Clinical Trials Register

Summary
EudraCT Number:	2015-002177-37
Sponsor's Protocol Code Number:	1321.7
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:	2016-05-10
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2015-002177-37

A.3

Full title of the trial

Single dose, open label, uncontrolled, safety trial of intravenous administration of idarucizumab to paediatric patients enrolled from ongoing phase IIb/III clinical trials with dabigatran etexilate for the treatment and secondary prevention of venous thromboembolism.

Studio clinico in aperto, non controllato, per valutare la sicurezza di una singola dose di idarucizumab, somministrato per via endovenosa in pazienti pediatrici arruolati negli studi in corso di fase IIb/III con dabigatran etexilato per il trattamento e la prevenzione secondaria del tromboembolismo venoso.

A.3.1

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

Reversal of dabigatran anticoagulant effect with idarucizumab.

Studio di sicurezza sull’inattivazione rapida dei effetti anticoagulati di dabigatran mediante idarucizumab

A.4.1

Sponsor's protocol code number

1321.7

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/069/2014

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Boehringer Ingelheim Italia S.p.A.
B.1.3.4	Country	Italy
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	Boehringer Ingelheim Italia S.p.A.
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	Boehringer Ingelheim Pharma GmbH & Co. KG
B.5.2	Functional name of contact point	QRPE PSC CT Information Disclosure
B.5.3	Address:
B.5.3.1	Street Address	Binger Strasse 173
B.5.3.2	Town/ city	Ingelheim am Rhein
B.5.3.3	Post code	55216
B.5.3.4	Country	Germany
B.5.4	Telephone number	+1 800 243 0127
B.5.5	Fax number	+1 800 821 7119
B.5.6	E-mail	clintriage.rdg@boehringer-ingelheim.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	Praxbind
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	idarucizumab
D.3.2	Product code	BI 655075
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	IDARUCIZUMAB
D.3.9.2	Current sponsor code	BI 655075
D.3.9.4	EV Substance Code	SUB166928
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

Serious bleeding/emergency surgery or urgent procedure after treatment with dabigatran

pazienti pediatrici arruolati negli studi in corso di fase IIb/III con dabigatran etexilato per il trattamento e la prevenzione secondaria del tromboembolismo venoso.

E.1.1.1

Medical condition in easily understood language

Serious bleeding/emergency surgery or urgent procedure after treatment with dabigatran

pazienti pediatrici arruolati negli studi in corso di fase IIb/III con dabigatran etexilato per il trattamento e la prevenzione secondaria del tromboembolismo venoso.

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10066899
E.1.2	Term	Venous thromboembolism
E.1.2	System Organ Class	100000004866

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10049909
E.1.2	Term	Venous thromboembolism prophylaxis
E.1.2	System Organ Class	100000004865

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 the safety of idarucizumab, as assessed by the occurrence of patients with drug related adverse events (including immune reactions) and all-cause mortality in paediatric venous thromboembolism (VTE) patients treated with dabigatran in ongoing clinical trials who require emergency surgery/urgent procedures or patients who have life-threatening or uncontrolled bleeding which requires urgent intervention, when rapid reversal of the anticoagulant effects of dabigatran is needed.

l’obiettivo primario è quello di dimostrare la sicurezza di idarucizumab, mediante la valutazione di eventi avversi correlati al farmaco (incluso reazioni immunogeniche) e morti per tutte le cause, in pazienti pediatrici con tromboembolismo venoso (TEV) trattati con dabigatran nei studi clinici in corso e che necessitano di un intervento chirurgico di emergenza/procedura urgente oppure in pazienti con un sanguinamento potenzialmente fatale o non controllato che necessitano di un intervento urgente, e quindi, quando è necessaria l’inattivazione rapida dei effetti anticoagulati di dabigatran.

E.2.2

Secondary objectives of the trial

Assessments of the reversal of dabigatran, bleeding status or emergency surgery/urgent procedures, clinical outcomes, pharmacokinetics of dabigatran and idarucizumab.

Valutazione degli outcam clinici di idarucizumab e farmacocinetica di dabigatran e idarucizumab

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients taking dabigatran etexilate in the paediatric trials 1160.106 or 1160.108 are eligible for this trial if they meet the following criteria:

Group A:

- Overt bleeding judged by the treating physician to require a reversal agent.
- Currently taking dabigatran etexilate in the context of a clinical trial with dabigatran etexilate (1160.106 or 1160.108).
- Male or female patients from 0 to less than 18 years of age at the time of informed consent/assent for participation in trial 1160.106 or in trial 1160.108.
- Female patients of childbearing potential (defined as having experienced menarche) must have followed the contraception requirements according to the dabigatran trial 1160.106 or trial 1160.108 in which they are enrolled.
- Written informed consent provided by the patient (and/or the patient¿s legally accepted representative) and assent provided by the patient (if applicable) at the time of informed consent signature in accordance with GCP and local legislation prior to admission to the trial. If the child is unable to give assent at the time of the emergency, the assent, when applicable will be obtained as soon as feasible.

Group B:

- A condition requiring an emergency surgery or invasive procedure where adequate haemostasis is required. Emergency is defined as need for surgery or intervention within the following 8 hours.
- Currently taking dabigatran etexilate in the context of a clinical trial with dabigatran etexilate (1160.106 or 1160.108).
- Male or female patients from 0 to less than 18 years of age at the time of informed consent/assent for participation in trial 1160.106 or in trial 1160.108.
- Female patients of childbearing potential (defined as having experienced menarche) must have followed the contraception requirements according to the dabigatran trial 1160.106 or trial 1160.108 in which they are enrolled.
- Written informed consent provided by the patient (and/or the patient¿s legally accepted representative) and assent provided by the patient (if applicable) at the time of informed consent signature in accordance with GCP and local legislation prior to admission to the trial. If the child is unable to give assent at the time of the emergency, the assent, when applicable will be obtained as soon as feasible.

Pazienti in trattamento con dabigatran etexilato nell’ambito degli studi pediatrici 1160.106 e 1160.108 sono eleggibili per questo studio se rispettano i seguenti criteri:
Gruppo A:
1.Chiara condizione di sanguinamento che, secondo il giudizio del medico, necessiti di un agente revertente.
2.Pazienti attualmente in trattamento con dabigatran etexilato nel contesto di uno studio clinico con dabigatran (1160.106 e 1160.108).
3.Pazienti di sesso maschile o femminile di età da 0 anni a meno di 18 anni al momento del consenso/assenso alla partecipazione allo studio 1160.106 o studio 1160.108.
4.Pazienti di sesso femminile in età fertile (definito come il verificarsi del menarca) avranno dovuto seguire i metodi contraccettivi richiesti durante la partecipazione allo studio 1160.106 oppure allo studio 116.108 con dabigatran.
5.Consenso informato scritto del paziente (e/o del legale rappresentante riconosciuto) e assenso del paziente (se applicabile) ottenuto al momento della firma del consenso, in accordo alle GCP e legislazione locale e prima della partecipazione allo studio. Nel caso in cui il paziente non fosse in grado di dare l’assenso al momento dell’emergenza, l’assenso, quando applicabile, sarà ottenuto il prima possibile.

Gruppo B:
1.Una condizione che necessita di un intervento di chirurgia d’emergenza o procedura invasiva dove sia richiesta un’adeguata omeostasi. Emergenza è definita come la necessita di chirurgia o intervento entro le successive 8 ore .
2.Pazienti attualmente in trattamento con dabigatran etexilato nel contesto di uno studio clinico con dabigatran (1160.106 e 1160.108).
3.Pazienti di sesso maschile o femminile di età da 0 anni a meno di 18 anni al momento del consenso/assenso alla partecipazione allo studio 1160.106 o studio 1160.108.
4.Pazienti di sesso femminile in età fertile (definito come il verificarsi della presenza del ciclo mestruale) avranno dovuto seguire i metodi contraccettivi richiesti durante la partecipazione allo studio 1160.106 oppure allo studio 116.108 con dabigatran.
5.Consenso informato scritto del paziente (e/o del legale rappresentante riconosciuto) e assenso del paziente (se applicabile) ottenuto al momento della firma del consenso, in accordo alle GCP e legislazione locale e prima della partecipazione allo studio. Nel caso in cui il paziente non fosse in grado di dare l’assenso al momento dell’emergenza, l’assenso, quando applicabile, sarà ottenuto il prima possibile.

E.4

Principal exclusion criteria

Group A:

- Patients with minor bleeding (e.g. epistaxis, haematuria) who can be managed with standard supportive care.
- Patients with no clinical signs of bleeding.
- Patients with body weight < 2.5 kg
- Contraindications to trial medication including known hypersensitivity to the drug or its excipients; i.e. patients with hereditary fructose intolerance who may react to sorbitol or infants with unknown hereditary fructose intolerance status.
- Female patients who are pregnant, nursing, or who plan to become pregnant while in the trial.

