Clinical Trials Register

Summary
EudraCT Number:	2009-011186-88
Sponsor's Protocol Code Number:	ABB–09–001
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-09-04
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

Portugal - INFARMED

A.2

EudraCT number

2009-011186-88

A.3

Full title of the trial

Inhibitor Development in Previously Untreated Patients (PUPs) or Minimally Blood Component-Treated Patients (MBCTPs) when Exposed to plasma-derived von Willebrand Factor-Containing Factor VIII (VWF/FVIII) Concentrates and to Recombinant Factor VIII (rFVIII) Concentrates: An Independent, International, Multicentre, Prospective, Controlled, Randomised, Open Label, Clinical Trial

Desenvolvimento de Inibidor em Doentes Previamente Não Tratados (PNTs) ou Doentes Minimamente Tratados com Componentes Sanguíneos (MTCS) quando Expostos a Concentrados Derivados do Plasma Contendo Factor von Willebrand / Factor VIII (FVW/FVIII) e a Concentrados de Factor VIII Recombinante (FVIIIr): Um Ensaio Clínico Independente, Internacional, Multicêntrico Prospectivo, Controlado, Aleatorizado e Aberto

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

SIPPET

A.4.1

Sponsor's protocol code number

ABB–09–001

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 CENTRO EMOFILIA E TROMBOSI ANGELO BIANCHI BONOMI
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	N/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	ANAGRAM-ESIC, S.L.
B.5.2	Functional name of contact point	Medical Director
B.5.3	Address:
B.5.3.1	Street Address	Compte Urgell, 143
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08036
B.5.3.4	Country	Spain
B.5.4	Telephone number	34934515250
B.5.5	Fax number	34934516631
B.5.6	E-mail	m.cardona@anagram-esic.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	FANHDI
D.2.1.1.2	Name of the Marketing Authorisation holder	GRIFOLS
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	PLASMA DERIVED VON WILLEBRAND FACTOR CONTAINING
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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	Yes
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	REFACTO AF
D.2.1.1.2	Name of the Marketing Authorisation holder	WYETH Europa Lta
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	RECOMBINANT PRODUCT WITHOUT VON WILLEBRAND FACTOR
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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	Yes
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

E.1.1.1

Medical condition in easily understood language

Severe Haemophilia type A

Haemophilia A grave

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10018937
E.1.2	Term	Haemophilia A
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the immunogenicity of VWF/FVIII and of rFVIII concentrates by determining the frequency of inhibitor development in PUPs and MBCTs in the first 50 EDs or in the first 3 years from enrolment, whichever comes first

E.2.2

Secondary objectives of the trial

•To evaluate the anamnestic response of inhibitor patients
•To evaluate the frequency of transient inhibitors
•To evaluate the modality of occurrence of inhibitors (number of EDs, titre at onset, etc)
•To evaluate clinical factors potentially associated to inhibitor development (age at first treatment, severity of bleeding episodes, surgery, intensity of treatment, modality of treatment, time of treatment in relation to vaccinations, concurrent diseases (in particular viral infections), complications of venous access and/or medications, type of delivery, breast feeding, type of milk formula)
•To evaluate laboratory factors potentially associated to inhibitor development (severity of FVIII defect, FVIII gene defect, FVIII Ag, HLA phenotype, IL-10.G, TNF alpha, CTLA-4 polymorphisms), analyses of FVIII mRNA expression levels, epitope mapping, FII and FV gain-of-function thrombophilic mutation

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Male subjects
•Any ethnicity
•Age <6 years
•Severe haemophilia A (FVIII:C <1%), as confirmed by the central laboratory
o Patients with FVIII levels >1% and < 2% will be separately recorded in the screening list
•Previously untreated (0 EDs to any FVIII concentrate or blood products) or minimally treated (<5 EDs) with blood components, namely whole blood, fresh frozen plasma, packed red blood cells, platelets or cryoprecipitate
o Patients not meeting these criteria will be separately recorded in the screening list
•Negative inhibitor measurement at both local and central laboratory at screening
•Ability to comply with study requirements
•Signed informed consent of legal tutors
o Patients who will not accept to enter into the study or to be randomized will be separately recorded

E.4

Principal exclusion criteria

•Plasma FVIII level ≥1%, as assayed at the central laboratory
o Those patients originally diagnosed locally as severe but subsequently found to have FVIII levels ranging from 1% to 2% on testing at the central laboratory will be separately recorded in the screening list.
•Previous history of FVIII inhibitor
•Other congenital or acquired bleeding defects
•Concomitant congenital or acquired immunodeficiency
•Concomitant treatment with systemic immunosuppressive drugs
•Concomitant treatment with any investigational drug

E.5 End points

E.5.1

Primary end point(s)

•To assess the immunogenicity of plasma derived VWF/FVIII and rFVIII concentrates by determining the frequency of inhibitor development in the first 50 EDs or in the first 3 years from enrolment, whichever comes first in PUPs and MBCTs

• Avaliar a imunogenicidade dos concentrados VWF/FVIII e de rFVIII determinando a frequência de desenvolvimento de inibidores nos Doentes PNT e MTCS nos primeiros 50 DE ou nos 3 primeiros anos, o que ocorrer primeiro.

E.5.1.1

Timepoint(s) of evaluation of this end point

Patients will be monitored for inhibitor development in case of treatment failure or every 3 to 4 EDs for the first 20 EDs and every 10 EDs thereafter, or every 3 months, whichever come first, and at any time inhibitor development would be clinically suspected. Patients on prophylaxis will be tested every 2 weeks.

E.5.2

Secondary end point(s)

• To evaluate the anamnestic response of inhibitor patients
• To evaluate the frequency of transient inhibitors
• To evaluate the modality of occurrence of inhibitors (number
of EDs, titre at onset, etc)
• To evaluate clinical factors potentially associated to inhibitor
development (age at first treatment, severity of bleeding
episodes, surgery, intensity of treatment, modality of
treatment, time of treatment in relation to vaccinations,
concurrent diseases (in particular viral infections),
complications of venous access and/or medications, type of
delivery, breast feeding, type of milk formula)
• To evaluate laboratory factors potentially associated to
inhibitor development (severity of FVIII defect, FVIII gene
defect, FVIII Ag, HLA phenotype, IL-10.G, TNF alpha, CTLA-4
polymorphisms), analyses of FVIII mRNA expression levels,
epitope mapping, FII and FV gain-of-function thrombophilic
mutations.
• To evaluate the incidence of all other adverse events related
and not related to the products used

E.5.2.1

Timepoint(s) of evaluation of this end point

evaluation timing when the first 150 patients achieve the 20 days of exposure and at the end fo the study

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

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

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

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

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

Information not present in EudraCT

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

European Union

Austria

Belgium

Brazil

Chile

Colombia

Egypt

France

Germany

India

Iran, Islamic Republic of

Italy

Mexico

Portugal

Saudi Arabia

South Africa

Spain

Turkey

United Kingdom

United States

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

31.03.2014

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:

300

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:

180

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)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

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

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

Yes

F.3.3.7.1

Details of other specific vulnerable populations

MALE SUBJECT <6 YAERS

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

100

F.4.2.2

In the whole clinical trial

300

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)

After the subject has ended the participation in the trial the treatment will be available through the Hospital Pharmacy

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

2010-01-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-12-04

P. End of Trial
P.	End of Trial Status	Completed

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