Clinical Trials Register

Summary
EudraCT Number:	2016-003930-26
Sponsor's Protocol Code Number:	DU176B-C-U4001
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-04-10
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2016-003930-26

A.3

Full title of the trial

Edoxaban Versus Standard of Care and Their Effects on Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve Implantation – In Atrial Fibrillation. ENVISAGE TAVI-AF

Edoxaban vs. el tratamiento estándar y sus efectos en los resultados clínicos de pacientes que se han sometido a una cirugía de implante de válvula aórtica transcatéter - en fibrilación auricular

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Edoxaban Treatment Versus VKA in patients with AF undergoing TAVI Procedure in Atrial Fibrillation.

Tratamiento con Edoxaban vs. tratamiento con antagonistas de la Vitamina K en pacientes que se han sometido a una cirugía de implante de válvula aórtica transcatéter en fibrilación auricular

A.3.2

Name or abbreviated title of the trial where available

ENVISAGE TAVI-AF

A.4.1

Sponsor's protocol code number

DU176B-C-U4001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Daiichi Sankyo Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Daiichi Sankyo Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Daiichi Sankyo Inc.
B.5.2	Functional name of contact point	Marlen Casabona-Rojas
B.5.3	Address:
B.5.3.1	Street Address	2 Hilton Court
B.5.3.2	Town/ city	Parsippany,
B.5.3.3	Post code	NJ 07054
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 973 944 2367
B.5.5	Fax number	+1 973 944 2680
B.5.6	E-mail	mcasabona-ro@dsi.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Lixiana 60 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Daiichi Sankyo Europe GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	edoxaban
D.3.2	Product code	DU-176b
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	edoxaban
D.3.9.1	CAS number	480449-70-5
D.3.9.3	Other descriptive name	EDOXABAN
D.3.9.4	EV Substance Code	SUB32701
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Lixiana 30 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Daiichi Sankyo Europe GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	edoxaban
D.3.2	Product code	DU-176b
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	edoxaban
D.3.9.1	CAS number	480449-70-5
D.3.9.3	Other descriptive name	EDOXABAN
D.3.9.4	EV Substance Code	SUB32701
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Lixiana 15 mg film-coated tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Daiichi Sankyo Europe GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	edoxaban
D.3.2	Product code	DU-176b
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	edoxaban
D.3.9.1	CAS number	480449-70-5
D.3.9.3	Other descriptive name	EDOXABAN
D.3.9.4	EV Substance Code	SUB32701
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	acenocumarol
D.3.2	Product code	vitamin K antagonist (VKA)
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ACENOCOUMAROL
D.3.9.1	CAS number	152-72-7
D.3.9.4	EV Substance Code	SUB05211MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1 to 4
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 5
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	warfarin
D.3.2	Product code	vitamin K antagonist (VKA)
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	warfarin sodium
D.3.9.1	CAS number	CAS 129-06-6
D.3.9.3	Other descriptive name	WARFARIN SODIUM
D.3.9.4	EV Substance Code	SUB05128MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1 to 10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

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)

Pacientes con fibrilación auricular (FA) e indicación de anticoagulación oral crónica (AOC) después de un implante de válvula aórtica transcatéter (IVAT)

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)

Pacientes con fibrilación auricular después de un implante de válvula aórtica transcatéter (procedimiento por catéter donde una válvula es colocada en la ubicación de la válvula antigua y estrechada)

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	19.1
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

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).

• Evaluar el efecto de Edoxaban en comparación con antagonistas de la vitamina K (AVK) en acontecimientos clínicos adversos netos (net adverse clinical events, NACE), es decir, el compuesto de muerte por cualquier causa, el infarto de miocardio (IM), el accidente cerebrovascular isquémico, la tromboembolia sistémica (SEE), la trombosis valvular y el sangrado significativo (definición de la Sociedad Internacional de Trombosis y Hemostasia [International Society on Thrombosis and Haemostasis, ISTH]).
• Evaluar el efecto de Edoxaban en comparación con AVK en sangrados significativos (definición de la 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
To compare Edoxaban with VKA with regards below safety endpoints:
•Major bleeding (defined by TIMI [major & minor], BARC 3 or 5, GUSTO [moderate & severe]
•Major & Clinically Relevant Non-Major (CRNM) bleeding (defined by ISTH, TIMI, BARC 2, 3 or 5, GUSTO)
•Clinically Relevant Non-Major bleeding (defined by ISTH, TIMI, BARC 2, GUSTO)
•Intracranial hemorrhage, Life-threatening bleeding, Fatal major bleeding (ISTH definition)
For full list, refer to Protocol

