| 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 |
| Soggetti sottoposti ad ablazione transcatetere della fibrillazione atriale non valvolare |
|
| E.1.1.1 | Medical condition in easily understood language |
Subjects undergoing catheter ablation of non-valvular
atrial fibrillation |
| Soggetti sottoposti ad ablazione transcatetere della fibrillazione atriale non valvolare |
|
| 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. |
Obiettivo primario di efficacia:
Confrontare in modo descrittivo l¿incidenza del composito di morte per ogni causa, ictus (ischemico, emorragico o indeterminato) ed emorragia maggiore (definita secondo i criteri della International Society on Thrombosis and Hemostasis [ISTH] nel gruppo di trattamento con edoxaban rispetto al gruppo di trattamento con antagonisti della vitamina K (AVK) in soggetti sottoposti ad ablazione transcatetere della fibrillazione atriale (FA) nel periodo compreso tra il termine dell¿intervento di ablazione fino al Giorno 90/fine del trattamento (EOT).
Obiettivo primario di sicurezza:
Confrontare in modo descrittivo l¿incidenza di emorragia maggiore (secondo i criteri ISTH) nel gruppo di trattamento con edoxaban rispetto al gruppo di trattamento con antagonisti della vitamina K (AVK) nel periodo compreso tra la data della prima somministrazione del farmaco in studio fino al Giorno 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 |
-Composito di morte per ogni causa, ictus (ischemico, emorragico o indeterminato, secondo una definizione alternativa [v. Prot. Sez. 7.4.2]) ed emorragia maggiore (criteri ISTH)
-Composito di ictus, eventi embolici sistemici (EES), mortalit¿ cardiovascolare (CV)
-Composito di ictus, EES e mortalit¿ per ogni causa
-Composito di ictus e attacco ischemico transitorio (TIA)
-Ictus
-EES
-TIA
-Ictus fatale
-Ictus non fatale
-Ictus disabilitante
-Ictus non disabilitante
-Emorragia maggiore [BARC] (grado pari o > 2)
-Emorr. maggiore ed emorr. non maggiore clinicamente rilevante (CRNM)
-Emorragia CRNM
-Emorragia minore
-Qualsiasi emorragia
-Emorr. intracranica (EIC)
-Emorr. potenzialmente fatale
-Emorr. maggiore fatale
-Emorr. maggiore non fatale
-Emorr. maggiore fatale (criteri TIMI, BARC [grado pari o > 2])
-Emorr. maggiore non fatale (criteri TIMI, BARC [grado pari o > 2])
-AE, SAE, parametri di laboratorio, ECG e parametri vitali
-HEOR
-Marker cardiaci e dell¿anticoagulazione |
|
| 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.
|
1. Soggetti di entrambi i sessi, di età minima di 18 anni, con anamnesi documentata di FA non valvolare parossistica (della durata o pari a 7 giorni), persistente (della durata > 7 giorni ma < o pari a 12 mesi) o persistente di lunga durata (> 12 mesi). La durata della FA può essere confermata da qualsiasi esame elettrocardiografico o dalla registrazione nella cartella clinica del soggetto (ad es., cartella clinica, scheda di dimissione ospedaliera).
2. Il soggetto è eleggibile e in attesa di intervento programmato di ablazione transcatetere a radiofrequenza (RF) o con crioablazione (sono inclusi il primo intervento e interventi ripetuti).
3. Informativa e consenso informato firmati. |
|
| 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 (LAA), left atrium (LA), left ventricle (LV), 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 (CABG) 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 (spontaneous or traumatic), or spontaneous intraocular, spinal, retroperitoneal, or intra-articular bleeding; overt gastrointestinal (GI) 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 (within 3 months prior to randomization) of a bioprosthetic heart valve, with or without AF.
7. Subjects with a history of LAA occlusion/exclusion (either by surgery or by a procedure).
8. Subjects with any contraindication for edoxaban, VKA, low molecular weight heparin (LMWH), 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 (UFH), low molecular weight heparins (LMWH; enoxaparin, dalteparin, etc.), 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 (acetylsalicylic acid [ASA]) (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 (use of NSAIDs via other routes is not restricted).
11. Subjects with active liver disease or persistent (confirmed by repeat assessments at least a week apart) elevation of liver enzymes/bilirubin:
- Alanine transaminase (ALT) or aspartate transaminase (AST) =2 times the upper limit of normal (ULN)
- 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 (calculated creatinine clearance [CrCL] <15 mL/min).
13. Subjects with hemoglobin <10 g/dL or platelet count <100,000 cells/µL or white blood cell (WBC) 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 investigational therapy during the study period).
16. Previous randomization in this study.
17. Female subjects of childbearing potential without using highly effective contraception (female of childbearing potential is defined as one who has not been postmenopausal for at least one year, or has not been surgically sterilised, or has not had a hysterectomy at least three months prior to the start of this study). 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.
Please refer to the Protocol for Exclusion Criteria No 19-23 due to the limit of characters available in the system. |
1.FA ritenuta essere di natura transitoria o reversibile (come in caso di miocardite, post-intervento, squilibri ionici, tireotossicosi, polmonite, anemia severa, ecc.).
2.Soggetti post-ictus o che hanno accusato un evento
tromboembolico sistemico nei6mesi precedenti alla
random.
3.Soggetti con presenza di trombo nell’auricola atriale sinistra(AAS),atrio sinistro(AS),ventricolo sinistro(VS) o aorta oppure con presenza di massa intracardiaca.
4.Soggetti colpiti da infarto miocardico(IM)nei2mesi
precedenti alla randomizzazione o sottoposti a intervento di bypass aortocoronarico(BPAC)nei3mesi precedenti alla random.
5.Soggetti con segni di emorragia, anamnesi di emorragia clinicamente significativa secondo i criteri ISTH o patologie associate a rischio elevato di emorragia, come anamnesi remota di emorragia intracranica (spontanea o traumatica), emorragia spontanea intraoculare, spinale, retroperitoneale o intrarticolare; emorragia gastrointestinale(GI) manifesta o ulcera attiva nell'anno precedente; recente trauma severo, chirurgia maggiore o biopsia profonda d’organo; endocardite infettiva in atto; ipertensione non controllata (pressione arteriosa [PA] superiore a 170/100 mmHg); o malattia emorragica comprese le patologie emorragiche o della coagulazione note o sospette, ereditarie o acquisite, negli ultimi12mesi precedenti alla random.
6.Soggetti portatori di valvole cardiache meccaniche, soggetti affetti da stenosi mitralica da moderata a severa e soggetti sottoposti di recente(nei3mesi precedenti alla randomizzazione)all’impianto di valvola cardiaca biologica (bioprotesi)con o senza FA.
7.Soggetti con anamnesi di occlusione/esclusione dell’AAS(sia mediante intervento chirurgico o altro intervento).
8.Soggetti che presentano controindicazioni alla terapia con edoxaban, AVK, LMWH o eparina comprese allergie note, ipersensibilità o intolleranza a qualsiasi componente di questi farmaci o ai suoi eccipienti.
9.Soggetti attualmente in doppia terapia antipiastrinica (DAPT, ossia aspirina e antagonista di P2Y12) o nei quali si prevede di avviare la DAPT durante lo studio.
10.Eparina non frazionata(UFH), eparine a basso peso
molecolare(LMWH; enoxaparina, dalteparina, ecc.), derivati dell'eparina(fondaparinux, ecc.) e anticoagulanti orali(warfarin, dabigatran etexilato, rivaroxaban, apixaban ecc.) non devono essere somministrati in concomitanza al farmaco in studio. È vietato qualsiasi “bridging” con le LMWH in prossimità della procedura di ablazione transcatetere. Durante la procedura di ablazione transcatetere, verrà utilizzata UFH secondo lo standard di cura per ottenere un ACT da 300 a 400 sec. Soggetti che necessitano di uso cronico di medicinali che influenzano l’emostasi, come aspirina (acido acetilsalicilico[ASA]) ad alti dosaggi (è ammesso l’uso di ASA fino a 100 mg/die) o l’assunzione orale o parenterale cronica di farmaci antinfiammatori non steroidei (FANS) diversi
dall’aspirina per=4giorni/settimana(l’uso di FANS
somministrati per altre vie non è limitato).
11.Soggetti affetti da patologia epatica in atto o innalzamento persistente (confermato da ripetute analisi effettuate almeno a una settimana di intervallo) degli enzimi epatici/bilirubina:
-Alanina aminotransferasi(ALT)e aspartato
aminotransferasi (AST)=2 volte il limite superiore della
norma (ULN)
-Bilirubina totale (TBL)=1,5 volte l’ULN(possono essere inclusi nello studio i soggetti con valori elevati di TBL
causati da nota sindrome di Gilbert)
-Patologia epatica associata a coagulopatia e rischio di
emorragia clinicamente rilevante.
12.Soggetti con insufficienza renale (clearance della creatinina [CrCL] calcolata<15 mL/min).
13.Soggetti con valori di emoglobina<10 g/dL o conta
piastrinica<100.000 cellule/µL o conta leucocitaria(WBC)<3.000 cellule/µL.
14.Soggetti che devono essere sottoposti durante il periodo dello studio a interventi/accertamenti invasivi d’elezione (diversi dall’endoscopia), diagnostici o terapeutici, che possono comportare episodi emorragici.
15.Partecipazione ad altri studi interventistici (soggetti che hanno ricevuto altri farmaci o dispositivi sperimentali nei30giorni precedenti alla randomizzazione, o per i quali è previsto il trattamento con una terapia sperimentale durante il periodo dello studio).
16.Precedente randomizzazione a questo studio.
17.Soggetti di sesso femminile in età fertile che non adottano metodi contraccettivi altamente efficaci (per donne in età fertile si intendono le donne non in postmenopausa da almeno1anno o non sottoposte a sterilizzazione chirurgica o a sterectomia perlomeno nei tre mesi precedenti all’inizio di questo studio). Le donne che assumono contraccettivi orali devono essere in terapia da almeno3mesi. I metodi contraccettivi adeguati comprendono: [si prega di fare riferimento al protocollo e al punto E.4.EN per i criteri di esclusione n. 17-23 a causa del limite di caratteri disponibile nel sistema]. |
|
| 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 | 8 |
| 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 | 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 |
| Belgium |
| Canada |
| Czechia |
| 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 | 2 |
| 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 | 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 |
Print
