Clinical Trials Register

Summary
EudraCT Number:	2018-002176-41
Sponsor's Protocol Code Number:	IRAS236886
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-01-21
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-002176-41

A.3

Full title of the trial

Prevention of Stroke in Intracerebral Haemorrhage Survivors with Atrial Fibrillation (PRESTIGE-AF)

Prevenzione dell'ictus nei sopravvissuti ad emorragia intracerebrale e affetti da fibrillazione atriale (PRESTIGE-AF)

A.3.1

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

Prevention of Stroke in Survivors of Brain Bleeding with Atrial Fibrillation

Prevenzione dell'ictus nei pazienti con fibrillazione atriale che abbiano avuto recentemente un sanguinamento cerebrale, noto anche come emorragia intracerebrale .

A.3.2

Name or abbreviated title of the trial where available

PRESTIGE-AF

A.4.1

Sponsor's protocol code number

IRAS236886

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	Imperial College of Science, Technology and Medicine
B.1.3.4	Country	United Kingdom
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	Unione Europea
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Imperial College of Science, Technology and Medicine
B.5.2	Functional name of contact point	Gisela Pereira Barreto
B.5.3	Address:
B.5.3.1	Street Address	Joint Research Compliance Office, Room 221, Level 2
B.5.3.2	Town/ city	Medical School Building, Norfolk Place, London
B.5.3.3	Post code	W2 1PG
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	02075949480
B.5.6	E-mail	g.pereira-barreto@imperial.ac.uk

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	Xarelto
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG
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	Xarelto
D.3.2	Product code	[non disponibile]
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	RIVAROXABAN
D.3.9.1	CAS number	366789-02-8
D.3.9.2	Current sponsor code	BAY 59-7939
D.3.9.4	EV Substance Code	EMEA/H/C/000944
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	15 to 20
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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
D.2.1.1.2	Name of the Marketing Authorisation holder	Daiichi Sankyo , Inc.
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	Lixiana
D.3.2	Product code	[non disponibile]
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.3.9.2	Current sponsor code	DU-176b
D.3.9.4	EV Substance Code	EMEA/H/C/002629
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	30 to 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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Pradaxa
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International 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	Pradaxa
D.3.2	Product code	[BIBR1048MS]
D.3.4	Pharmaceutical form	Capsule, hard
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	DABIGATRAN ETEXILATO
D.3.9.1	CAS number	211915-06-9
D.3.9.2	Current sponsor code	BIBR1048MS
D.3.9.4	EV Substance Code	EMEA/H/C/000829
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	110 to 150
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	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	Eliquis 2,5 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb / Pfizer EEIG
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	Eliquis
D.3.2	Product code	[BMS 562247]
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	APIXABAN
D.3.9.1	CAS number	503612-47-3
D.3.9.2	Current sponsor code	BMS 562247
D.3.9.4	EV Substance Code	EMEA/H/C/002148
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	2 to 5
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Ischaemic stroke prevention in patients with atrial fibrillation and previous intracerebral haemorrhage

Prevenzione dell'ictus in pazienti con fibrillazione atriale e precedente emorragia intracerebrale

E.1.1.1

Medical condition in easily understood language

Prevention of stroke (caused by a blood clot) in patients with a heart arrhythmia (atrial fibrillation) who have had a previous brain bleed (intracerebral haemorrhage)

Prevenzione dell'ictus (causato da un coagulo di sangue) in pazienti con aritmia cardiaca (fibrillazione atriale) che hanno avuto un precedente sanguinamento cerebrale (emorragia intracerebrale)

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.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10055815
E.1.2	Term	Haemorrhage intracerebral
E.1.2	System Organ Class	100000004852

E.1.2 Medical condition or disease under investigation

E.1.2	Version	22.1
E.1.2	Level	LLT
E.1.2	Classification code	10067816
E.1.2	Term	Cardioembolic 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

Do particular anti-clotting drugs called direct oral anticoagulants reduce the rate of ischaemic stroke, that is strokes caused by a blood clot blocking a blood vessel, compared to no anticoagulation (control group) without unacceptably increasing the risk of recurrent brain bleeds in patients with atrial fibrillation and a previous brain bleed within 6 months before enrolment.

