Clinical Trials Register

Summary
EudraCT Number:	2016-004232-37
Sponsor's Protocol Code Number:	D5134C00003
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:	2017-12-01
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

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2016-004232-37

A.3

Full title of the trial

A Randomised, Double-Blind, Placebo-Controlled, International, Multicentre, Phase III Study to Investigate the Efficacy and Safety of Ticagrelor and ASA Compared with ASA in the Prevention of Stroke and Death in Patients with Acute Ischaemic Stroke or Transient Ischaemic Attack

Ensayo Fase III, aleatorizado, doble ciego, internacional, multicéntrico, controlado con placebo, para evaluar la eficacia y seguridad de ticagrelor y AAS, comparado con AAS en la prevención de ictus y muerte en pacientes con ictus isquémico agudo o accidente isquémico transitorio” (THALES)

A.3.1

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

Study to investigate if the study drug ticagrelor and ASA is more effective than Placebo (inactive tablet) and ASA in preventing new stroke events.

Ensayo para investigar si el medicamento del estudio ticagrelor y el AAS son más efectivos que el placebo (comprimido inactivo) y el AAS en la prevención nuevos eventos de ictus.

A.3.2

Name or abbreviated title of the trial where available

THALES

A.4.1

Sponsor's protocol code number

D5134C00003

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	AstraZeneca AB
B.1.3.4	Country	Sweden
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	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca Farmacéutica Spain, S.A.
B.5.2	Functional name of contact point	Unidad de Investigación Clínica
B.5.3	Address:
B.5.3.1	Street Address	C/ Serrano Galvache, 56; Parque Norte, Edificio Álamo
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28033
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034900200444
B.5.6	E-mail	informacionEECC-Spain@astrazeneca.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	Brilique
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB
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.3.4	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	Ticagrelor
D.3.9.1	CAS number	274693-27-5
D.3.9.2	Current sponsor code	AZD6140, AR-C126532XX
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	180
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Ischaemic stroke, transient ischaemic attack

Ictus isquémico o accidente isquémico transitorio

E.1.1.1

Medical condition in easily understood language

Stroke, transient ischaemic attack

Ictus, accidente isquémico transitorio

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	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10055221
E.1.2	Term	Ischemic stroke
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To demonstrate superior efficacy of ticagrelor and ASA compared with placebo and ASA in patients with acute ischaemic stroke (AIS) or TIA in the prevention of the composite of stroke and death at 30 days

Demostrar superioridad en eficacia de ticagrelor más AAS en comparación con el placebo más AAS para prevenir la combinación de ictus y muerte al cabo de 30 días en pacientes con IIA/AIT.

E.2.2

Secondary objectives of the trial

1. To demonstrate superior efficacy of ticagrelor and ASA compared with placebo and ASA in AIS/TIA patients in the prevention of ischaemic stroke at 30 days
2. To demonstrate superior efficacy of ticagrelor and ASA compared with placebo and ASA in AIS/TIA patients in reducing overall disability at 30 days

1. Demostrar superioridad en eficacia de ticagrelor más AAS en comparación con el placebo más AAS para prevenir el ictus isquémico al cabo de 30 días.
2.Demostrar superioridad en eficacia de ticagrelor más AAS en comparación con el placebo más AAS para reducir el grado de discapacidad general al cabo de 30 días en pacientes con IIA/AIT.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Provision of signed informed consent prior to any study-specific procedure
3.≥40 years of age
3.Acute onset of cerebral ischaemia due to
(a) AIS with NIHSS ≤5. AIS is defined as acute onset of neurological deficit attributed to focal brain ischaemia, and either of the following:
-Persistent signs or symptoms of the ischaemic event at the time of
randomisation, OR
-Acute ischaemic brain lesion documented before randomisation by computed tomography (CT) scan or magnetic resonance imaging (MRI) (diffusion-weighted imaging) and that could account for the clinical presentation
(b) High-risk TIA, defined as neurological deficit of acute onset attributed to focal ischaemia of the brain by history or examination with complete resolution of the deficit, and at least one of the following:
-ABCD2 score ≥6 and TIA symptoms not limited to isolated numbness, isolated visual changes, or isolated dizziness/vertigo
-Symptomatic intracranial arterial occlusive disease that could account for the clinical presentation, documented by transcranial Doppler or vascular imaging and defined as at least 50% narrowing in the diameter of the vessel lumen
-Internal carotid arterial occlusive disease that could account for the clinical presentation, documented by Doppler, ultrasound, or vascular imaging and defined as at least 50% narrowing in diameter of the vessel lumen
4. Randomisation occurring within 24 hours after onset of symptoms; for wake-up strokes (when the time of symptom onset is not known), within 24 hours from the time point at which the patient was reported to be in their normal condition
5. CT or MRI performed after symptom onset ruling out intracranial haemorrhage or
other pathology, such as vascular malformation, tumour, or abscess that according
to the Investigator could explain symptoms or contraindicate study treatment

