Clinical Trials Register

Summary
EudraCT Number:	2010-020113-85
Sponsor's Protocol Code Number:	CSLCT-BIO-10-67
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:	2012-03-07
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2010-020113-85

A.3

Full title of the trial

A Multi-center, Interventional, Non-randomized, Open-label, Single-group Phase III Study to evaluate Plasma-Derived Antihemophilic Factor/von Willebrand Factor Concentrate (Biostate®) for Immune Tolerance Induction in Male Pediatric Subjects with Hemophilia A (≤2%) who have Developed High-titer Antibodies to Factor VIII (Factor VIII Inhibitors)

Studio multicentrico, interventistico, non randomizzato, in aperto, a gruppo singolo di fase III per valutare il fattore antiemofilico derivato da plasma/ fattore di von Willebrand concentrato (Biostate®) nell`™induzione della tolleranza immunitaria in soggetti pediatrici di sesso maschile con emofilia A (2%) che abbiano sviluppato un elevato titolo anticorpale per il fattore VIII (inibitori del fattore VIII)

A.3.1

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

This is a clinical study to investigate how well Biostate works in treatment of male patients below the age of 12 years who have a clotting factor deficiency that is aggravated by the development of antibodies. The antibodies are directed against the clotting factor that is given for replacement therapy and usually make therapy unsuccessful. The treatment used in this study is called immune tollerance therapy.

Questo studio clinico ha lo scopo di valutare quanto bene funziona Biostate nel trattamento di pazienti maschi sotto i 12 anni che abbiano un deficit di un fattore della coagulazione aggravato dallo sviluppo di anticorpi. Gli anticorpi sono diretti verso il fattore di coagulazione che viene dato come terapia sostitutiva e che normalmente funziona. Il trattamento usato in questo studio si chiama terapia di immunotolleranza

A.3.2

Name or abbreviated title of the trial where available

SWIFT-ITI

A.4.1

Sponsor's protocol code number

CSLCT-BIO-10-67

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/164/2009

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	CSL BEHRING 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	CSL Behring GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ICON Plc
B.5.2	Functional name of contact point	Anna Folcioni
B.5.3	Address:
B.5.3.1	Street Address	Via Washington, 70
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20146
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39 02 46571103
B.5.5	Fax number	+39 80581834
B.5.6	E-mail	anna.folcioni@iconplc.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	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	Biostate
D.3.2	Product code	NA
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Human Coagulation Factor VIII/von Willebrand factor complex
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	Human Coagulation Factor VIII ( piu' von Willenbrand factor)
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
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	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	Biostate
D.3.2	Product code	NA
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Human Coagulation Factor VIII/von Willebrand factor complex
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	Human Coagulation Factor VIII (piu' von Willenbrand factor)
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
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

Male paediatric subjects with Haemophilia A who developed high titre antibodies to human coagulation Factor VIII

Soggetti pediatrici di sesso maschile con Emofilia A che abbiano sviluppato un elevato titolo anticorpale verso il fattore umano di coagulazione VIII

E.1.1.1

Medical condition in easily understood language

Treatment of patients with hereditary deficiency of blood coagulation factor VIII that developed neutralizing antibodies against factor VIII is investigated

Viene valutato il trattamento in pazienti con un deficit ereditario del fattore VIII per la coagualazione che hanno sviluppato anticorpi che neutralizzano il fattore VIII.

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

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	10018941
E.1.2	Term	Haemophilia NOS
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic 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 the proportion of subjects who achieve a complete response (success) following ITI treatment with Biostate.

Determinare la proporzione di soggetti che ottiene una risposta completa (esito positivo) dopo il trattamento ITI con Biostate.

E.2.2

Secondary objectives of the trial

To assess the safety of Biostate when administered to subjects with haemophilia A and inhibitors to FVIII in an ITI treatment regimen.

Valutare la sicurezza di Biostate somministrato a soggetti con emofilia A e inibitori del FVIII in un regime di trattamento ITI.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Male subjects diagnosed with haemophilia A (≤2% FVIII level in the absence of factor replacement, according to their medical history). 2.Age 28 days to <12 years. 3.ITI treatment can be initiated if: a.An inhibitor level of >5 and <200 BU/mL was confirmed in 2 repeated tests by the central laboratory during the screening period and no waiting period is required as judged by the investigator. b.An inhibitor level of >5 and <200 BU/mL was confirmed in 2 repeated tests by the central laboratory during the screening period and the inhibitor titre decreased from the peak titre during a waiting period (maximum 11 months) added at the discretion of the investigator. c.A subject has pre-existing inhibitors, determined no more than 11 months prior to the Screening visit, which decreased from the peak titre, and an inhibitor level of >5 and <200 BU/mL was confirmed in 2 repeated tests by the central laboratory during the screening period. A waiting period could still be added if the total duration from inhibitor diagnosis until start of ITI treatment (ie, including the screening period) does not exceed 12 months. 4.The subject and/or his legally acceptable representative understand the nature of the study and have given written informed consent to participate in the study. 5.Sufficient peripheral venous access or central venous line.

1.Soggetti di sesso maschile a cui sia stata diagnosticata l’emofilia A (la cui anamnesi mostra un livello del FVIII ≤ 2% in assenza di fattore di sostituzione). 2.Età da 28 giorni a <12 anni. 3.Il trattamento ITI può essere iniziato se: a.È stato confermato un livello dell’inibitore >5 e <200 BU/ml in 2 test ripetuti dal laboratorio centrale durante il periodo di screening e, secondo il parere dello sperimentatore, non è necessario un periodo di attesa. b.È stato confermato un livello dell’inibitore >5 e <200 BU/ml in 2 test ripetuti dal laboratorio centrale durante il periodo di screening e il titolo dell’inibitore è calato dal valore picco durante il periodo di attesa (massimo 11 mesi) aggiunto a discrezione dello sperimentatore. c.Il soggetto ha inibitori preesistenti, determinati non oltre 11 mesi prima della visita di screening, che sono calati dal picco del titolo ed è stato confermato un livello di inibitore >5 e <200 BU/ml in 2 test ripetuti dal laboratorio centrale durante il periodo di screening. È possibile aggiungere un altro periodo di attesa se la durata totale dalla diagnosi dell’inibitore all’inizio del trattamento ITI (ossia che include il periodo di screening) non supera i 12 mesi. 4.Il soggetto e/o il suo rappresentante legalmente riconosciuto comprendono la natura dello studio e hanno espresso consenso informato per iscritto a partecipare allo studio. 5.Sufficiente accesso venoso periferico o linea venosa centrale.

E.4

Principal exclusion criteria

1. The subject has received ITI previously. 2. Subjects with a historical peak inhibitor titre of ≥200 BU/mL. 3. Concomitant treatment with drugs with immunosuppressive side effects (eg, systemic corticosteroids), azathioprine, cyclophosphamide, high dose immunoglobulin or the use of a protein A column or plasmapheresis and interferons. 4. High risk of cardiovascular, cerebrovascular, or other thromboembolic events (excluding catheter thrombosis) as judged by the investigator. 5.Subjects who are human immunodeficiency virus (HIV)-1 or HIV-2 positive (as reported in the medical records or determined at screening). 6.The subject has evidence or a history (within the previous 12 months) of abuse of any drug substance, licit or illicit. 7.The subject has a known or suspected hypersensitivity or has previous evidence of severe side effects to von Willebrand factor (VWF)/FVIII or FVIII concentrates or human albumin. 8.The subject has participated in a clinical study or used an investigational compound (eg, a new chemical entity not approved for clinical use) in the past 3 months, unless the study was for haemophilia A and the subject developed an inhibitor (then, a wash-out period of at least 4 weeks must be applied), or is planning to enter such a study during the study period. 9.Subjects or legal guardians/representatives with suspected inability (eg, language problems) or unwillingness to comply with study procedures. 10.The subject has an acute or chronic medical condition other than haemophilia A, which may, in the opinion of the investigator, affect the conduct of the study. 11.Mental condition rendering the subject (or the subject’s legally acceptable representative) unable to understand the nature, scope and possible consequences of the study). 12.Any condition that is likely to interfere with evaluation of the investigational medicinal product (IMP) or satisfactory conduct of the study. 13.Employee at the study site, or spouse/partner or relative of the investigator or subinvestigators.