Comparar Edoxaban con AVK con respecto a los siguientes criterios de valoración de eficacia:
•NACE definidos como el compuesto de muerte por cualquier causa, IM, accidente cerebrovascular isquémico, SEE, trombosis valvular y sangrado significativo y menor, según las definiciones de TIMI
•NACE definidos como el compuesto de muerte por cualquier causa, IM, accidente cerebrovascular isquémico, SEE, trombosis valvular y sangrado significativo (definición 3ó5 BARC)
•NACE definidos como el compuesto de muerte por cualquier causa, IM, accidente cerebrovascular isquémico, SEE, trombosis valvular y sangrado significativo y moderado (definición de GUSTO)
Comparar Edoxaban con AVK respecto a los siguientes criterios de valoración de seguridad:
•Sangrado significativo (definido según TIMI [significativo y menor], BARC 3ó5, GUSTO [moderado y grave])
•Sangrado significativo y no significativo clínicamente relevante
Consulte el protocolo para la revision de la lista completa

E.2.3

Trial contains a sub-study

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 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 (> 30 seconds documented by ECG recording)
3. Provision of signed informed consent
4. Age ≥18 years

Los pacientes deben cumplir todos los siguientes criterios para que se les incluya en el estudio:
1. IVAT transfemoral exitoso (solo se pueden utilizar otras vías de acceso si se convierten en tratamiento estándar con un resultado superior comprobado y después de la aprobación por escrito del Comité Ejecutivo de este estudio) con cualquier dispositivo aprobado/comercializado; éxito se define como:
a.Ubicación correcta de una sola válvula cardíaca prostética en el lugar anatómico adecuado
b.Presencia de las 3 afecciones posteriores a un IVAT
i.Gradiente promedio de la válvula aórtica <20 mm Hg
ii.Velocidad transvalvular pico <3,0 m/s
iii.Insuficiencia de la válvula aórtica de 2 o menos
c.Ningún accidente cerebrovascular evidente
d.Ningún sangrado no controlado al momento de la aleatorización
2.Indicación de AOC crónicos
a.Fibrilación auricular (FA) documentada preexistente
b.Aparición reciente de FA (>30 segundos, documentada por registro ECG)
3.Entrega de consentimiento informado firmado
4.Edad ≥18 años

E.4

Principal exclusion criteria

1. History of life-threatening or major bleeding event ≥ BARC 3b definitions within the last year
2. 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 3 months prior to randomization, malignancy at high risk of bleeding, recent unresolved brain or spinal injury, spinal or ophthalmic surgery (within the last 3 months prior to randomization), any intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or major intraspinal or intracerebral vascular abnormalities.
3. Other known bleeding diatheses
4. Serious unresolved periprocedural complications
5. Hypersensitivity or contraindications to Edoxaban, VKA, 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) within 1 month prior to 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. Antecedentes de sangrado significativo o potencialmente mortal ≥ BARC 3b en el año anterior
2. Otras afecciones con alto riesgo de sangrado
Esto puede incluir, entre otros: úlcera péptica activa con sangrado gastrointestinal (GI) superior en los últimos 3 meses antes de la aleatorización, neoplasia maligna con alto riesgo de sangrado, lesión cerebral o de la columna vertebral reciente no resuelta, cirugía de la columna vertebral u oftalmológica reciente (en los últimos 3 meses antes de la aleatorización), cualquier hemorragia intracraneal, várices esofágicas conocidas o presuntas, malformaciones arteriovenosas, aneurismas vasculares, o anomalías vasculares intraespinales o intracerebrales significativas.
3. Otra diátesis hemorrágica conocida
En relación con el procedimiento
4. Complicaciones graves no resueltas en relación con el procedimiento
En relación con el medicamento
5. Hipersensibilidad o contraindicación a Edoxaban, AVK, AAS, y/o antagonistas de P2Y12
6. Tratamiento concomitante con otros agentes antitrombóticos (AAS) >100 mg/día, terapia fibrinolítica o uso crónico (>4 días/semana) de fármacos antiinflamatorios no esteroideos (nonsteroidal anti-inflammatory drugs, NSAID)
7. Necesidad de recibir terapia antiplaquetaria dual (DAPT) en el plazo de 1 mes antes de la aleatorización
8. Tratamiento con otros fármacos o dispositivos en investigación en los 30 días anteriores a la al reclutamiento o uso planificado de fármacos o dispositivos en investigación durante el estudio

Para lista completa de criterios de exclusion: Consulte el Protocolo, sección 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)

Criterio de valoración principal de la eficacia:
•NACE, es decir, el compuesto de muerte por cualquier causa, IM, accidente cerebrovascular isquémico, SEE, trombosis valvular y sangrado significativo (definición de la ISTH)

Criterio de valoración principal de la seguridad:
•Sangrado significativo (definición de la ISTH)

E.5.1.1

Timepoint(s) of evaluation of this end point

First occurrence of any component.