1. Disposición del consentimiento informado firmado antes de cualquier procedimiento especifico del estudio.
2. > o = a 40 años de edad.
3. Inicio agudo de una isquemia cerebral debido a:
(a) IIA con NIHSS < o = 5. IIA se define como déficit neurológico de inicio agudo atribuido a una isquemia cerebral focal, y cualquiera de los siguientes:
- Signos y síntomas persistentes de los acontecimientos isquémicos en el momento de la aleatorización, O
- Lesión cerebral isquémica aguda documentada antes de la aleatorización mediante tomografía computarizada (TC), escáner o imagen por resonancia magnética (IRM) (imagen difusión-peso) y que puede explicar la presentación clínica.
(b) AIT de alto riesgo definido como déficit neurológico de inicio agudo atribuido a una isquemia focal del cerebro por su historial o una exploración con una resolución completa del déficit, y al menos uno de los siguientes:
- Puntuación ABCD2 > o = a 6 y síntomas de AIT no limitados a adormecimiento aislados, cambios visuales aislados, o mareo/vértigo aislado.
- Enfermedad oclusiva arterial intracraneal sintomática que podría explicar la presentación clínica, documentada por Doppler transcraneal o imagen vascular y definido al menos un 50% del estrechamiento en el diámetro de la luz de los vasos.
- Enfermedad oclusiva arterial de la carótida interna que podría explicar la presentación clínica, documentada por Doppler, ultrasonido, o imagen vascular y definido al menos un 50% del estrechamiento en el diámetro de la luz de los vasos
4. Aleatorización que se produce dentro de las 24 horas después del inicio de los síntomas; que desencadene el ictus (cuando se desconoce el momento en el que iniciaron los síntomas), dentro de las 24 horas desde el momento por el cual se notificó que el paciente se encontraba en una condición normal.
5. TC o IRM realizados después de la aparición de los síntomas que descarta una hemorragia intracraneal u otras patologías, como malformaciones vasculares, tumores, o abscesos de acuerdo al investigador podrían explicar los síntomas o contraindicar el tratamiento del estudio.

E.4

Principal exclusion criteria

1.Need for or an anticipated need for any of the following:
(a) Dual antiplatelet therapy with ASA and P2Y12 inhibitors (including patients with carotid artery stenting and percutaneous coronary intervention)
(b) Antiplatelets other than ASA (eg, GPIIb/IIIa inhibitors, clopidogrel, ticlopidine, prasugrel, dipyridamole, ozagrel, cilostazol, ticagrelor) and other antithrombotic agents with antiplatelet effects, including traditional/herbal medicine agents
(c) Anticoagulants (eg, warfarin, oral thrombin and factor Xa inhibitors, bivalirudin, hirudin, argatroban, fondaparinux, or unfractionated heparin and long-term treatment with low-molecular weight heparins). Short-term treatment (≤7 days) with low-dose low-molecular weight heparin may be used in immobilised patients at the discretion of the Investigator
2.Any history of atrial fibrillation/flutter, ventricular aneurysm, or suspicion of other cardioembolic pathology for TIA or stroke
3.Patients who should receive or have received any intravenous or intra-arterial thrombolysis or mechanical thrombectomy within 24 hours prior to randomisation
4.Planned carotid endarterectomy that requires halting investigational product within 3 days of randomisation or is expected to require unblinding of investigational product (planned carotid endarterectomy is in itself not an exclusion criterion)
5.History of previous intracranial haemorrhage at any time (asymptomatic microbleeds do not qualify), gastrointestinal haemorrhage within the past 6 months, or major surgery within 30 days
6.Patients considered to be at risk of bradycardic events (eg, known sick sinus syndrome or second- or third-degree atrioventricular block) unless already treated with a permanent pacemaker
7.Inability of the patient to understand and/or comply with study procedures and/or follow-up, in the opinion of the Investigator
8.Known hypersensitivity to ticagrelor or ASA
9.Need for or an anticipated need for oral or intravenous therapy with any of the following:
(a) Strong cytochrome P450 3A (CYP3A4) inhibitors (eg, ketoconazole, clarithromycin [but not erythromycin or azithromycin], nefazadone, ritonavir, atazanavir) that cannot be stopped for the course of the study
(b) Long-term (>7 days) non-steroidal anti-inflammatory drugs
10.Known bleeding diathesis or coagulation disorder (eg, thrombotic thrombocytopenic purpura)
11.Known severe liver disease (eg, ascites or signs of coagulopathy)
12.Renal failure requiring dialysis
13.Pregnancy or breastfeeding. Women of child-bearing potential who are not willing to use a medically accepted method of contraception that is considered reliable in the judgment of the Investigator
14.Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
15.Previous enrolment or randomisation in the present study
16.Participation in another clinical study with an investigational product at any time during the 30 days prior to randomisation (regardless of when treatment with the investigational product was discontinued)

