Clinical Trials Register

Summary
EudraCT Number:	2017-002340-32
Sponsor's Protocol Code Number:	APIDULCIS
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-11-04
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

2017-002340-32

A.3

Full title of the trial

APIDULCIS: Extended anticoagulation with low-dose apixaban after a standard course anticoagulation in patients with a first venous thromboembolism who have positive d-dimer

APIDULCIS: Terapia estesa con bassa dose di apixaban in pazienti con un primo evento di tromboembolismo venoso che hanno già effettuato il periodo standard di anticoagulazione e che hanno D-dimero positivo

A.3.1

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

APIDULCIS: Extended anticoagulation treatment with low-dose apixaban in patients with a first venous thromboembolism and a positive d-dimer, who were treated with standard course of anticoagulation

APIDULCIS: Trattamento a lungo termine con Apixaban a basso dosaggio in pazienti con un primo episodio di tromboembolismo venoso e D-dimero positivo e che sono già stati trattati con terapia anticoagulante

A.3.2

Name or abbreviated title of the trial where available

APIDULCIS

A.4.1

Sponsor's protocol code number

APIDULCIS

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03678506

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	FONDAZIONE ARIANNA ANTICOAGULAZIONE
B.1.3.4	Country	Italy
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	Bristol-Myers Squibb (BMS)
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione Arianna Anticoagulazione
B.5.2	Functional name of contact point	Clinical Trial Operations
B.5.3	Address:
B.5.3.1	Street Address	Via Paolo Fabbri 1/3
B.5.3.2	Town/ city	Bologna
B.5.3.3	Post code	40138
B.5.3.4	Country	Italy
B.5.4	Telephone number	051341471
B.5.5	Fax number	051343604
B.5.6	E-mail	s.zorzi@ariannafoundation.org

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	ELIQUIS - 2.5 MG-COMPRESSA RIVESTITA CON FILM-USO ORALE-BLISTER (PVC/PVDC/ALU) 60 COMPRESSE
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	Italy
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	Apixaban
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2500
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

a first episode of proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE)

Primo episodio di trombosi venosa profonda (TVP) prossimale degli arti inferiori e/o Embolia Polmonare (EP)

E.1.1.1

Medical condition in easily understood language

A first episode of proximal deep vein thrombosis (DVT) with or without a pulmonary embolism (PE)

Un primo episodio di trombosi venosa profonda prossimale agli arti inferiori con o senza embolia polmonare associata

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	21.0
E.1.2	Level	PT
E.1.2	Classification code	10037377
E.1.2	Term	Pulmonary embolism
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10051055
E.1.2	Term	Deep vein thrombosis
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 study seeks to assess whether a management procedure involving D-dimer testing assessment can identify a subset of subjects at high risk of recurrence in whom an extended anticoagulation (administering apixaban 2.5 mg BID) should be done.

Identificare i pazienti a più alto rischio di recidiva, mediante la positività del test del D-dimero, e fornire loro un trattamento anticoagulante efficace ed a basso rischio emorragico.

E.2.2

Secondary objectives of the trial

In addition, whether the same management procedure can identify a subset of subjects at low risk of recurrence in whom an extended anticoagulation can be safely avoided

Identificare i soggetti a più basso rischio di recidiva tromboembolica, che presentano D-dimeri persistentemente negativi, per i quali proponiamo la definitiva sospensione di qualsiasi terapia anticoagulante orale.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- outpatients with a single episode of venous thromboembolism (VTE), at a first episode of proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE),
- unprovoked VTE or associated with weak risk factors for thrombosis
- Age older than 18 or younger than 75 years
- Capacity to give written informed consent
- Males and females of any ethnic group
- 12 months of previous anticoagulant therapy (with any anticoagulant drug)

- Pazienti con primo episodio di TVP prossimale isolata o associata ed EP (TVP ±EP)
- Pazienti con primo episodio di EP isolata (senza diagnosi di TVP)

1.Firma del consenso informato
2. Età maggiore/uguale a 18 anni e inferiore a 75 anni al momento dell'arruolamento
3. Primo evento idiopatico di TEV
4. Evento TEV associato ad uno o più fattori di rischio deboli e/o rimossi
5. Maschio e femmina di qualsiasi gruppo etnico
6. Aver effettuato almeno 12 mesi (con qualsiasi farmaco)

E.4

Principal exclusion criteria

1) Events usually associated with low risk of recurrence

• DVT/PE occurred within 3 months from major surgery or major trauma
• Isolated Distal DVT (thrombosis of calf veins)
2) Events associated with a very high risk of recurrence or occurrence of life-threatening recurrent events
• PE episode with shock or life-threatening
• Isolated PE with a systolic pulmonary artery pressure > 60 mmHg at presentation
• DVT/PE associated with active cancer, antiphospholipid syndrome or long-standing medical illnesses
• More than one idiopathic event
3) Index VTE events not included in the study
• All VTE events that occurred in different sites than deep veins of the lower limbs or pulmonary arteries