Primera aparición de cualquier componente.

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)
• 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
• Major bleeding (defined by TIMI [major and minor], BARC 3 or 5, GUSTO [moderate and severe])
• Major and Clinically Relevant Non-Major (CRNM) bleeding (defined by ISTH, TIMI, BARC 2, 3 or 5, GUSTO)
• Clinically Relevant Non-Major bleeding (defined by ISTH, TIMI, BARC 2, GUSTO)
• Minor Bleeding (defined by ISTH, TIMI [minimal], BARC 1 [non-actionable], GUSTO)
• Any bleeding
• Intracranial hemorrhage
• Life-threatening bleeding
• Fatal major bleeding (ISTH 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

Comparar Edoxaban con AVK con respecto con los siguientes criterios de valoración de eficacia:
• NACE definidos como el compuesto de muerte por cualquier causa, IM, accidente cerebrovascular isquémico, SEE, trombosis valvular y sangrado significativo y menor, según las definiciones de trombosis en infarto de miocardio (TIMI)
• NACE definidos como el compuesto de muerte por cualquier causa, IM, accidente cerebrovascular isquémico, SEE, trombosis valvular y sangrado significativo (definición 3 o 5 del Consorcio de Investigación Académica en Sangrado [Bleeding Academic Research Consortium, BARC])
• NACE definidos como el compuesto de muerte por cualquier causa, IM, accidente cerebrovascular isquémico, SEE, trombosis valvular y sangrado significativo y moderado (definición de Utilización global de estreptocinasa y activador tisular del plasminógeno para arterias ocluidas [Global Utilization of Streptokinase And Tissue Plasminogen Activator For Occluded arteries, GUSTO])
• Accidente cerebrovascular (isquémico, hemorrágico, o no determinado)
• Accidente cerebrovascular (isquémico)
• Accidente cerebrovascular (hemorrágico)
• Accidente cerebrovascular (no determinado)
• Accidente cerebrovascular mortal (isquémico, hemorrágico, o no determinado)
• Accidente cerebrovascular no mortal (isquémico, hemorrágico, o no determinado)
• SEE
• Infarto de miocardio
• Trombosis valvular
Comparar Edoxaban con AVK con respecto con los siguientes criterios de valoración de seguridad:
• Sangrado significativo (definido según TIMI [significativo y menor], BARC 3 o 5, GUSTO [moderado y grave])
• Sangrado significativo y no significativo clínicamente relevante (Clinically Relevant Non-Major, CRNM) (definido según ISTH, TIMI, BARC 2, 3 o 5, GUSTO)
• Sangrado no significativo clínicamente relevante (definido según ISTH, TIMI, BARC 2, GUSTO)
• Sangrado menor (definido según ISTH, TIMI [mínimo], BARC 1 [mínimo], GUSTO)
• Cualquier sangrado
• Hemorragia intracraneal
• Sangrado potencialmente mortal
• Sangrado significativo mortal (definición de la ISTH)
• Sangrado significativo no mortal (definición de la ISTH)
• Mortalidad por cualquier causa
• Mortalidad cardiovascular
• Parámetros de seguridad como acontecimientos adversos (graves), parámetros de laboratorio, ECG y signos vitales

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.

Todos los criterios de valoración clínicos se analizarán como el tiempo hasta la primera aparición de cualquiera de sus componentes.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

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

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Antagonista de la vitamina K

Vitamin K Antagonist

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

Netherlands

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 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.

Como estudio dirigido por eventos, los sujetos continuarán el tratamiento hasta que el estudio se detenga debido a que se alcancen los 320 eventos adjudicados (aproximadamente 2500 años-sujetos) , o discontinúen permanentemente del estudio (por cualquier razón). Para los últimos pacientes reclutados , la duración mínima del tratamiento será de al menos 6 meses. Los sujetos también tendrán una visita de seguimiento aproximadamente 30 días después de la visita de fin de tratamiento.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

280

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1120

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

110

F.4.2

For a multinational trial

F.4.2.1

In the EEA

921

F.4.2.2

In the whole clinical trial

1400

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

The subjects on Edoxaban will use the Sponsor provided transition kit to transition from Edoxaban to a VKA. The choice of VKA will be made by the Investigator in consultation with the subject’s personal physician and per local guidelines

Los sujetos de Edoxaban usarán el kit de transición proporcionado por el Promotor para la transición de Edoxaban a VKA. La elección de VKA será hecha por el Investigador en conjunto con el médico de cabecera del sujeto y por las guías locales.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-06-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-05-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-02-28

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials