Clinical Trials Register

Summary
EudraCT Number:	2017-000065-73
Sponsor's Protocol Code Number:	Sobi.Elocta-003
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:	2021-05-25
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

2017-000065-73

A.3

Full title of the trial

A Non-Controlled, Open-Label, Multicenter, Study of Immune Tolerance Induction Performed with rFVIIIFc within a Timeframe of 60 Weeks in Severe Haemophilia A Patients with Inhibitors who have Failed Previous Immune Tolerance Induction Therapies

Studio multicentrico, non controllato, in aperto sull'induzione dell'immuno tolleranza ottenuta con rFVII1Fc entro un periodo di 60 settimane in pazienti con emofilia A grave e con inibitori, che hanno fallito precedenti terapie di immuno tolleranza indotta.

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

nap

A.4.1

Sponsor's protocol code number

Sobi.Elocta-003

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	SWEDISH ORPHAN BIOVITRUM AB (PUBL)
B.1.3.4	Country	Sweden
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	Swedish Orphan Biovitrum AB (publ)
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	Bioverativ Therapeutics Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Swedish Orphan Biovitrum AB
B.5.2	Functional name of contact point	Clinical Program Management
B.5.3	Address:
B.5.3.1	Street Address	Tomtebodavägen 23A
B.5.3.2	Town/ city	Stoccolma
B.5.3.3	Post code	SE-112 76
B.5.3.4	Country	Sweden
B.5.4	Telephone number	004686970000
B.5.5	Fax number	000000
B.5.6	E-mail	Emma.hakansson@sobi.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	ELOCTA
D.2.1.1.2	Name of the Marketing Authorisation holder	Swedish Orphan Biovitrum AB (publ)
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	rFVII1Fc
D.3.2	Product code	[nap]
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	EFMOROCTOCOG ALFA
D.3.9.2	Current sponsor code	nap
D.3.9.4	EV Substance Code	SUB168409
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
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	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	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.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	ELOCTA
D.2.1.1.2	Name of the Marketing Authorisation holder	Swedish Orphan Biovitrum AB (publ)
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	rFVII1Fc
D.3.2	Product code	[nap]
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	EFMOROCTOCOG ALFA
D.3.9.2	Current sponsor code	nap
D.3.9.4	EV Substance Code	SUB168409
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
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	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	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.IMP: 3
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	ELOCTA
D.2.1.1.2	Name of the Marketing Authorisation holder	Swedish Orphan Biovitrum AB (publ)
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	rFVII1Fc
D.3.2	Product code	[nap]
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	EFMOROCTOCOG ALFA
D.3.9.2	Current sponsor code	nap
D.3.9.4	EV Substance Code	SUB168409
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
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	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	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.IMP: 4
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	ELOCTA
D.2.1.1.2	Name of the Marketing Authorisation holder	Swedish Orphan Biovitrum AB (publ)
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	rFVII1Fc
D.3.2	Product code	[nap]
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	EFMOROCTOCOG ALFA
D.3.9.2	Current sponsor code	nap
D.3.9.4	EV Substance Code	SUB168409
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2000
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	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	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.IMP: 5
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	ELOCTA
D.2.1.1.2	Name of the Marketing Authorisation holder	Swedish Orphan Biovitrum AB (publ)
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	rFVII1Fc
D.3.2	Product code	[nap]
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	EFMOROCTOCOG ALFA
D.3.9.2	Current sponsor code	nap
D.3.9.4	EV Substance Code	SUB168409
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3000
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	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	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

Severe Haemophilia A Patients with Inhibitors who have Failed Previous Immune Tolerance Induction Therapies

Pazienti con emofilia A grave con inibitori che hanno fallito precedenti terapie di immuno tolleranza indotta

E.1.1.1

Medical condition in easily understood language

patients with haemophilia A who have developed inhibitors towards factor VIII replacement therapy and has not been helped by previous attempts to erradicate the inhibitors

Pazienti con emofilia A che hanno sviluppato degli inibitori attraverso le terapie di sostituzione del fattore VIII e che hanno fallito precedenti tentativi di rimozione degli inibitori.

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	20.0
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 describe the outcome of ITI treatment performed with rFVIIIFc within a timeframe of 60 weeks in patients who failed previous attempts at tolerization including use of immunosuppressants

Descrivere l'esito del trattamento di induzione dell'immuno tolleranza (ITI) mediante rFVII1Fc durante un periodo di 60 settimane in pazienti che hanno fallito precedenti tentativi di tollerizzazione, incluso l'uso di immunosoppressori

E.2.2

Secondary objectives of the trial

To describe time to tolerization of ITI performed with rFVIIIFc within a timeframe of 60 weeks in patients who failed previous attempts at tolerization including use of immunosuppressants.
To describe the relapse rate over a 48-week period following successful ITI performed with rFVIIIFc.
To describe the intercurrent bleeding during ITI and during the 48-week period after successful ITI performed with rFVIIIFc.
To describe safety and tolerability of rFVIIIFc when used for ITI.
To describe the impact of ITI treatment with rFVIIIFc on health economy.
To describe adherence of rFVIIIFc when used for ITI.

Descrivere il tempo alla tollerizzazione dell'ITI mediante rFVII1Fc durante un periodo di 60 settimane in pazienti che hanno fallito precedenti tentativi di tollerizzazione, incluso l'uso di immunosoppressori.
Descrivere il tasso di recidiva nell'arco di 48 settimane successivamente al trattamento ITI avvenuto con successo mediante rFVII1Fc.
Descrivere il sanguinamento intercorrente durante I'ITI e nell'arco di 48 settimane successive al trattamento ITI avvenuto con successo mediante rFVII1Fc.
Descrivere Ia sicurezza e Ia tollerabilita di rFVII1Fc utilizzato per I'ITI.
Descrivere l'impatto del trattamento ITI mediante rFVII1Fc sull'economia sanitaria.
Descrivere l'aderenza al trattamento con rFVII1Fc quando utilizzato per I'ITI.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed and dated informed consent provided by the patient, or the patient's legally authorized representative for patients under the legal age. Assent should be obtained from pediatric patients according to local regulations
2. Male patients of any age diagnosed with severe haemophilia A, as confirmed from the medical record
3. Previously treated with any plasma-derived or recombinant conventional or extended half-life FVIII
4. Diagnosed with high titer inhibitors (historical peak =5 BU/mL according to medical records)
5. Inhibitor titer >0.6 BU at screening
6. Failed previous ITI attempt(s) with any plasma-derived or recombinant conventional or extended half-life FVIII including the use of immunosuppressant The attempt should be documented in the medical records and have the following characteristics:
• A minimum FVIII dose equivalent to the low dose arm of the International ITI study (50 IU/kg, 3 times/week)
• A minimum ITI treatment period of 33 months or
• Shorter than 33 months if no downward trend of at least 20% in the inhibitor titer in a 6-month period after the initial 3 months of the ITI treatment
7. All patients must practice effective contraception during the study and for 3 months after their last dose of study treatment. Acceptable forms of birth control include barrier method (e.g. male condom, female condom, cervical cap, diaphragm, contraceptive sponge).

1. Consenso informato firmato e datato dal paziente, o dal legale rappresentante in caso di pazienti minorenni. L'assenso dei pazienti in eta pediatrica va ottenuto conformemente alle normative locali
2. Pazienti di sesso maschile di qualsiasi eta con diagnosi di emofilia A grave, come confermato dalla cartella clinica
3. Precedente trattamento con qualsiasi FVIII plasma-derivato o ricombinante di tipo convenzionale o a emivita prolungata
4. Diagnosi di inibitori ad alto titolo (picco storico a5 BU/mL in base alla cartella clinica)
5. Titolo degli inibitori >0,6 BU allo screening
6. Fallimento di precedente/i tentativo/i di induzione di immunotolleranza (ITI) con qualsiasi FVIII plasma-derivato o ricombinante di tipo convenzionale o a emivita prolungata, incluso I'uso di immunosoppressori. II tentativo deve essere documentato nella cartella clinica e presentare le caratteristiche seguenti:
• dose minima di FVIII equivalente a quella del braccio a basso dosaggio dello Studio ITI internazionale (50 IU/kg, 3 volte/settimana)
• periodo di trattamento ITI minimo di 33 mesi oppure
• inferiore a 33 mesi qualora it titolo degli inibitori non mostri una tendenza a diminuire almeno del 20% in un periodo di 6 mesi
successivi ai primi 3 mesi di trattamento ITI
7. Tutti i pazienti devono utilizzare metodi di contraccezione efficaci durante lo studio e per 3 mesi dopo l'ultima dose di trattamento in studio. Metodi di barriera accettabili includono metodi meccanici (ad es. condom maschile, condom femminile, cappuccio cervicale, diaframma, spugna contraccettiva).

E.4

Principal exclusion criteria

1. Other coagulation disorder(s) in addition to haemophilia A
2. History of hypersensitivity reactions associated with any rFVIIIFc administration
3. High risk of cardiovascular, cerebrovascular, or other thromboembolic events, as judged by the investigator
4. Planned major surgery to be deferred after study completion. Minor surgery such as tooth extraction or insertion/replacement of central venous access device is allowed.
5. Concurrent systemic treatment with immunosuppressive drugs within 12 weeks prior to screening. Exceptions to this include: ribavirin for treatment of HCV, and/or systemic steroids (a total of 2 courses of pulse treatments lasting no more than 7 days within 12 weeks prior to Day 1) and/or inhaled steroids
6. Abnormal renal function (serum creatinine >2.0 mg/dL) as assessed by local lab
7. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × upper limit of normal (ULN) as assessed by local lab
8. Serum total bilirubin >3 × ULN as assessed by local lab
9. CD4 lymphocytes =200 mm3 if known as HIV antibody positive at Screening
10. Viral load of =400 copies/mL if known HIV antibody positive at Screening
11. Patients with a documented history of alcohol or substance abuse within 12 months prior to randomization
12. Previous inclusion in this study
13. Participation in another concurrent clinical interventional study within 30 days of screening or intake of an investigational drug within five half-lives of that investigational drug has passed
14. Foreseeable inability to cooperate with given instructions or study procedures
15. Presence of any medical or psychological condition or laboratory result that in the opinion of the investigator can interfere with the patient’s ability to comply with the protocol requirements or makes the patient not appropriate for inclusion to the study and treatment with rFVIIIFc

Exclusion criteria 9 and 10 refer to tests performed within 26 weeks prior to Screening. If results are not available, a new test should be drawn at the screening visit and analyzed locally prior to inclusion.

1. Altro/i disturbo/i della coagulazione oltre all'emofilia A
2. Storia di reazioni di ipersensibilita associate alla somministrazione di qualsiasi rFVII1Fc
3. Rischio elevato di eventi cardiovascolari, cerebrovascolari o altri eventi tromboembolici, secondo it giudizio dallo sperimentatore
4. Intervento di chirurgia maggiore programmato da posticipare dopo la conclusione dello studio. Sono consentiti interventi di chirurgia minore come l'estrazione di un dente o l'inserimento/la sostituzione di un accesso venoso centrale
5. Trattamento sistemico concomitante con immunosoppressori nelle 12 settimane precedenti lo screening.
Fanno eccezione: il trattamento con ribavirina per I'HCV e/o steroidi sistemici (un totale di 2 cicli di trattamento pulsatile per non piu di 7 giorni nelle 12 settimane precedenti il Giorno 1) e/o steroidi per via inalatoria
6. Funzionalitb renale anomala (creatinina sierica >2,0 mg/dL), come valutato dal laboratorio locale
7. Alanina aminotransferasi (ALT) o aspartato aminotransferasi (AST) sierica >5 x it limite superiore della norma (ULN), come valutato dal laboratorio locale
8. Bilirubina totale sierica >3 x ULN, come valutato dal laboratorio locale
9. Linfociti CD4 s200 mm3 in caso di positivity nota agli anticorpi anti-HIV allo screening
10. Carica virale 2400 copie/mL in caso di positivity nota agli anticorpi anti-HIV allo screening
11. Pazienti con una storia documentata di abuso di alcol o sostanze nei 12 mesi precedenti Ia randomizzazione
12. Precedente inclusione in questo studio
13. Partecipazione a un altro studio clinico interventistico concomitante nei 30 giorni precedenti lo screening o precedente
assunzione di un farmaco sperimentale entro un periodo inferiore a cinque emivite di detto farmaco
14. Prevedibile incapacity di attenersi alle istruzioni ricevute o alle procedure di studio
15. Presenza di qualsiasi condizione medica o psicologica o risultato di esami di laboratorio che, nell'opinione dello sperimentatore,
pub interferire con Ia capacity del paziente di rispettare i requisiti del protocollo o rende il paziente inidoneo all'inclusione nello
studio e al trattamento con rFVII1Fc
I criteri di esclusione 9 e 10 si riferiscono a esami effettuati nelle 26 settimane precedenti lo screening. Qualora i risultati non siano
disponibili, l'esame dovra essere ripetuto alla visits di screening e il campione analizzato dal laboratorio locale prima
dell'inclusione.

E.5 End points

E.5.1

Primary end point(s)

ITI success defined as achieving all 3 of the following criteria:
• Negative titer for inhibitor (<0.6 BU/mL by the Nijmegen-modified Bethesda assay) at 2 consecutive visits
• FVIII incremental recovery (IR) >66% of the expected IR at 2 consecutive visits
• FVIII half-life (t½) =7 hours

Successo dell'ITI definito come raggiungimento di tutti e 3 i seguenti criteri:
• Titolo dell'inibitore negativo (<0,6 BU/ml secondo il metodo Bethesda modificato Nijmegen) in 2 visite consecutive
• Recupero incrementale (IR) di FVIII >66% dell'IR previsto in 2 visite consecutive
• Emivita di FVIII (tY2) 7 ore

E.5.1.1

Timepoint(s) of evaluation of this end point

60 weeks

60 settimane

E.5.2

Secondary end point(s)

Time to ITI success
Occurrence of relapse during a 48-week period following successful ITI treatment
Number of bleedings during ITI treatment
Bleeding rate during a 48-week period following successful ITI treatment
Adverse events
Consumption of rFVIIIFc
Number of days missed school or work during ITI treatment
Number of days missed school or work during a 48-week period following successful ITI treatment
Number of hospitalizations during ITI treatment
Number of hospitalizations during a 48-week period following successful ITI treatment
Adherence

Tempo al successo dell'ITI
Comparsa di recidiva nell'arco di 48 settimane successive al trattamento ITI avvenuto con successo
Numero di sanguinamenti durante il trattamento ITI
Tasso di sanguinamento nell'arco di 48 settimane successive al trattamento ITI avvenuto con successo
Eventi avversi
Assunzione di rFVII1Fc
Numero di giorni di assenza da scuola o dal lavoro durante il trattamento ITI
Numero di giorni di assenza da scuola o dal lavoro nell'arco di 48 settimane successive al trattamento ITI avvenuto con successo
Numero di ricoveri in ospedale durante il trattamento ITI
Numero di ricoveri in ospedale nell'arco di 48 settimane successive al trattamento ITI avvenuto con successo
Aderenza

E.5.2.1

Timepoint(s) of evaluation of this end point

60 weeks for the following secondary endpoints -
- Time to ITI success
- Number of bleedings during ITI treatment
- Time to ITI Success
- Number of days missed school or work during ITI treatment
- ITI treatment Adherence

108 weeks for the following secondary endpoint
- Occurrence of relapse during a 48-week period following successful ITI
- Bleeding rate during a 48-week period following successful ITI
- treatment
- Adverse events
- Consumption of rFVIIIFc
- Number of days missed school or work during a 48-week period
- following successful ITI treatment
- Number of hospitalizations during a 48-week period following successful

60 settimane per i seguenti endpoint secondari
- Tempo di successo ITI
- Numero di sanguinamenti durante il trattamento ITI
- Tempo di successo ITI
- Numero di giorni di assenza da scuola o da lavoro durante il trattamento ITI
- Aderenza al trattamento ITI
108 settimane per i seguenti endpoint secondari
- Presenza di ricaduta durante il periodo di 48 settimane in seguito al successo ITI
- Tasso di sanguinamento durante il periodo di 48 settimane in seguito al successo con trattamento ITI
- Eventi avversi
- Consumo di rFVII1Fc
- Numero di giorni di assenza da scuola o da lavoro durante il periodo di 48 settimane in seguito al successo con trattamento ITI
- Numero si ospedalizzazioni durante il periodo di 48 settimane in seguito al successo

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

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

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

Tollerabilita

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

Canada

United States

Belgium

France

Germany

Ireland

Italy

Sweden

United Kingdom

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

the date of the last patient’s last visit

La data dell'ultima visits dell'ultimo paziente

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.1.1.1

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)

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)

Yes

F.1.3.1

Number of subjects for this age range:

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

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

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 patient has completed the end of treatment visit, they should be treated and followed-up according to investigator judgement and local practice and no further investigational medicinal product will be provided.

Al termine della visita di fine trattamento, i pazienti verranno trattati e sottoposti a follow-up secondo it parere dello sperimentatore e la pratica locale, e non riceveranno piu it prodotto medicinale sperimentale

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

2017-12-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-11-08

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

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