2Y12
6. Trattamento concomitante con altri agenti antitrombotici (ASA) > 100 mg/die, terapia fibrinolitica o utilizzo cronico (> 4 giorni/settimana) di farmaci antinfiammatori non steroidei (FANS)
7. Necessità di doppia terapia antipiastrinica (DAPT) alla randomizzazione che sarà indicata per più di 4 settimane oltre la randomizzazione |
|
| 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)
|
|
| 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, ischem,ic 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 event (MACE) defined as the composite of all cause death (excluing 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; - 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 endpoint: - Bleeding defined by TIMI major or minor, BARC 3 or 5, and GUSTO moderate or severe; - bleeding defined by ISTH major and CRNM, TIMI major/minor bleeds or requiring medical attention, BARC 2, 3 or 5 and GUSTO moderate or severe; - Bleeding defined by 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 non actionable; and GUSTO mild; Any bleeding; - INtracranial hemorrhage; - Life threatening bleeding; - Fatal bleedin (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 |
| Vitamin K Antagonist |
| Vitamin K Antagonist |
|
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 90 |
| 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 | Information not present in EudraCT |
| 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 |
| Canada |
| United States |
| Austria |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| Switzerland |
| 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
|
| As an event driven study, the subjects will continue on treatment until the study is stopped 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 Follow-up Visit approximately 30 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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