Clinical Trials Register

Summary
EudraCT Number:	2021-003927-13
Sponsor's Protocol Code Number:	REAC-TAVI2
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-10-18
Trial 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

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2021-003927-13

A.3

Full title of the trial

Single antiplatelet therapy with Ticagrelor vs Aspirin after Transcatheter Aortic Valve Implantation: multicenter randomized clinical trial. REAC TAVI 2

Tratamiento antiplaquetario único con ticagrelor frente a aspirina después del implante percutáneo de válvula aórtica: ensayo clínico aleatorizado multicéntrico. REAC TAVI 2

A.3.1

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

Single therapy after transcatheter aortic valve implantation

Terapia antiplaquetaria simple después de la implantación de válvula aórtica transcatéter

A.3.2

Name or abbreviated title of the trial where available

REAC-TAVI 2

A.4.1

Sponsor's protocol code number

REAC-TAVI2

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	Fundación Biomédica Galicia Sur
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Fundación Biomedica Galicia Sur
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Hospital Alvaro Cunqueiro
B.5.2	Functional name of contact point	Cardiovascular Research Unit
B.5.3	Address:
B.5.3.1	Street Address	Estrada Clara Campoamor Nº341
B.5.3.2	Town/ city	Vigo
B.5.3.3	Post code	36213
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34986825564
B.5.5	Fax number	+34986825564
B.5.6	E-mail	pablo.juan@iisgaliciasur.es

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	Ticagrelor 60 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Brilique
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	Ticagrelor 60mg
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	Ticagrelor
D.3.9.1	CAS number	274693-27-5
D.3.9.3	Other descriptive name	TICAGRELOR
D.3.9.4	EV Substance Code	SUB30898
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	120
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	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.2.1.1.1	Trade name	acetylsalicylic acid 100mg
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	acetylsalicylic acid
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	ACETYLSALICYLIC ACID
D.3.9.1	CAS number	50-78-2
D.3.9.3	Other descriptive name	ACETYLSALICYLIC ACID
D.3.9.4	EV Substance Code	SUB12730MIG
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	100
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

Symptomatic severe aortic stenosis

Estenosis aórtica severa sintomática

E.1.1.1

Medical condition in easily understood language

Narrowing of the aortic valve

Estrechamiento de la válvula aórtica

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	LLT
E.1.2	Classification code	10077017
E.1.2	Term	TAVI
E.1.2	System Organ Class	100000004865

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	10002918
E.1.2	Term	Aortic valve stenosis
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10002906
E.1.2	Term	Aortic stenosis
E.1.2	System Organ Class	10047065 - Vascular 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

The aim of this study is to compare two SAPT strategies: Aspirin 100mg once per day versus Ticagrelor 60 mg twice per day as antiplatelet treatment for the prevention of net adverse clinical events (NACE) following a successful TAVI

El objetivo de este estudio es comparar dos estrategias SAPT: Aspirina 100 mg una vez al día versus Ticagrelor 60 mg dos veces al día como tratamiento antiplaquetario para la prevención de eventos clínicos adversos netos (NACE) después de una TAVI exitosa.

E.2.2

Secondary objectives of the trial

•Key secondary efficacy endpoint: Subclinical valve thrombosis (SVT) detected by hypoattenuated leaflet thickening (HALT) and reduced leaflet motion(RLM) at 3 and 12 months after TAVI assessed by 4-dimensional computed tomography (4D-CT) imaging (performed only in pre-specified centers).
•Key secondary safety endpoint: Major bleeding (type 2, 3 and 5) at 12 months after TAVI according BARC (Bleeding Academic Research Consortium).
•Complementary secondary endpoints: Patient-oriented composite endpoints (POCE) at 12 months after TAVI (POCE is a composite of all-cause mortality,TIA/stroke, myocardial infarction, progressive angina leading to emergency evaluation, rehospitalization or new coronary angiography). Individual components of NACE at 12 months after TAVI

• Criterio de valoración secundario clave de la eficacia: trombosis valvular subclínica (TSV) detectada por engrosamiento de la valva hipoatenuada (HALT) y movimiento reducido de la valva (RLM) a los 3 y 12 meses después del TAVI evaluado por imágenes de tomografía computarizada de 4 dimensiones (4D-CT) (realizada solo en centros preespecificados).
• Criterio de valoración secundario clave de seguridad: Sangrado mayor (tipo 2, 3 y 5) a los 12 meses después del TAVI según BARC (Bleeding Academic Research Consortium).
• Criterios de valoración secundarios complementarios: Criterios de valoración combinados orientados al paciente (POCE) 12 meses después del TAVI (POCE es un compuesto de mortalidad por todas las causas, AIT / accidente cerebrovascular, infarto de miocardio, angina progresiva que conduce a una evaluación de emergencia, rehospitalización o nueva angiografía coronaria). Componentes individuales de NACE a los 12 meses después del TAVI

