Clinical Trials Register

Summary
EudraCT Number:	2016-001478-14
Sponsor's Protocol Code Number:	071301
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:	2016-11-30
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

2016-001478-14

A.3

Full title of the trial

A PROSPECTIVE, PHASE 3, OPEN LABEL, INTERNATIONAL
MULTICENTER STUDY ON EFFICACY AND SAFETY OF PROPHYLAXIS
WITH rVWF IN SEVERE VON WILLEBRAND DISEASE

Studio prospettico, di fase 3, in aperto, internazionale, multicentrico sull’efficacia e la sicurezza della profilassi con rVWF nella malattia grave di von Willebrand.

A.3.1

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

A study to determine the effectiveness and Safety of rVWF used to prevent bleeding episodes in patients with severe von Willebrand disease

Studio per determinare l’efficacia e la sicurezza del Fattore rocombinante di Von Willebrand usato per prevenire episodi di sanguinamento in pazienti con malattia grave di von Willebrand.

A.3.2

Name or abbreviated title of the trial where available

rVWF IN PROPHYLAXIS

rVWF nella profilassi.

A.4.1

Sponsor's protocol code number

071301

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	Baxalta Innovations GmbH
B.1.3.4	Country	Austria
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	Baxalta Innovations GmbH
B.4.2	Country	Austria
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Baxalta Innovation GmbH
B.5.2	Functional name of contact point	Sanhita Abrol
B.5.3	Address:
B.5.3.1	Street Address	650 East Kendall Street
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	MA02142
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 617 588 8128
B.5.6	E-mail	sanhita.abrol1@shire.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/10/814
D.3 Description of the IMP
D.3.1	Product name	Recombinant von Willebrand Factor 650IU
D.3.2	Product code	BAX 111
D.3.4	Pharmaceutical form	Powder and solution 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	Vonicog alfa
D.3.9.2	Current sponsor code	BAX 111
D.3.9.3	Other descriptive name	HUMAN VON WILLEBRAND FACTOR
D.3.9.4	EV Substance Code	SUB22288
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	650
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.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/10/814
D.3 Description of the IMP
D.3.1	Product name	Recombinant von Willebrand Factor 1300IU
D.3.2	Product code	BAX 111
D.3.4	Pharmaceutical form	Powder and solution 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	Vonicog alfa
D.3.9.2	Current sponsor code	BAX111
D.3.9.3	Other descriptive name	HUMAN VON WILLEBRAND FACTOR
D.3.9.4	EV Substance Code	SUB22288
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	1300
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.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	ADVATE 500 IU powder and solvent for solution for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxter AG
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	Advate
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	OCTOCOG ALFA
D.3.9.1	CAS number	139076-62-3
D.3.9.4	EV Substance Code	SUB16449MIG
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	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	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: 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	ADVATE 1000 IU powder and solvent for solution for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Baxter AG
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	Advate
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	OCTOCOG ALFA
D.3.9.1	CAS number	139076-62-3
D.3.9.4	EV Substance Code	SUB16449MIG
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	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	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

Hereditary severe von Willebrand Disease

grave forma di malattia di von Willebrand (VWD) ereditaria

E.1.1.1

Medical condition in easily understood language

Inherited severe bleeding disorder (von Willebrand Disease)

disturbo della coagulazione grave ereditaria (di von Willebrand Disease)

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	19.0
E.1.2	Level	PT
E.1.2	Classification code	10047715
E.1.2	Term	Von Willebrand's disease
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

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	10055168
E.1.2	Term	Von Willebrand's factor deficiency
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

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

The primary objective of this study is to prospectively evaluate the annualized bleeding rate (ABR) for
spontaneous bleeding episodes while on prophylactic treatment with rVWF and to compare it to the
subject’s historical ABR for spontaneous bleeding episodes during on-demand treatment.

L’obiettivo primario di questo studio consiste nel valutare in modo prospettico il tasso emorragico annuale (ABR) per gli episodi emorragici spontanei nel corso del trattamento profilattico con rVWF e confrontarlo con l’ABR storico del soggetto per gli episodi emorragici spontanei durante il trattamento al bisogno.

E.2.2

Secondary objectives of the trial

Secondary Objectives are
 Additional efficacy assessments of prophylactic treatment
 Safety and immunogenicity
 Pharmacokinetics (PK)
 Efficacy of the treatment of bleeding episodes

• Valutazioni aggiuntive dell’efficacia del trattamento profilattico
• Sicurezza e immunogenicità
• Farmacocinetica (PK)
• Efficacia del trattamento degli episodi emorragici

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject has a documented diagnosis of severe VWD (baseline VWF:RCo <20 IU/dL) with a history
of requiring substitution therapy with von Willebrand factor concentrate to control bleeding:
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤3 IU/dL).
2. Diagnosis is confirmed by genetic testing and multimer analysis, documented in patient history or at
screening.
3. Subject currently receiving on-demand treatment for whom prophylactic treatment is recommended
according to standard of care at the center.
4. Has ≥3 documented spontaneous bleeds requiring VWF treatment during the past 12 months
5. Availability of records to reliably evaluate type, frequency and treatment of bleeding episodes
during 12 months of on-demand treatment prior to enrollment.
6. Subject is ≥18 years old at the time of screening and has a body mass index ≥15 but <40 kg/m2.
7. If female of childbearing potential, subject presents with a negative blood/urine pregnancy test at
screening and agrees to employ adequate birth control measures for the duration of the study.
8. Subject is willing and able to comply with the requirements of the protocol.

Saranno considerati idonei a entrare in questo studio i soggetti che soddisfano TUTTI i seguenti criteri:
1. Il soggetto presenta una diagnosi documentata di VWF grave (VWF:RCo al basale <20 UI/dl) con un’anamnesi di terapia sostitutiva con fattore di von Willebrand concentrato per il controllo emorragico:
a. Tipo 1 (VWF:RCo < 20 UI/dl) oppure
b. Tipo 2A (in base a una valutazione con pattern multimerico), Tipo 2B (in base alla diagnosi per genotipo), Tipo 2M oppure
c. Tipo 3 (VWF:Ag ≤ 3 UI/dl).
2. La diagnosi è confermata mediante analisi genetiche e analisi multimerica, documentata nell’anamnesi del paziente o allo screening.
3. Il soggetto sta attualmente ricevendo un trattamento al bisogno per il quale, secondo lo standard di cura del centro, è raccomandato un trattamento profilattico.
4. Il soggetto presenta ≥ 3 emorragie spontanee documentate che richiedono un trattamento della VWF durante gli ultimi 12 mesi.
5. Disponibilità di dati per una valutazione affidabile di tipo, frequenza e trattamento degli episodi emorragici durante i 12 mesi di trattamento al bisogno prima dell’arruolamento.
6. Al momento dello screening, il soggetto ha un’età ≥ 18 anni e presenta un indice di massa corporea ≥ 15 ma < 40 kg/m2.
7. Se donna in età fertile, allo screening il soggetto deve presentare un test di gravidanza urinario/ematico negativo e acconsentire all’impiego di misure contraccettive adeguate per tutta la durata dello studio.
8. Il soggetto è disposto e in grado di attenersi ai requisiti previsti dal protocollo.

E.4

Principal exclusion criteria

Subjects who meet ANY of the following criteria are not eligible for this study:
1. The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another hereditary or
acquired coagulation disorder other than VWD (e.g., qualitative and quantitative platelet disorders
or elevated prothrombin time (PT)/international normalized ratio [INR] 1.4).
2. The subject has received prophylaxis treatment in the 12 months prior to screening (including those
who received treatment once a month for menorrhagia but were not treated for any other bleeds).
3. The subject is currently receiving prophylaxis treatment.
4. The subject has a history or presence of a VWF inhibitor at screening.
5. The subject has a history or presence of a FVIII inhibitor with a titer ≥0.4 BU (by Nijmegen
modified Bethesda assay) or ≥0.6 BU (by Bethesda assay).
6. The subject has a known hypersensitivity to any of the components of the study drugs, such as to
mouse or hamster proteins.
7. The subject has a medical history of immunological disorders, excluding seasonal allergic
rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8. The subject has a medical history of a thromboembolic event.
9. The subject is HIV positive with an absolute Helper T cell (CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease as evidenced by any of the following:
serum alanine aminotransferase (ALT) 5 times the upper limit of normal; hypoalbuminemia; portal
vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal
varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical treatment (e.g.,
ointments, nasal sprays), within 30 days prior to signing the informed consent.
14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection,
dysplasia).
16. The subject has participated in another clinical study involving another investigational product (IP)
or investigational device within 30 days prior to enrollment or is scheduled to participate in another
clinical study involving an IP or investigational device during the course of this study.
17. The subject has a progressive fatal disease and/or life expectancy of less than 15 months.
18. The subject is identified by the investigator as being unable or unwilling to cooperate with study
procedures.
19. The subject has a mental condition rendering him/her unable to understand the nature, scope and
possible consequences of the study and/or evidence of an uncooperative attitude.
20. The subject is in prison or compulsory detention by regulatory and/or juridical order
21. The subject is member of the study team or in a dependent relationship with one of the study team
members which includes close relatives (i.e., children, partner/spouse, siblings and parents) as well
as employees.

Delay criteria
1. If the subject presents with an acute bleeding episodes or acute illness (e.g., influenza, flu-like
syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) the screening visit will be postponed
until the subject has recovered.

Non sono idonei a entrare nello studio i soggetti che soddisfano UNO QUALUNQUE dei criteri seguenti:
1. Al soggetto è stata diagnosticata una VWD di tipo 2N, una pseudo-VWD o altro disturbo della coagulazione ereditario o acquisito diverso dalla VWD (ad es. disturbi piastrinici qualitativi e quantitativi oppure tempo di protrombina [PT]/rapporto internazionale normalizzato [INR] elevato 1,4).
2. Il soggetto ha ricevuto un trattamento profilattico nei 12 mesi precedenti allo screening (compresi i soggetti che hanno ricevuto un trattamento mensile per menorragia, ma non sono stati trattati per eventuali altre emorragie).
3. Il soggetto sta attualmente ricevendo un trattamento profilattico.
4. Il soggetto ha un’anamnesi o presenta un inibitore di VWF allo screening.
5. Il soggetto ha un’anamnesi o presenta un inibitore di FVIII con titolazione ≥ 0,4 UB (in base al saggio Bethesda modificato di Nijmegen) o ≥ 0,6 UB (in base al saggio Bethesda).
6. Il soggetto presenta ipersensibilità nota a qualunque componente dei farmaci dello studio, come le proteine murine o del criceto.
7. Il soggetto ha un’anamnesi di disturbi immunologici, ad esclusione di rinite/congiuntivite allergica stagionale, asma lieve, allergie alimentari o allergie ad animali.
8. Il soggetto ha un’anamnesi di evento tromboembolico.
9. Il soggetto è positivo per virus dell’immunodeficienza umana (HIV) con una conta assoluta di linfociti T helper (CD4) pari a 200/mm3.
10. Al soggetto è stata diagnosticata una malattia epatica significativa, dimostrata da uno dei seguenti valori: alanina aminotransferasi (ALT) sierica 5 volte il limite superiore della norma; ipoalbuminemia; ipertensione portale (ad es. presenza di splenomegalia non altrimenti giustificata, anamnesi di varici esofagee).
11. Al soggetto è stata diagnosticata una nefropatia, con un livello di creatinina sierica ≥ 2,5 mg/dl.
12. Allo screening, il soggetto presenta una conta piastrinica < 100.000/ml.
13. Il soggetto è stato trattato con farmaci immunomodulatori, esclusi i trattamenti topici (es. unguenti, spray nasali), nei 30 giorni precedenti la firma del consenso informato.
14. Al momento dell’arruolamento, il soggetto è in gravidanza o in allattamento.
15. Il paziente presenta patologie cervicali o uterine che provocano menorragia o metrorragia (comprese infezioni, displasia).
16. Il soggetto ha già partecipato a un altro studio clinico che prevedeva l’impiego di un altro prodotto sperimentale (IP) o di un dispositivo sperimentale nei 30 giorni precedenti l’arruolamento o ha programmato di partecipare, durante questo studio, a un altro studio clinico che prevede l’uso di un IP o di un dispositivo sperimentale.
17. Il soggetto è affetto da una malattia progressiva con esito fatale e/o ha un’aspettativa di vita inferiore a 15 mesi.
18. Il soggetto viene identificato dallo sperimentatore come non in grado o non disposto a cooperare durante le procedure dello studio.
19. Il soggetto è affetto da una patologia mentale che lo rende incapace di comprendere la natura, lo scopo e le possibili conseguenze dello studio e/o mostra un’attitudine non collaborativa.
20. Il soggetto si trova in carcere o in ricovero obbligatorio a seguito di un provvedimento normativo e/o giuridico.
21. Il soggetto è un membro del personale dello studio o in rapporto di dipendenza con uno dei membri del personale dello studio; ciò include i parenti stretti (ovvero: figli, compagno/a/coniuge, fratelli e genitori) nonché i dipendenti.

Criteri di differimento
1. Se il soggetto si presenta con un episodio emorragico acuto o con una malattia acuta (ad es. influenza, sindrome simil-influenzale, rinite/congiuntivite allergica, asma non stagionale), la visita di screening sarà posticipata fino a quando il soggetto non si sarà ripreso.

E.5 End points

E.5.1

Primary end point(s)

Prospectively recorded ABR for spontaneous (not related to trauma) bleeding episodes during prophylactic treatment with rVWF and the subjects’ historical ABR for spontaneous bleeding episodes during on-demand treatment.

ABR per episodi emorragici spontanei (non correlati a un trauma) registrato in maniera prospettica durante il trattamento profilattico con rVWF e ABR storico dei soggetti per episodi emorragici spontanei durante il trattamento al bisogno.

E.5.1.1

Timepoint(s) of evaluation of this end point

On completion of 12 month prophylactic treatment.

Al termine di 12 mesi trattamento profilattico.

E.5.2

Secondary end point(s)

Efficacy

Number (proportion) of subjects with reduction of ABR for spontaneous (not related to trauma) bleeding episodes during prophylaxis relative to the subjects’ own historical ABR during on-demand treatment.

Number (proportion) of subjects with 0 bleeds during prophylactic treatment with rVWF.

Number of infusions and total weight adjusted consumption of rVWF and ADVATE (recombinant factor VIII/rFVIII) per month and per year during on-demand treatment.

Safety

Adverse events (AEs)

Incidence of thromboembolic events

Incidence of severe hypersensitivity reactions

Development of neutralizing antibodies to VWF and FVIII

Development of total binding antibodies to VWF and FVIII

Development of antibodies to Chinese hamster ovary (CHO) proteins, mouse immunoglobulin G (IgG) and rFurin.

Pharmacokinetic

Incremental recovery (IR), terminal half-life (T1/2), mean residence time (MRT), area under the curve/dose (AUC/dose), area under moment curve/dose (AUMC/dose), volume of distribution at steady state (Vss) and clearance (CL) based on Von Willebrand factor Ristocetin cofactor activity (VWF:RCo), Von Willebrand factor antigen (VWF:Ag), Von Willebrand collagen binding activity
(VWF:CB) , INNOVANCE VWF Ac (exploratory assay) and time course (72 hours) of FVIII clotting activity (FVIII:C) levels.

Efficacy of the treatment of bleeding episodes

Number of infusions of rVWF and ADVATE (rFVIII) per spontaneous bleeding episode.

Number of infusions of rVWF and ADVATE (rFVIII) per traumatic bleeding episode.

Weight-adjusted consumption of rVWF and ADVATE (rFVIII) per spontaneous bleeding episode.

Weight-adjusted consumption of rVWF and ADVATE (rFVIII) per traumatic bleeding episode.

Overall hemostatic efficacy rating at resolution of bleed

Efficacia
• Numero (percentuale) di soggetti con riduzione dell’ABR per episodi emorragici spontanei (non correlati a un trauma) durante la profilassi in relazione all’ABR storico proprio dei soggetti durante il trattamento al bisogno
• Numero (percentuale) di soggetti con 0 episodi emorragici durante il trattamento profilattico con rVWF
• Numero di infusioni e consumo totale di rVWF e ADVATE (fattore VIII ricombinante/rFVIII) rettificato per il peso per mese e per anno durante il trattamento al bisogno
Sicurezza
• Eventi avversi (EA)
• Incidenza degli eventi tromboembolici
• Incidenza delle reazioni da ipersensibilità gravi
• Sviluppo di anticorpi neutralizzanti contro VWF e FVIII
• Sviluppo di anticorpi leganti totali contro VWF e FVIII
• Sviluppo di anticorpi contro le proteine prodotte dalle cellule ovariche del criceto cinese (CHO), le immunoglobuline G (IgG) murine e la furina ricombinante
Farmacocinetica
• Recupero incrementale (IR), emivita terminale (T1/2), tempo medio di permanenza (MRT), area sotto la curva/dose (AUC/dose), area sottesa al momento della curva/dose (AUMC/dose), volume di distribuzione allo stato di equilibrio (Vss) e clearance (CL) basati sull’attività del cofattore ristocetinico del fattore di Von Willebrand (VWF:RCo), antigene del fattore di Von Willebrand (VWF:Ag), attività legante il collagene del fattore di Von Willebrand (VWF:CB), INNOVANCE VWF Ac (saggio esplorativo) ed evoluzione temporale (72 ore) dei livelli dell’attività coagulante di FVIII (FVIII:C).
Efficacia del trattamento degli episodi emorragici
• Numero di infusioni di rVWF e ADVATE (rFVIII) per episodio emorragico spontaneo
• Numero di infusioni di rVWF e ADVATE (rFVIII) per episodio emorragico traumatico
• Consumo di rVWF e ADVATE (rFVIII) rettificato per il peso per episodio emorragico spontaneo
• Consumo di rVWF e ADVATE (rFVIII) rettificato per il peso per episodio emorragico traumatico
• Valutazione complessiva dell’efficacia emostatica alla risoluzione dell’emorragia.

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy parameters evaluated at end of study.

Safety parameters evaluated within 24 hrs of awareness.

Overall hemostatic efficacy rating at resolution of each bleed within 24 hrs.

parametri di efficacia valutati alla fine dello studio.
Parametri di sicurezza valutati entro 24 ore di consapevolezza.
Valutazione dell'efficacia emostatica generale con risoluzione di ogni sanguinamento entro 24 ore.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

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)

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

Denmark

Finland

France

Germany

Italy

Netherlands

Sweden

United Kingdom

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

ultima visita 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

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

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

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

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)

Subjects will be offered the option to continue to receive BAX111 in a long-term continuation study.

Ai soggetti sarà offerta la possibilità di continuare a ricevere BAX111 in uno studio di continuazione a lungo termine.

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

2017-01-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-12-13

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

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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