1. Necesidad o necesidad anticipada de cualquiera de los siguientes:
(a) Tratamiento antiagregante dual con AAS y inhibidores P2Y12 (incluyendo pacientes con stent de la arteria carótida e intervención coronaria percutánea).
(b) Otros antiagregantes plaquetarios diferentes al AAS (e.j., inhibidores de GPIIb/IIIa, clopidogrel, ticlopidina, prasugrel, dipiridamol, ozagrel, cilostazol, ticagrelor) y otros agentes anticoagulantes con efectos antiagregante plaquetario, incluyendo agentes de medicina tradicional u herbolarios.
(c) Anticoagulantes (e.j. warfarina, inhibidores orales de la trombina y del factor Xa,
bivalirudina, hirudina, argatrobán, fondaparinux, heparinas no fraccionadas y tratamiento a largo plazo con heparinas de bajo peso molecular). El tratamiento a corto plazo (< o = 7 días) con bajas dosis de heparinas de bajo peso molecular y que se pueden utilizar en pacientes inmovilizados a discreción del investigador.
2. Cualquier antecedente de fibrilacion/aleteo arterial, aneurisma ventricular, o sospecha de una patología cardioembolica para AIT o ictus.
3. Pacientes que deben recibir o han recibido cualquier forma de trombólisis intravenosa o intrarterial o trombectomía mecánica en las 24 horas previas a la aleatorización.
4. Endarteriectomía carotídea planificada que requiere suspender el producto en investigación dentro de los 3 días de la aleatorización o se espera que requiera un desenmascaramiento del producto en investigación (endarteriectomía carotídea planificada en si mismo no es un criterio de exclusión).
5. Antecedentes de una hemorragia intracraneal previa en cualquier momento (no cuentan las microhemorragias asintomáticas), hemorragia gastrointestinal en los últimos 6 meses, o cirugía mayor en los 30 días previos.
6. Los pacientes que se consideren un riesgo en acontecimientos de bradicardia (e.j., síndrome del sinus enfermo conocido, bloqueo auriculoventricular de segundo o tercer grado) al menos que ya hayan sido tratados con un marcapasos permamente.
7. Incapacidad del paciente para entender y/o cumplir con los procedimientos del estudio y/o el seguimiento, en la opinión del investigador.
8. Hipersensibilidad conocida a ticagrelor o AAS
9. Necesidad o necesidad anticipada para el tratamiento oral o intravenoso con cualquiera de los siguientes:
(a) Inhibidores fuertes del citocromo P450 3A (CYP3A4) (e.j., ketoconazol, claritromicina [pero no eritromicina o azitromicina], nefazadona, ritonavir, atazanavir) que no puede ser interrumpido para el curso del estudio.
(b) Fármacos antiinflamatorios no esteroideos a largo plazo (>7 días).
10. Diátesis hemorrágica conocida o trastorno de la coagulación (e.j., púrpura trombocitopénica trombótica).
11. Enfermedad hepática grave conocida (ej., ascitis o signos de coagulopatía).
12. Fallo renal que requiere diálisis.
13. Embarazadas o en periodo de lactancia. Mujeres en edad fértil que no están dispuestas a utilizar un método anticonceptivo médicamente aceptado que se considere seguro a juicio del investigador.
14. Participación en la planificación y / o realización del estudio (se aplica tanto al personal de AstraZeneca como al personal del sitio de estudio).
15. Reclutamiento previo o aleatorización en el estudio presente.
16. Participación en otro estudio con un producto en investigación en cualquier momento durante los 30 días previos a la aleatorización (independientemente de cuando se interrumpió el tratamiento con el producto en investigación)

E.5 End points

E.5.1

Primary end point(s)

Time from randomisation to first subsequent stroke or death

Tiempo transcurrido entre la aleatorización y el primer acontecimiento posterior de ictus o muerte

E.5.1.1

Timepoint(s) of evaluation of this end point

From randomization up to 30 days

Desde la aleatorización hasta 30 días

E.5.2

Secondary end point(s)

1. Time from randomisation to first subsequent ischaemic stroke
2. mRS score >1 at Visit 3

1.Tiempo transcurrido entre la aleatorización y el primer acontecimiento posterior de ictus isquémico.
2.mRS>1 en la visita 3.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. From randomization up to 30 days.
2. Day 30.

1. Desde la aleatorización hasta 30 días
2. Día 30

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

E.8.2.2

Placebo

Yes

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

200

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

Argentina

Australia

Belgium

Brazil

Bulgaria

Canada

Chile

China

Czech Republic

France

Germany

Hong Kong

Hungary

India

Italy

Korea, Republic of

Mexico

Peru

Poland

Romania

Russian Federation

Slovakia

Spain

Sweden

Taiwan

Thailand

Ukraine

Vietnam

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

The end of the trial is defined as the last visit of the last subject undergoing the trial.

El fin del ensayo se define como la última visita del último sujeto que participe en el estudio.

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 months

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:

6000

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

7000

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

Yes

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

800

F.4.2

For a multinational trial

F.4.2.1

In the EEA

6000

F.4.2.2

In the whole clinical trial

13000

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

Ninguno

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

2017-12-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-12-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-12-13

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