Clinical Trials Register

Summary
EudraCT Number:	2016-001478-14
Sponsor's Protocol Code Number:	071301
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-12-27
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

Spain - AEMPS

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

Estudio en fase III prospectivo, abierto, internacional y multicéntrico sobre la eficacia y la seguridad de la profilaxis con rVWF en la enfermedad grave de 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

Estudio para determinar la efectividad y seguridad de rVWF utilizado para prevenir episodios hemorrágicos en pacientes con enfermedad grave de von Willebrand

A.3.2

Name or abbreviated title of the trial where available

rVWF IN PROPHYLAXIS

A.4.1

Sponsor's protocol code number

071301

A.7

Trial is part of a Paediatric Investigation Plan

Yes

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	+34900866662128
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

Enfermedad grave de Von Willebrand hereditaria

E.1.1.1

Medical condition in easily understood language

Inherited severe bleeding disorder (von Willebrand Disease)

Trastorno hemorrágico grave hereditario (enfermedad de von Willebrand)

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.

El objetivo principal de este estudio es evaluar de forma prospectiva la tasa anualizada de hemorragia (TAH) de los episodios hemorrágicos espontáneos que se producen durante el tratamiento profiláctico con rVWF y compararla con la TAH histórica del sujeto correspondiente a los episodios hemorrágicos espontáneos durante el tratamiento bajo demanda.

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

Los objetivos secundarios son:
• Evaluaciones adicionales de la eficacia del tratamiento profiláctico.
• Seguridad e inmunogenicidad.
• Farmacocinética (FC).
• Eficacia del tratamiento de episodios hemorrágicos.

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.

Los sujetos que cumplan TODOS los criterios siguientes serán aptos para este estudio:
1. Sujetos con un diagnóstico documentado de VWD grave (VWF:RCo inicial <20 UI/dl) con antecedentes de tratamiento de reemplazo con concentrado de factor de Von Willebrand para controlar la hemorragia:
a. tipo 1 (VWF:RCo <20 UI/dl);
b. tipo 2A (verificado por patrón de multímeros), tipo 2B (diagnosticado por el genotipo), tipo 2M; o
c. tipo 3 (VWF:Ag ≤3 UI/dl).
2. Diagnóstico confirmado por pruebas genéticas y análisis de multímeros, documentados en el historial clínico del sujeto o en la selección.
3. Sujetos que reciben actualmente tratamiento bajo demanda para los cuales está recomendado el tratamiento profiláctico según la práctica clínica habitual del centro.
4. Sujetos que presentan ≥3 hemorragias espontáneas documentadas que requieren tratamiento con VWF en los últimos 12 meses.
5. Disponibilidad de registros para evaluar con fiabilidad el tipo, la frecuencia y el tratamiento de los episodios hemorrágicos durante 12 meses de tratamiento bajo demanda antes de la inscripción.
6. Sujetos de ≥18 años de edad en el momento de la selección y con un índice de masa corporal ≥15 pero <40 kg/m2.
7. En el caso de mujeres en edad fértil, deben presentarun test de embarazo en orina/sangre negativo en la selección y acceder a emplear medidas de control de la natalidad adecuadas durante todo el estudio.
8. Sujetos que están dispuestos y son capaces de cumplir con los requisitos del protocolo.

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.

