| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Atrial fibrillation (AF) is one cause of stroke. Stroke rate is increased in patients with atrial high rate episodes (AHRE, an early stage of AF) as well, even if stroke rates are lower when compared to stroke rates in patients with diagnosed AF.
Prevention of stroke, systemic embolism or cardiovascular death in patients with AHRE but without diagnosed atrial fibrillation (AF) and in addition at least two stroke risk factors by intake of NOACs shall be investigated. |
| Il tasso di ictus è aumentato nei pazienti con episodi atriale ad alta frequenza, anche se i tassi di ictus sono più bassi rispetto ai tassi di ictus nei pazienti con fibrillazione atriale diagnosticata. La sperimentazione indaga la prevenzione di ictus, l’embolia sistemica o morte cardiovascolare nei pazienti con AHRE in assenza di una diagnosi di fibrillazione atriale e con almeno due fattori di rischio di ictus attraverso la somministrazione dei NOAC. |
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| E.1.1.1 | Medical condition in easily understood language |
| AF is a common type of heart rhythm disorder. It carries the risk of increased clotting of blood particles which can occlude blood vessels. AHRE are atrial tachyarrhythmia episodes, a pre-stage of AF. |
| La fibrillazione atriale è una forma diffusa del disturbo del ritmo cardiaco.È associata al rischio di un’aumentata coagulazione di particelle sanguigne che possono occludere i vasi sanguigni |
|
| 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 | 23.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003656 |
| E.1.2 | Term | Atrial arrhythmia |
| E.1.2 | System Organ Class | 100000004849 |
|
| 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 |
| To demonstrate that oral anticoagulation with the NOAC edoxaban is superior to current therapy (antiplatelet therapy or no therapy depending on cardio-vascular risk) to prevent stroke, systemic embolism, or cardiovascular death in patients with AHRE but without overt AF and at least two stroke risk factors leading to a modified CHA2DS2VASc score of 2 or more. |
| Dimostrare che l'anticoagulazione orale con il NOAC edoxaban è superiore all'attuale terapia (terapia antipiastrinica o nessuna terapia a seconda del rischio cardiovascolare) nel prevenire l'ictus, l'embolia sistemica o la morte cardiovascolare in pazienti con AHRE ma senza FA evidente e almeno due fattori di rischio di ictus portando a un punteggio CHA 2 DS 2 VASc almeno pari a 2. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Pacemaker, defibrillator or insertable cardiac monitor implanted for any reason with feature of detection of AHRE, implanted at least 2 months prior to randomisation.
- AHRE detection feature activated for adequate detection of AHRE
- AHRE (= 170 bpm atrial rate and = 6 min duration) documented by the implanted device.
Any AHRE episode recorded is potentially eligible, but AHRE episodes detected in the first 2 months after implantation of a new device involving placement or repositioning of atrial electrodes are not eligible.
AHRE episodes recorded in the first two months after a simple "box change" operation, i.e. exchange of a pacemaker or defibrillator device without exchange or repositioning of atrial electrodes, are eligible.
- Age = 65 years
- In addition, at least one of the following cardiovascular conditions leading to a modified CHA2DS2VASc score of 2 or more: Age = 75 years, heart failure (clinically overt or LVEF < 45%), arterial hypertension (chronic treatment for hypertension, estimated need for continuous antihypertensive therapy or resting blood pressure > 145/90 mmHg), diabetes mellitus, prior stroke or transient ischemic attack (TIA), vascular disease (previous myocardial infarction, peripheral, carotid/cerebral, or aortic plaques on transesophageal echocardiogram [TEE]).
- Provision of signed informed consent |
- Pacemaker , defibrillatore o monitor cardiaco impiantabile per qualsiasi motivo con funzione di rilevazione di AHRE, impiantato almeno 2 mesi della randomizzazione
- Funzione di rilevazione di AHRE attivata per l'adeguata rilevazione di AHRE.
- AHRE (frequenza atriale =170 bpm e durata =6 min) documentato attraverso il dispositivo impiantato tramite Età =65 anni
- Inoltre, almeno una delle seguenti malattie cardiovascolari che determinano un punteggio CHA2DS2VASc modificato almeno pari a 2:
* Età =75 anni,
* insufficienza cardiaca (evidente clinicamente o LVEF <45%),
* ipertensione arteriosa (trattamento cronico per l'ipertensione, necessità stimata di terapia antipertensiva continua o pressione arteriosa a riposo >145/90 mmHg),
* diabete mellito,
* ictus o attacco ischemico transitorio (TIA) precedente,
* malattia vascolare (infarto del miocardio pregresso, placche periferiche, carotidee/cerebrali o aortiche all'ecocardiogramma transesofageo [TEE ]).
- Consenso informato firmato |
|
| E.4 | Principal exclusion criteria |
- Any disease that limits life expectancy to less than 1 year.
- Participation in another controlled clinical trial, either within the past two months or still ongoing.
- Previous participation in the present trial NOAH - AFNET 6.
- Drug abuse or clinically manifest alcohol abuse.
- Any history of overt AF or atrial flutter.
- Indication for oral anticoagulation (e.g. deep venous thrombosis).
- Contraindication for oral anticoagulation in general.
- Contraindication for edoxaban as stated in the current SmPC.
-Indication for long-term antiplatelet therapy other than acetylsalicylic acid or a need for treatment with any antiplatelet agent in addition to edoxaban, especially dual antiplatelet therapy (DAPT). Patients with a transient requirement for DAPT (e.g. after receiving a stent) will be eligible when the need for DAPT is no longer present.