Valutare, nei pazienti sopravvissuti a emorragia intracerebrale (ICH) ed affetti da fibrillazione atriale (FA), l’efficacia e la sicurezza degli anticoagulanti diretti rispetto a nessuna terapia anticoagulante (cioè nessuna terapia antitrombotica (noAT) o terapia antipiastrinica (APA) in termini di riduzione del rischio di eventi ischemici cerebrali e di recidiva di ICH.

E.2.2

Secondary objectives of the trial

1. To examine the effect of anticoagulation with DOAC versus no anticoagulation on major cardiovascular outcomes and mortality in ICH patient with AF. Cardiovasular outcomes include stroke, embolism attributed to blood clot formation, death of any cause or attributed to cardiovascular causes and major adverse cardiac events such as death, cardiac stent thrombosis, recurrent heart attacks.
2.To compare the effect of DOACs versus no anticoagulation on major systemic and intracranial bleeding in this Study population (safety)
3. To examine the effect of DOACs versus no anticoagulation on net clinical benefit in ICH patients with AF. Net clinical benefit is defined as composite of all stroke, embolic events attributed to blood clots, heart attack, death attributed to cardiovascular causes, and massive bleeding.
4. To explore the impact of DOAC vs. no anticoagulation on quality of life, cognition and psychological morbidity in patients with ICH and AF over time

1. Valutare l'efficacia della terapia anticoagulante con DOAC rispetto a nessun trattamento anticoagulante in termini di riduzione degli eventi cardiovascolari e della mortalità nei pazienti con ICH e AF
2. Valutare la sicurezza della terapia anticoagulante con DOACs rispetto a nessun trattamento anticoagulante in termini di riduzione dei sanguinamenti maggiori sistemici e dei sanguinamenti intracranici nella popolazione di studio
3. Valutare il beneficio clinico netto dei DOAC rispetto alla non anticoagulazione nei pazienti con ICH e AF
4. Esplorare nel corso del tempo l'impatto della terapia antitrombotica sulla qualità della vita, sullo sviluppo di deficit cognitivi e sulla morbidità psicologica nei pazienti con ICH e AF.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Other types of substudies
Specify title, date and version of each substudy with relative objectives: The firstsubstudy called “Predictive Modelling of Risk” (Version 1.0 Section 14.1 of PRESTIGE-AF Study Protocol) aims to develop tools for prediction of individual risk of subsequent ischaemic or haemorrhagic strokes in ICH patients with concomitant AF. For this purpose, observational information on clinical characteristics, biological material for genetic analysis and determination of proteins in the blood and brain images will be analysed in parallel to data collection in the main PRESTIGE-AF Study.
The second substudy called “longitudinal magnetic resonance imaging (MRI) Substudy” will enroll 200 PRESTIGEAF participants. Participants of the substudy must have had a brain MRI after their intracerebral haemorrhage (ICH) before study enrolment. Participants of the MRI Substudy will undergo a second brain MRI at their 12-month visit.
The aim of this observational prospective Substudy is to clarify the amount of subclinical progression of haemorrhagic and ischaemic damage in ICH patients and test if such dynamics are possibly further predictors of ICH or ischaemic infarction.
The third substudy called “Pharmacology Substudy” is exploring adherence to direct anticoagulants and exposure levels in the patient group. Using an innovative technique called the dried blood spot (DBS) sampling technique,single or multiple venous or capillary whole blood samples can be easily collected by Participants or caregivers at various time points within the dosing interval, thus providing objective evidence for DOAC adherence and exposure.
Dried blood samples on a paper card will be shipped to a specialised central laboratory which can measure the blood concentrations of DOACs and correlate the findings with patient characteristics at the end of the study.

Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Il primo sottostudio denominato "Predictive Modeling of Risk" (Versione 1.0 Sezione 14.1 del PRESTIGE-AF Study Protocol) ha lo scopo di sviluppare strumenti per la previsione del rischio individuale di ictus ischemico o emorragico successivo nei pazienti con ICH e AF concomitante. A tale scopo, le informazioni relative alle caratteristiche cliniche, il materiale biologico per l'analisi genetica e la determinazione delle proteine ¿¿nelle immagini del sangue e del cervello saranno analizzate parallelamente alla raccolta di dati nello studio principale PRESTIGE-AF.
Il secondo sottostudio denominato "sottostudio di risonanza magnetica longitudinale (RMN)" arruolerà 200 partecipanti dello studio principale PRESTIGEAF. I partecipanti al sottostudio devono aver avuto una risonanza magnetica cerebrale dopo la loro emorragia intracerebrale (ICH) prima della partecipazione allo studio. I partecipanti al sottostudio MRI subiranno una seconda risonanza magnetica cerebrale alla loro visita di 12 mesi. Lo scopo di questo sottostudio prospettico osservazionale è quello di quantificare la progressione subclinica del danno emorragico e ischemico nei pazienti con ICH e verificare se tali dinamiche siano ulteriori predittori di ICH o infarto ischemico.
Il terzo sottostudio denominato "Sottostudio di farmacologia" sta esplorando l'aderenza diretta agli anticoagulanti e i livelli di esposizione nei pazienti. Utilizzando una tecnica innovativa chiamata tecnica di campionamento del sangue secco (DBS), campioni di sangue intero venoso o capillare singolo o multiplo possono essere facilmente raccolti dai partecipanti o da chi si prende cura di loro in vari momenti all'interno dell'intervallo di somministrazione, fornendo così una prova oggettiva per l'aderenza e l'esposizione al DOAC .
I campioni di sangue essiccato su un supporto cartaceo verranno inviati a un laboratorio specializzato centralizzato che può misurare le concentrazioni ematiche di DOAC e correlare i risultati con le caratteristiche del paziente alla fine dello studio.

E.3

Principal inclusion criteria

- Age = 18 years
- Written informed consent
- Recent history of a non-traumatic spontaneous ICH during the 6 months before enrolment
- Documented evidence of AF (paroxysmal, persistent or permanent)
- CHA2DS2-VASc score=2 for male, and CHA2DS2-VASc score= 3 for female patients
- Availability of brain imaging following the index Intracerebral Haemorrhage (ICH)

- Età = 18 anni
- Paziente in grado di fornire il consenso informato
- Recente ICH spontanea non traumatica (esordio di ICH tra 15 giorni prima fino a 6 mesi prima l’arruolamento)
- Presenza di AF (parossistica, persistente, permanente)
- Punteggio CHA2DS2-VASc =2 per il sesso maschile e CHA2DS2-VASc =3 per pazienti di sesso femminile
- Disponibilità di una TC Encefalo eseguita tra l’esordio dell'ICH e l’arruolamento

E.4

Principal exclusion criteria

1. Patient lacks capacity to consent
2. Fully dependent (defined as a modified Rankin Scale score of over 4)
3. Women who are pregnant, breastfeeding, or plan to become pregnant during the Study period
4. Women of childbearing potential (WOCBP) who are unable or unwilling to take measures for effective contraception
5. ICH occurring within the last 14 days before enrolment
6. ICH occurring longer than 6 months before enrolment
7. ICH resulting from trauma or vascular malformation
8. Another indication for long-term anticoagulation
9. Contraindication for long-term anticoagulant therapy with DOACs (other than ICH)
10. Absolute need for antiplatelet therapy at enrolment
11. Presence of a left atrial appendage occlusion device (LAAO) or plan to implant an LAAO
12. Presence of any medical, psychological, or psychiatric condition which in the opinion of the Principal or Co-Investigator would cause participation in the Study to be unwise
13. Participation in any clinical study with an Investigational Medicinal Product within the past 30 days (observationalstudies are permitted)