Los sujetos que cumplan ALGUNO de los criterios siguientes no serán aptos para este estudio:
1. Sujetos diagnosticados deVWD tipo 2N, pseudo-VWD u otro trastorno de la coagulación adquirido o hereditario diferente de VWD (p. ej., trastornos plaquetarios cualitativos y cuantitativos o niveles elevados de tiempo de protrombina [TP]/índice internacional normalizado [INR] >1.4).
2. Sujetos que han recibido tratamiento profiláctico en los 12 meses anteriores a la selección (incluidas aquellas pacientes que recibieron tratamiento una vez al mes para la menorragia pero que no fueron tratadas para otras hemorragias).
3. Sujetos que reciben actualmente tratamiento profiláctico.
4. Sujetos con antecedentes o presencia de un inhibidor del VWF en la selección.
5. Sujetos con antecedentes o presencia de un inhibidor del FVIII con un valor de ≥0,4 UB (según el ensayo de Bethesda modificado por Nijmegen) o de ≥0,6 UB (según el ensayo de Bethesda).
6. Sujetos con hipersensibilidad conocida a cualquiera de los componentes de los fármacos del estudio, por ejemplo, a las proteínas de hámster o de ratón.
7. Sujetos con antecedentes médicos de trastornos inmunológicos, excluidos la rinitis/conjuntivitis alérgicas estacionales, el asma leve, las alergias alimentarias o las alergias a animales.
8. Sujetos con antecedentes médicos de un acontecimiento tromboembólico.
9. Sujetos positivos para el VIH con un recuento absoluto de linfocitos T cooperadores (CD4) de <200/mm3.
10. Sujetos con un diagnóstico de enfermedad hepática significativa, probada por cualquiera de los siguientes datos:nivel de alanina aminotransferasa (ALT) sérica 5 veces el límite superior de la normalidad, hipoalbuminemia, hipertensión de la vena porta (p. ej., existencia de esplenomegalia sin otra explicación o antecedentes de varices esofágicas).
11. Sujetos con un diagnóstico de enfermedad renal, con un nivel de creatinina sérica ≥2,5 mg/dl.
12. Sujetos con un recuento plaquetario <100 000/ml en la selección.
13. Sujetos que han recibido tratamiento con un fármaco inmunomodulador, excluidos los tratamientos tópicos (p. ej., pomadas o nebulizadores nasales) en los 30 días anteriores a la firma del consentimiento informado.
14. Pacientes embarazadas o en periodo de lactancia en el momento de la inscripción.
15. Pacientes con afecciones del cuello uterino o del útero que causanmenorragia o metrorragia (incluyendo infección, displasia).
16. Sujetos que han participado en otro estudio clínico que utilizó otro producto en investigación (PEI) o un dispositivo en investigación durante los 30 días anteriores a la inscripción, o que está programado que participen en otro estudio clínico con un PEI o un dispositivo en investigación durante el transcurso de este estudio.
17. Sujetos que presentan una enfermedad mortal progresiva o esperanza de vida inferior a los 15 meses.
18. Determinación por el investigadorde que el sujeto no es capaz de colaborar con los procedimientos del estudio o no está dispuesto a hacerlo.
19. Sujetos con una enfermedad mental que les incapacita para entender la naturaleza, el alcance y las posibles consecuencias delestudio; o con indicios de una actitud poco colaboradora.
20. Sujetos que están en prisión o en internamiento forzoso por orden de un órgano administrativo o judicial.
21. Sujetos miembros del equipo del estudio o con una relación de dependencia con alguno de los miembros del equipo del estudio, como familia cercana (es decir, hijos, pareja/cónyuge,hermanos y padres) y los empleados.
Criterios de retraso
1. Si un sujeto presenta episodios hemorrágicos agudos o enfermedad aguda (p. ej., gripe, síndrome gripal, rinitis alérgica/conjuntivitis, asma no estacional) la visita de selección se pospondrá hasta que el sujeto se haya recuperado.

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.

La tasa anualizada de hemorragias (TAH) registrada de forma prospectiva de los episodios hemorrágicos espontáneos (no relacionados con traumatismos) durante el tratamiento profiláctico con rVWF y TAH histórica del sujeto correspondiente a los episodios hemorrágicos espontáneos durante eltratamiento bajo demanda.

E.5.1.1

Timepoint(s) of evaluation of this end point

On completion of 12 month prophylactic treatment.

Al completar 12 meses de tratamiento profiláctico.

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

Eficacia
• Número (proporción) de sujetos con reducción de la TAH de episodios hemorrágicos espontáneos (no relacionados con traumatismos) durante la profilaxis en comparación con la TAH histórica de los sujetos durante el tratamiento bajo demanda.
• Número (proporción) de sujetos con 0 hemorragias durante el tratamiento profiláctico con rVWF.
• Número de infusiones y consumo total ajustado al peso de rVWF y ADVATE (factor VIII/rFVIII recombinante) al mes y al año durante el tratamiento bajo demanda.
Seguridad
• Acontecimientos adversos (AA).
• Incidencia de acontecimientos tromboembólicos.
• Incidencia de reacciones de hipersensibilidad graves.
• Desarrollo de anticuerpos neutralizadores de VWF y FVIII.
• Desarrollo de anticuerpos de unión a VWF y FVIII totales.
• Desarrollo de anticuerpos contra las proteínas de ovario de hámster chino (Chinese hamster ovary, CHO), la inmunoglobulina G (IgG) murina y la furina-r.
Farmacocinética
• Recuperación incremental (RI), semivida terminal (T1/2), tiempo medio de residencia (TMR), área bajo la curva/dosis (ABC/dosis), área bajo la curva del primer momento/dosis (ABCM/dosis), volumen de distribución en estado de equilibrio (volume of distribution at steady state,Vss) y aclaramiento (Acl) sobre la base de la actividad del cofactor de ristocetina del factor de Von Willebrand (VWF:RCo [Ristocetin cofactor]), el antígeno del factor de Von Willebrand (VWF:Ag), la actividad de unión al colágeno del factor de Von Willebrand (VWF:CB [collagen binding]), INNOVANCE VWF Ac (ensayo exploratorio) y evolución temporal (72 horas) de los niveles de actividad del factor de coagulación FVIII (FVIII:C).

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.

Parámetros de eficacia evaluados al final del ensayo.
Parámetros de seguridad evaluados dentro de las 24 h de su conocimiento
Clasificación general de la eficacia hemostática en la resolución de cada hemorragia en 24 horas.

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 último paciente

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.

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

2017-02-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-07-06

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Orphan Designation Number:
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