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Provisión de consentimiento informado antes de cualquier procedimiento específico del estudio.
2) Pacientes adultos (mayores de 18 años) con capacidad para comprender y aceptar la participación en el ensayo clínico.
3) Pacientes con EA degenerativa sintomática grave aceptados para TAVI con cualquiera de los dispositivos TAVI comercialmente aprobados después de la evaluación del Heart Team de cada centro, y con al menos una de las siguientes comorbilidades:
• Diabetes Mellitus, deben mantenerse los criterios diagnósticos actuales de la OMS para la diabetes: glucosa plasmática en ayunas ≥ 7,0 mmol / l (126 mg / dl) o glucosa plasmática a las 2 h ≥ 11,1 mmol / l (200 mg / dl), o en tratamiento con un hipoglucemiante oral o insulina
• Enfermedad arterial coronaria previa (STEMI, NSTEMI, angina estable u otras) documentada mediante pruebas de detección de isquemia invasivas o no invasivas o estudios de imágenes
• Enfermedad arterial periférica previa documentada mediante pruebas de detección de isquemia invasivas o no invasivas o estudios de imágenes.
4) TAVI exitoso realizado por cualquier acceso vascular.
5) Pacientes que no están participando en ningún otro ensayo clínico o estudio de investigación (registros permitidos).

E.4

Principal exclusion criteria

1) Patients under chronic oral anticoagulation for any specific pathology
2)Patients that cannot undergo a regimen of single antiplatelet therapy after TAVI
3) History of overt major bleeding or intracranial hemorrhage
4) Active pathological bleeding
5) History of ischemic stroke within the last 30 days prior TAVI
6) Patients with documented severe hepatic insufficiency
7) Known pregnancy, breast-feeding, or intend to become pregnant during the study period
8) Concomitant oral or intravenous therapy with potent inhibitors of cytochrome P450 3A (CYP3A) that cannot be suspended during the study. Section 13.1 Ticagrelor Overdose: any dose over the clinically intended dose.
9) Patients randomized in another clinical trial with an investigational product or device over the past 30 days
10) Patients who cannot attend follow-up visits scheduled in the study.
11) History of allergic reactions or intolerance to Ticagrelor orAspirin or any of the excipients

1) Pacientes en anticoagulación oral crónica por alguna patología específica
2) Pacientes que no pueden someterse a un régimen de terapia antiplaquetaria única después de TAVI
3) Historia de hemorragia mayor manifiesta o hemorragia intracraneal
4) Sangrado patológico activo
5) Historia de accidente cerebrovascular isquémico en los últimos 30 días previos al TAVI
6) Pacientes con insuficiencia hepática grave documentada
7) Embarazo conocido, lactancia o intención de quedar embarazada durante el período de estudio
8) Terapia oral o intravenosa concomitante con potentes inhibidores del citocromo P450 3A (CYP3A) que no se pueden suspender durante el estudio. Sección 13.1 Sobredosis de ticagrelor: cualquier dosis por encima de la dosis clínicamente prevista.
9) Pacientes aleatorizados en otro ensayo clínico con un producto o dispositivo en investigación durante los últimos 30 días
10) Pacientes que no pueden asistir a las visitas de seguimiento programadas en el estudio.
11) Historia de reacciones alérgicas o intolerancia a Ticagrelor o Aspirina o cualquiera de los excipientes

E.5 End points

E.5.1

Primary end point(s)

Incidence of NACE (All-cause mortality, Transient ischemic attack (TIA) or stroke, Myocardialinfarction, Progressive angina leading to emergency evaluation,rehospitalization or new coronary angiography, Valve thrombosis, Claudication, Acute limb ischemia leading to hospitalization, Any bleeding)

Incidencia de NACE (mortalidad por todas las causas, accidente isquémico transitorio (AIT) o accidente cerebrovascular, infarto de miocardio, angina progresiva que conduce a una evaluación de emergencia, rehospitalización o nueva angiografía coronaria, trombosis valvular, claudicación, isquemia aguda de las extremidades que conduce a la hospitalización, cualquier sangrado)

E.5.1.1

Timepoint(s) of evaluation of this end point

At 12 months after TAVI

A los 12 meses después de la TAVI

E.5.2

Secondary end point(s)

1) Subclinical valve thrombosis (SVT)

2) Major bleeding (type 2, 3 and 5) according BARC (Bleeding Academic Research Consortium).

3) Patient-oriented composite endpoints (POCE) after TAVI (POCE is a composite of all-cause mortality,TIA/stroke, myocardial infarction, progressive angina leading to emergency evaluation, rehospitalization or new coronary angiography)

1) Trombosis valvular subclinica

2) Sangrados mayores (tipo 2, 3 y 5) de acuerdo a la escala BARC (Bleeding Academic Research Consortium).

3) Criterios de valoración combinados orientados al paciente (POCE) después de la TAVI, (POCE es un compuesto de mortalidad por todas las causas, AIT / accidente cerebrovascular, infarto de miocardio, angina progresiva que conduce a una evaluación de emergencia, rehospitalización o nueva angiografía coronaria)

E.5.2.1

Timepoint(s) of evaluation of this end point

1) 180 ± 7 days and 365 ± 14 days

2) At 12 months after TAVI

3) At 12 months after TAVI

1) 180 ± 7 días y 365 ± 14 días

2) A los 12 meses después de la TAVI

3) A los 12 meses después de la TAVI

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

LVLS

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1196

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

1206

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1206

F.4.2.2

In the whole clinical trial

1206

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)

None

Niguno

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

2021-10-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-10-01

P. End of Trial
P.	End of Trial Status	Ongoing

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