- Paziente non in grado di fornire il proprio consenso
-. Disabilità severa (modified Rankin scale> 4)
- Donne in gravidanza, allattamento o che stanno pianificando una gravidanza
- Donne in età fertile (WOCBP 12.1) che non sono in grado o non sono disposte a prendere misure di contraccezione efficace
- ICH verificatasi nei 14 giorni precedenti l'arruolamento
- ICH verificatasi oltre i 6 mesi dall'arruolamento
- ICH secondaria a traumi o malformazioni vascolari
- Indicazione alla terapia anticoagulante a lungo termine diversa dalla AF
- Ipertensione non controllata dalla terapia farmacologica
- Qualsiasi controindicazione (eccetto l’emorragia intracerebrale) al trattamento con apixaban, dabigatran, edoxaban, rivaroxaban come da Summary of Product Charasteristics (SmPC)
- Necessità assoluta di terapia antipiastrinica all'arruolamento
- Presenza di un dispositivo di occlusione dell'appendice atriale sinistra (LAAO) o pianificazione di impianto di LAAO
- Presenza di qualsiasi condizione medica, psicologica o psichiatrica che, secondo il parere dell’Investigatore Principale o del Co-Investigatore, rende imprudente la partecipazione allo studio
- Partecipazione a qualsiasi studio clinico con un prodotto medicinale sperimentale negli ultimi 30 giorni (sono consentiti studi osservazionali)

E.5 End points

E.5.1

Primary end point(s)

There are two co-primary binary endpoints in the Study (evaluated by time-to-event analysis): Ischaemic stroke and recurrent intracerebral haemorrhage. The Study will perform hierarchical testing of the two co-primary endpoints in a parallel group design.

Nello studio sono presenti due endpoint binari co-primari (valutati mediante analisi “time-to-event”): IS e ICH ricorrente. Lo studio verrà eseguito mediante test gerarchici dei due endpoint in un disegno a gruppi paralleli.

E.5.1.1

Timepoint(s) of evaluation of this end point

Anytime during follow-up period the end points will be evaluated and adjudicated

Gli endpoint saranno valutati e giudicati in qualsiasi momento durante il periodo di follow-up.

E.5.2

Secondary end point(s)

- all stroke and systemic embolism
- all-cause mortality
- cardiovascular mortality
- major adverse cardiac events
- net clinical benefit defined as composite endpoint of all stroke, systemic embolic event, myocardial infarction,cardiovascular mortality, and major bleeding
Secondary safety endpoints comprise of
- any major haemorrhage according to International Society of Thrombosis and Hemostasis (ISTH) bleeding
assessment tool
- any intracranial haemorrhage

- Tutti gli ictus ed gli eventi embolici sistemici
- Mortalità per tutte le cause
- Mortalità cardiovascolare
- Eventi avversi cardiaci maggiori
- Beneficio clinico netto, definito come endpoint composito di: tutti gli ictus, eventi embolici sistemici, infarto miocardico, mortalità cardiovascolare e sanguinamenti maggiori.
o Gli endpoint secondari di sicurezza comprendono:
- Qualsiasi emorragia maggiore definita secondo i criteri ISTH
- Qualsiasi emorragia intracranica

E.5.2.1

Timepoint(s) of evaluation of this end point

Anytime during follow-up period the end points will be evaluated and adjudicated

Gli endpoint saranno valutati e giudicati in qualsiasi momento durante il periodo di follow-up.

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

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

Yes

E.8.1.7.1

Other trial design description

con end-point in cieco (PROBE) che ha lo scopo di confrontare l’efficacia e la sicurezza dei DOAC (b

blinded end-point assessment (PROBE) clinical trial comparing DOACs (interventional arm) against no

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

nessun anticoagulante

no anticoagulant

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

Information not present in EudraCT

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:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

554

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

200

F.4.2

For a multinational trial

F.4.2.1

In the EEA

654

F.4.2.2

In the whole clinical trial

654

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)

Each participant will have a final consultation with a study doctor (PI or CO-I) to discuss whether they wish to continue on their current course of treatment. Ultimately, it is at the discretion of the patient and the patient's treating physician (e.g. GP), to continue prescribing or not for patients who have received DOAC in the trial. Similarly the patients treating physician should decide whether a patient who did not receive anticoagulant treatment during the trial should be anticoagulated.

Ciascun partecipante avrà una visita finale con un medico dello studio (PI o CO-I) per discutere se desidera continuare l'attuale ciclo di trattamento.La prescrizione o meno del DOAC per i pazienti che lo hanno ricevuto è a discrezione del paziente e del medico curante del paziente (ad esempio GP). Allo stesso modo i medici dovrebbero decidere se un paziente che non ha ricevuto un trattamento anticoagulante durante lo studio dovrebbe ricevere un anticoagulante.

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

2019-10-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-09-26

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

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