Clinical Trials Register

Summary
EudraCT Number:	2014-001397-33
Sponsor's Protocol Code Number:	ARTESIA
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-06-03
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-001397-33

A.3

Full title of the trial

APIXABAN FOR THE REDUCTION OF THROMBO-EMBOLISM IN PATIENTS
WITH DEVICE-DETECTED SUB-CLINICAL ATRIAL FIBRILLATION

Uso di Apixaban per la riduzione del tromboembolismo in pazienti con fibrillazione atriale subclinica rilevata tramite device

A.3.1

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

APIXABAN FOR THE REDUCTION OF THROMBO-EMBOLISM IN PATIENTS
WITH DEVICE-DETECTED SUB-CLINICAL ATRIAL FIBRILLATION

Uso di Apixaban per la riduzione del tromboembolismo in pazienti con fibrillazione atriale subclinica rilevata tramite device

A.3.2

Name or abbreviated title of the trial where available

ARTESIA

A.4.1

Sponsor's protocol code number

ARTESIA

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01938248

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	Hamilton Health Sciences through the Population Health Research Institute
B.1.3.4	Country	Canada
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	Canadian Institutes for Health Research
B.4.2	Country	Canada
B.4.1	Name of organisation providing support	Bristol-Myers Squibb
B.4.2	Country	Canada
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Hamilton Health Sciences through the Population Health Research Institute
B.5.2	Functional name of contact point	ARTESIA Study Reserach Coordinator
B.5.3	Address:
B.5.3.1	Street Address	237 Barton Street East
B.5.3.2	Town/ city	Hamilton
B.5.3.3	Post code	L8L 2X2
B.5.3.4	Country	Canada
B.5.4	Telephone number	19055274322
B.5.5	Fax number	19052973786
B.5.6	E-mail	artesia@phri.ca

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	No
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	APIXABAN
D.3.2	Product code	BMS-562247-01
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-562247-01
D.3.9.4	EV Substance Code	SUB25425
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	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	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	No
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	APIXABAN
D.3.2	Product code	BMS-562247-01
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-562247-01
D.3.9.4	EV Substance Code	SUB25425
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	2.5
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	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	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	No
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	ASPIRIN
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	ASPIRIN
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	81
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	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated 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

Device-detected sub-clinical atrial fibrillation

fibrillazione atriale rilevata da dispositivo

E.1.1.1

Medical condition in easily understood language

Sub-clinical atrial fibrillation detected by pacemaker, ICD or loop recorder

fibrillazione atriale rilevata da pacemaker, ICD o loop recorder

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	18.0
E.1.2	Level	PT
E.1.2	Classification code	10003658
E.1.2	Term	Atrial fibrillation
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine if the use of apixaban in patients with SCAF will reduce the incidence of stroke and systemic embolism compared to aspirin.

Determinare se l’uso di apixiban in pazienti con FASC riduce l’incidenza di ictus e di embolia sistemica rispetto all’uso di aspirina.

E.2.2

Secondary objectives of the trial

not applicable

non applicabile

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Permanent pacemaker or defibrillator (with or without resynchronization) or insertable cardiac monitor capable of detecting SCAF
2. At least one episode of device-detected SCAF ≥ 6 minutes in duration (Atrial rate > 175/min if an atrial lead is present), but no single episode > 24 hours in duration at any time prior to enrollment. SCAF requires electrogram confirmation (at least one episode) unless ≥ 6 hours in duration
3. Age ≥ 18 years
4. CHA2DS2-VASc score of ≥ 4

1. Presenza di PM permanente o defibrillatore (con o senza ri-sincronizzazione) o MCI in grado di rilevare episodi di FASC.
2. Almeno un episodio di FASC, rilevato dal dispositivo, della durata di almeno 6 minuti (con frequenza atriale > 175 / min se è presente un elettrocatetere atriale), ma nessun singolo episodio di FASC della durata maggiore di 24 ore in qualsiasi momento prima dell'arruolamento. La FASC richiede la conferma diagnostica mediante l’esecuzione di un elettrocardiogramma (almeno un episodio) a meno che la durata non sia superiore a 6 ore.
3. Età ≥ 18 anni.
4. Punteggio CHA2DS2-VASc ≥ 4.

E.4

Principal exclusion criteria

1. Clinical atrial fibrillation documented by surface ECG (12 lead ECG, Telemetry, Holter) lasting ≥ 6 minutes, with or without clinical symptoms
2. Mechanical valve prosthesis, recent (within past 6 months) deep vein thrombosis or pulmonary embolism or other condition requiring treatment with an anticoagulant
3. Allergy to aspirin or apixaban
4. Severe renal insufficiency (serum creatinine > 2.5 mg/dL [221 μmol/L] or a calculated creatinine clearance < 25 ml/min)
5. Serious bleeding in the last 6 months or at high risk of bleeding (this includes, but is not limited to: prior intracranial hemorrhage, active peptic ulcer disease, clinically significant thrombocytopenia or anemia, recent stroke within past 10 days, documented hemorrhagic tendencies or blood dyscrasias)
6. Moderate to severe hepatic impairment
7. Ongoing need for combination therapy with aspirin and clopidogrel (or other combination of two platelet inhibitors)
8. Meets criteria for requiring lower dose of apixaban AND also has ongoing need for strong inhibitors of both CYP3A4 and P-glycoprotein (e.g., ketoconazole, itraconazole, ritonavir or clarithromycin)
9. Ongoing need for strong dual inducers of both CYP3A4 and P-glycoprotein (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort)
10. Received an investigational drug in the past 30 days
11. Participants considered by the investigator to be unsuitable for the study for any of the following reasons:
 Not agreeable for treatment with either aspirin or apixaban or anticipated to have poor compliance on study drug treatment
 Unwilling to attend study follow-up visits
 Life expectancy less than 2 years due to concomitant disease
12. Women who are pregnant, breast-feeding or of child-bearing potential without an acceptable form of contraception in place (sterilization, abstinence or other method with less than 1% failure rate)