- Acute coronary syndrome, coronary revascularisation (PCI or bypass surgery), or overt stroke within 30 days prior to randomisation.
- End stage renal disease (creatinine clearance (CrCl) < 15 ml/min as calculated by the Cockcroft-Gault method)
Legal exclusion criterion (applicable in countries where legally required)
- All persons exempt from participation in a clinical trial by law. |
- Ogni malattia che riduce l’aspettativa di vita a meno di un anno.
- Partecipazione ad un altro studio clinico controllato condotto negli ultimi due mesi oppure ancora in corso.
- Precedente partecipazione al presente studio NOAH - AFNET 6
- Abuso di stupefacente o abuso di alcol clinicamente evidente
- Pazienti con storia clinica di fibrillazione atriale o flutter atriale.
- Indicazione per coagulanti orali (per esempio trombosi venosa profonda).
- Controindicazione generale per anticoagulanti orali.
- Controindicazione per edoxaban come descritto nell’attuale RCP.
- Indicazione per una terapia a lungo termine con antiaggreganti piastrinici diversi dall‘acido acetilsalicilico, o pazienti con evidente necessità di terapia con qualsiasi agente antipiastrinico oltre a edoxaban specialmente la doppia terapia antiaggreganti (DTA). Pazienti con una necessità transitoria di DTA (per esempio dopo aver ricevuto uno stent) saranno eleggibili appena la necessità per DTA non sarà più presente.
- Sindrome coronarica acute, rivascolarizzazione coronarica (angioplastica coronarica o bypass) oppure ictus palese manifestatosi entro 30 giorni prima della randomizzazione.
- Malattia renale allo stadio terminale (creatinine clearance (CrCl) < 15 ml/min calcolato con il metodo Cockroft-Gault).
- Criterio di esclusione legale (applicabile in paesi dove richiesto dalla legge) - Tutte le persone esentate per legge dalla partecipazione a una sperimentazione clinica. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Time from randomisation to the first occurrence of stroke, systemic embolism, or cardiovascular death. A detailed definition of these outcome events is provided in Appendix III of the study protocol. |
| Tempo dalla randomizzazione alla prima comparsa di ictus, embolia sistemica o morte cardiovascolare. Una definizione dettagliata degli endpoint primari si trova nell‘appendice III allegato al protocollo di studio. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Evaluation of stroke, systemic embolism, or cardiovascular death by CRO: within 24 hours after SAE reporting by the investigator.
Evaluation of stroke, systemic embolism, or cardiovascular death by an Critical Event Committee (CEC) during the course of the trial on a regular basis (monthly). |
Evaluation of stroke, systemic embolism, or cardiovascular death by CRO: within 24 hours after SAE reporting by the investigator.
Evaluation of stroke, systemic embolism, or cardiovascular death by an Critical Event Committee (CEC) during the course of the trial on a regular basis (monthly). |
|
| E.5.2 | Secondary end point(s) |
1. components of the primary outcome,
2. major adverse cardiac events (MACEs: cardiovascular death, myocardial infarction, acute coronary syndrome (ACS), PCI, CABG)
3. stroke or systemic arterial embolism
4. all-cause death,
5. major bleeding events according to the International Society on Thrombosis and Haemostasis (ISTH) definitions,
6. quality of life changes at 12 and 24 months compared to baseline (assessed by EQ-5D including its visual-analogue scale and by the Karnofsky scale),
7. patient satisfaction at 12 and 24 months compared to baseline (assessed by modified EHRA score and PACT-Q))
8. cost effectiveness and health resource utilisation estimated by quantification of relevant events, interventions, nights spent in hospital and cardiovascular therapies,
9. changes of autonomy status only in patients with stroke during study participation, potentially assessed at each clinical follow-up visit by modified Rankin scale; a maximum of 2 subsequent assessments in follow-up per patient with stroke should be performed,
10. cognitive function (MoCA) at 12 and 24 months compared to baseline |
1. components of the primary outcome,
2. Eventi Avversi Cardiaci Maggiori (MACE): morte cardiovascolare, infarto miocardico, sindrome coronarica acuta (SCA), PCI, CABG
3. ictus o embolismo sistemico
4. Morte da tutte le cause,
5. Eventi di sanguinamento maggiore secondo le definizioni dell'ISTH,
6. Variazioni della qualità della vita a 12 e 24 mesi rispetto al basale,
7. Soddisfazione dei pazienti a 12 e 24 mesi rispetto al basale
8. Rapporto costo-efficacia e utilizzo di risorse sanitarie,
9. Variazioni dell'anatomia del paziente a 12 e 24 mesi rispetto al basale, incluse conseguenze croniche dell'ictus (afasia, emianopsia ("ictus leggero")),
10. Funzione cognitiva a 12 e 24 mesi rispetto al basale |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluation of 1., 2., 3. by CRO: within 24 hours after SAE reporting by the investigator.
Evaluation of 1., 2., 3. by an Critical Event Committee (CEC) during the course of the trial on a regular basis (monthly).
Evaluation of 4., 5., 7. by Investiagtors at month 12 and 24 after randomisation.
Evaluation of 4., 5., 6., 7. by study statistician after the end of the trial. |
Evaluation of 1., 2., 3., 4., 5. by
CRO: within 24 hours after SAE reporting by the investigator.Evaluation of 1., 2., 3., 4., 5. by an Critical Event Committee (CEC) during the course of the trial on a regular basis (monthly).Evaluation of 6., 7., 9. by Investiagtors at month 12 and 24 after randomisation. Evaluation of 6., 7., 8., 9. by study statistician after the end of the trial. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 220 |
| 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 |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 62 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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