1.Il soggetto ha già ricevuto ITI. 2.Soggetti con picco storico del titolo dell’inibitore ≥200 BU/ml. 3.Trattamento concomitante a base di farmaci con effetti collaterali immunosoppressivi (es. corticosteroidi sistemici), azatioprina, ciclofosfamide, immunoglobuline ad alte dosi o l’uso di una colonna della proteina A o plasmaferesi e interferoni. 4.Alto rischio di eventi cardiovascolari, cerebrovascolari o altri eventi tromboembolici (esclusa la trombosi da catetere) a discrezione dello sperimentatore. 5.Soggetti positivi all’HIV-1 (virus dell’immunodeficienza umana -1) o HIV-2 (segnalato nelle cartelle cliniche o determinato allo screening). 6.Anamnesi presente o remota (nei 12 mesi precedenti) di abuso di qualsiasi sostanza farmacologica lecita o illecita da parte del soggetto. 7.Il soggetto ha ipersensibilità nota o sospetta o anamnesi remota di gravi effetti collaterali del fattore di Willebrand (VWF)/FVIII o di concentrati di FVIII o albumina umana. 8.Il soggetto ha partecipato a uno studio clinico o ha usato un composto sperimentale (es. una nuova entità chimica il cui uso clinico non è approvato) nei 3 mesi scorsi, tranne studi per l’emofilia A dove il soggetto ha sviluppato un inibitore (in tal caso deve considerarsi un periodo di wash-out di minimo 4 settimane) o a cui voglia partecipare durante il periodo di studio. 9.Soggetti o tutori/rappresentanti legali con sospetta incapacità (es. problemi di lingua) o mancata volontà di osservanza delle procedure dello studio. 10.Il soggetto ha una condizione medica acuta o cronica diversa dall’emofilia A che, a parere dello sperimentatore, può influenzare lo svolgimento dello studio. 11.Condizione mentale che rende il soggetto (o il rappresentante legalmente riconosciuto del soggetto) incapace di comprendere la natura, l’ambito d’applicazione e le possibili conseguenze dello studio. 12.Qualunque condizione che possa interferire con la valutazione del prodotto medicinale sperimentale (IMP, (investigational medicinal product) o con uno svolgimento soddisfacente dello studio. 13.Dipendente del centro di studio, oppure consorte/partner o parente dello sperimentatore o co-sperimentatori.

E.5 End points

E.5.1

Primary end point(s)

Efficacy endpoints: •Response to ITI treatment: complete response (success), partial response (partial success), or ITI failure. •FVIII inhibitor titre. •Time to complete response (success). •Time to inhibitor <0.6 BU/mL for the first time. Safety endpoints: •Adverse events (AEs). •Clinical laboratory testing (haematology, biochemistry). •Thrombogenic risk assessment: markers of activation of coagulation (eg, fibrin fragments, thrombin-antithrombin complex [TAT]). •Frequency and nature of bleeding events. •Catheter-related complications (eg, line infections). •Physical examination. •Vital signs (blood pressure, heart rate, and body temperature).

Endpoint di efficacia: •Risposta al trattamento ITI: risposta completa (esito positivo), risposta parziale (esito parzialmente positivo) o esito ITI negativo. •Titolo dell’inibitore del FVIII. •Tempo alla risposta completa (esito positivo). •Tempo al titolo dell’inibitore <0,6 BU/ml per la prima volta. Endpoint di sicurezza: •Eventi avversi (EA). •Analisi cliniche di laboratorio (ematologia, biochimica). •Valutazione del rischio di trombogenesi: marcatori di attivazione della coagulazione (es. frammenti di fibrina, complesso trombina-antitrombina [TAT]). •Frequenza e natura degli episodi emorragici. •Complicazioni da catetere (es. infezioni da catetere). •Esame obiettivo. •Segni vitali (pressione sanguigna, frequenza cardiaca e temperatura corporea).

E.5.1.1

Timepoint(s) of evaluation of this end point

Information not available

Informazione non disponibile

E.5.2

Secondary end point(s)

Please see section primary endpoint(s)

Vedi sezione endpoint primario/i

E.5.2.1

Timepoint(s) of evaluation of this end point

Information not available

Informazione non disponibile

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

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

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)

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)

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

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

paediatric population

Popolazione pediatrica

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)

After the study participation the patients will be treated with the current standard therapy on the discretion of their treating doctor. It is expected at the end of the study Biostate will be licensed

Dopo la partecipazione allo studio, i pazienti saranno trattati con la terapia standard disponibile attualmente a discrezione del medico che li segue. Ci si aspetta che Biostate ottenga la licenza alla fine dello studio

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

2012-05-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-09-20

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2014-03-07

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