1. Presenza di Fibrillazione Atriale clinicamente evidente documentata mediante ECG di superficie (a 12 derivazioni o con telemetria o mediante Holter-ECG) della durata di almeno 6 minuti, con o senza sintomi clinici.
2. Presenza di protesi valvolare meccanica, presenza di trombosi venosa profonda recente (nei 6 mesi precedenti) o embolia polmonare recente (nei 6 mesi precedenti) o altre condizioni che richiedono trattamento con un anticoagulante.
3. Allergia ad aspirina o apixaban.
4. Severa insufficienza renale (creatinina sierica > 2,5 mg / dL [221 mcmol/L] o clearance della creatinina calcolata < 25 ml / min).
5. Sanguinamento grave negli ultimi 6 mesi o condizioni ad alto rischio di sanguinamento (inclusi ma non limitati a: precedente emorragia intracranica, ulcera peptica attiva, trombocitopenia o anemia clinicamente significative, ictus recente nei 10 giorni precedenti, documentate diatesi emorragica o discrasie ematiche).
6. Insufficienza epatica da moderata a severa.
7. Necessità continuativa di doppia terapia antiaggregante con aspirina e clopidogrel (o altra combinazione di due inibitori piastrinici).
8. Necessità della dose più bassa di apixaban associata alla necessità continuativa di forti inibitori del CYP3A4 e P-glicoproteina (per esempio, ketoconazolo, itraconazolo, ritonavir o claritromicina).
9. Necessità continuativa di forti induttori del CYP3A4 e P-glicoproteina (per esempio, rifampicina, carbamazepina, fenitoina, Iperico- Erba di San Giovanni).
10. Assunzione di un farmaco sperimentale negli ultimi 30 giorni.
11. Soggetti considerati dallo sperimentatore non adatti allo studio per uno dei seguenti motivi:
1- non idoneità al trattamento con aspirina o apixaban o prevedibile scarsa compliance all’assunzione del farmaco in studio;
2- indisponibilità a partecipare alle visite di follow-up;
3- aspettativa di vita inferiore ai 2 anni a causa di malattie concomitanti.
12. Donne in stato di gravidanza, in allattamento o in età fertile senza una forma accettabile di contraccezione (sterilizzazione, astinenza o altro metodo con un tasso di fallimento inferiore all’1%).

E.5 End points

E.5.1

Primary end point(s)

Efficacy: Composite of stroke (including transient ischemic attack (TIA) with evidence of cerebral infarction on diffusion-weighted MRI) and systemic embolism
Safety: Major bleeding as defined by the ISTH criteria

Efficacia: combinazione di ictus (inclusi gli attacchi ischemici transitori - TIA – con evidenza di infarto cerebrale alla risonanza magnetica cerebrale) ed embolia sistemica.
Sicurezza: sanguinamento maggiore come definito dai criteri ISTH.

E.5.1.1

Timepoint(s) of evaluation of this end point

All suspected strokes, TIAs and cases of systemic embolism as well as major bleeding events will undergo a blinded streamlined adjudication process

Tutti gli ictus sospetti, i TIA, i casi di embolia sistemica e i sanguinamenti maggiori saranno sottoposti ad un processo di valutazione in cieco, semplificato/accelerato.

E.5.2

Secondary end point(s)

 Ischemic stroke
 Myocardial infarction
 Vascular death
 Total death (vascular and non-vascular)
 Composite of stroke, myocardial infarction, systemic embolism and total death
 Composite of stroke, myocardial infarction, systemic embolism, total death and major bleeding

Ictus ischemico
Infarto miocardico
Morte vascolare
Morte totale (per cause vascolari e non)
Combinazione di ictus, infarto miocardico, embolia sistemica e morte
Combinazione di ictus, infarto miocardico, embolia sistemica, morte e sanguinamento maggiore.

E.5.2.1

Timepoint(s) of evaluation of this end point

All suspected strokes, TIAs and cases of systemic embolism as well as major bleeding events will undergo a blinded streamlined adjudication process

Tutti gli ictus sospetti, i TIA, i casi di embolia sistemica e i sanguinamenti maggiori saranno sottoposti ad un processo di valutazione in cieco, semplificato/accelerato.

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

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

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

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

Yes

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

Denmark

France

Germany

Hungary

Italy

Netherlands

Norway

Spain

Sweden

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

last patient/last visit

ultimo paziente/ultima visita

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:

1500

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

2500

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

300

F.4.2

For a multinational trial

F.4.2.1

In the EEA

2500

F.4.2.2

In the whole clinical trial

4000

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

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

2015-07-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-09-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-01-23

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