Group B:

- A surgery or procedure which is elective or where the risk of uncontrolled or unmanageable bleeding is low.
- Patients with body weight < 2.5 kg
- Contraindications to trial medication including known hypersensitivity to the drug or its excipients; i.e. patients with hereditary fructose intolerance who may react to sorbitol or infants with unknown hereditary fructose intolerance status.
- Female patients who are pregnant, nursing, or who plan to become pregnant while in the trial.

Gruppo A:
1.Pazienti con sanguinamento minore (ad esempio epistassi, ematuria) che possono essere gestiti con terapie standard.
2.Pazienti senza sintomi clinici di sanguinamento.
3.Pazienti con peso corporeo < 2.5 Kg
4.Controindicazioni per il farmaco in studio, incluso una ipersensibilità nota al farmaco o ai suoi eccipienti, ad esempio pazienti con una nota intolleranza ereditaria al fruttosio che potrebbero determinare una reazione al sorbitolo.
5.Pazienti di sesso femminile gravide, in allattamento, o che stanno pianificando una gravidanza durante la partecipazione allo studio.

Gruppo B:
1.Un intervento chirurgico o procedura elettiva dove il rischio di sanguinamento non controllato o non gestibile è basso.
2.Pazienti con peso corporeo < 2.5 Kg
3.Controindicazioni per il farmaco in studio, incluso una ipersensibilità nota al farmaco o ai suoi eccipienti, ad esempio pazienti con una nota intolleranza ereditaria al fruttosio che potrebbero determinare una reazione al sorbitolo.
4.Pazienti di sesso femminile gravide, in allattamento, o che stanno pianificando una gravidanza durante la partecipazione allo studio.

E.5 End points

E.5.1

Primary end point(s)

1: Safety of idarucizumab in a paediatric population as assessed by the occurrence of drug-related adverse events (including immune reactions) and all-cause mortality during the trial.

1) Dimostrare la sicurezza di idarucizumab, mediante la valutazione di eventi avversi correlati al farmaco (incluso reazioni immunogeniche) e morti per tutte le cause durante lo studio.

E.5.1.1

Timepoint(s) of evaluation of this end point

1: 30 days post-dose

1) 30 giorni post dose

E.5.2

Secondary end point(s)

1: Percent change of coagulation tests (dTT, ECT) at 30 minutes post-dose compared to pre-dose.

2: Time to achieve complete reversal of dabigatran effect, based on coagulation tests (dTT and ECT).

3: Duration of complete reversal of dabigatran effect sustained at 24 hours post-dose, based on coagulation tests (dTT and ECT).

4: Cessation of bleeding (Group A patients only).

5: Bleeding status and other clinical conditions that may contribute to bleeding (Group A patients only) during the trial.

6: Development of treatment-emergent ADA with cross reactivity to idarucizumab at
30 days post-dose of idarucizumab (binary).

1.Variazione in percentuale dei test della coagulazione (dTT, ECT) effettuati al basale (pre-dose) e dopo 30 minuti dall’assunzione di idarucizumab
2.Tempo per l’ottenimento dell’inattivazione dell’effetto di dabigatran, basato sui test della coagulazione (dTT e ECT)
3.Durata della completa inattivazione dell’effetto di dabigatran sostenuta a 24 ore dopo l’assunzione, basato sui test della coagulazione (dTT e ECT)
4.Cessazione del sanguinamento (solo per pazienti del gruppo A)*
5.Grado di severità del sanguinamento e altre condizioni cliniche che potrebbero contribuire al sanguinamento (solo per pazienti del gruppo A) durante lo studio.
6.Formazione di anticorpi anti farmaco (ADA) correlati al trattamento con cross-reattività verso idarucizumab dopo 30 minuti dall’assunzione di idarucizumab*.
*Per motivi di sicurezza

E.5.2.1

Timepoint(s) of evaluation of this end point

1: 30 minutes post-dose

2: Up to 24 hours post-dose

3: Up to 24 hours post-dose

4: Up to 24 hours post-dose

5: 30 days post-dose

6: 30 days post-dose

1: 30 minuti post-dose
2: Fino a 24 ore post-dose
3: Fino a 24 ore post-dose
4: Fino a 24 ore post-dose
5: 30 giorni post-dose
6: 30 giorni post-dose

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

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

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

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

Canada

Czech Republic

Germany

Italy

Lithuania

Norway

Russian Federation

Sweden

Switzerland

Turkey

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

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

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.3.1

Number of subjects for this age range:

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

(small) children

bambini piccoli

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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.

Nessuno

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

2016-07-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-07-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-10-19

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