• Age younger than 18 or older than 75 years
• More documented unprovoked VTE episodes
• Pregnancy or puerperium
• Severe post-thrombotic syndrome (=> 15 points at the Villalta score)
• Solid neoplasia or blood disease in active phase or requiring chemotherapy/radiotherapy
• All the clinical conditions requiring prolonged treatment with LMWH
• Presence of overt, active chronic diseases (i.e. inflammatory bowel disease)
• Known serious thrombophilic alterations:
• Any absolute contraindication to anticoagulant therapy
• Any contraindication to apixaban (as per local SmPC)
• Presence of antiphospolipid syndrome
• Presence of cava filter
• Concomitant conditions (such as atrial fibrillation) requiring indefinite anticoagulation
• Severe cardio-respiratory insufficiency (NYHA 3 or 4)
• Life expectancy shorter than 1 year
• Refuse interruption of anticoagulation to perform serial D-dimer assessment
• Geographically inaccessible location
• Inability or refusal to give consent
Concomitant enrollment in other non observational study

1. Eventi con basso rischio di recidiva
- TVP ± EP che si verificano entro tre mesi dopo un trauma maggiore o un intervento di chirurgia maggiore
- Trombosi Distale Isolata (trombosi del polpaccio)
2. Eventi con alto rischio di recidiva o eventi recidivanti pericolosi per la vita
-Embolia Polmonare con shock o che abbia messo in pericolo di vita
-Embolia Polmonare isolata con pressione polmonare sistolica >60 mm Hg all'insorgenza
-TVP ± EP associata a cancro attivo, sindrome da anticorpi antifosfolipidi o malattie croniche
-Episodi recidivanti di TVP ± EP
3. Evento tromboembolico indice non incluso nello studioo
-Tutti gli eventi tromboembolici che si verificano in sedi differenti dai vasi profondi degli arti inferiori o dalle arterie polmonari.

• Tromboembolismo idiopatico recidivante documentato
· Gravidanza o puerperio in atto al momento dello screening ed intenzione di intraprendere una gravidanza nei successivi 18 mesi
· Severa sindrome post-trombotica (score di Villalta >15)
· Neoplasia solida o ematica in fase attiva o per la quale sia necessaria chemio/radioterapia
· Tutte le condizioni cliniche che richiedono un trattamento prolungato con eparina a basso peso molecolare (LMWH)
· Presenza di malattie croniche in fase acuta o attiva (es: malattia infiammatoria intestinale)
· Presenza di note gravi alterazioni trombofiliche
· Controindicazione assoluta alla terapia anticoagulante
· Controindicazione alla terapia con Apixaban (come da scheda tecnica)
· Presenza di sindrome da anticorpi antifosfolipidi
· Presenza di filtro cavale
· Presenza di patologie concomitanti che richiedono un'anticoagulazione indefinita
· Insufficienza cardiorespiratoria grave (Classe NYHA 3-4)
· Aspettativa di vita inferiore ad 1 anno
· Rifiuto del paziente di interrompere la terapia anticoagulante o di effettuare la misurazione seriata dei D-dimeri
· Sede geografica disagiata
· Rifiuto o inabilità a fornire il consenso informato
· Paziente già arruolato ad altri studi clinici non osservazionali

E.5 End points

E.5.1

Primary end point(s)

1)Primary efficacy end-point: the composite of confirmed recurrent VTE and VTE-related death occurring during follow-up in all included patients 2)Primary safety end-point: major bleeding complications occurring during the follow-up period in all included patients

1) efficacia: evitare il verificarsi di recidiva di TEV, morte correlata a TEV
2) sicurezza: evitare il verificarsi di emorragia maggiore

E.5.1.1

Timepoint(s) of evaluation of this end point

The assessment of the endpoints will be carried out during follow up in all patients and for the entire duration of the study (36 months)

La rilevazione degli endpoint di efficacia e sicurezza verrà effettuata per tutta la durata dello studio (36 mesi)

E.5.2

Secondary end point(s)

1) Efficacy:
other thromboembolic events, (severe) post-thrombotic syndrome (at the end of follow-up period patients with DVT as index event should receive a final evaluation of the Villalta score; 2)Secondary safety end-points:
clinically relevant non major bleeding complications; overall mortality

1) Efficacia:
Tutti gli altri eventi tromboembolici; Sindrome post trombotica severa (valutazione con score di Villalta); 2) Sicurezza:
Emorragie clinicamente rilevanti non maggiori; Morte per qualsiasi causa

E.5.2.1

Timepoint(s) of evaluation of this end point

The assessment of the endpoints will be carried out during follow up in all patients and for the entire duration of the study (36 months); The assessment of the endpoints will be carried out during follow up in all patients and for the entire duration of the study (36 months)

La rilevazione degli end-point secondari verrà effettuata per tutta la durata dello studio (36 mesi); La rilevazione degli end-point secondari verrà effettuata per tutta la durata dello studio (36 mesi)

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

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

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

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 Follow up of the last enrolled patient

Ultimo follow up dell'ultimo paziente arruolato

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:

600

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

600

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

1200

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1200

F.4.2.2

In the whole clinical trial

1200

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)

At the end of the study patients will be followed as routine practice

I soggetti verranno seguiti come da normale pratica clinica

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

2019-01-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-03-19

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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