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

• Register: EUCTR
• Last refreshed on: 9 November 2020
• Main ID: EUCTR2016-001478-14-GB
• Date of registration: 10/11/2016
• Prospective Registration: Yes
• Primary sponsor: Baxalta Innovations GmbH
• Public title: A study to determine the effectiveness and Safety of rVWF used to prevent bleeding episodes in patients with severe von Willebrand disease
• Scientific title: A PROSPECTIVE, PHASE 3, OPEN LABEL, INTERNATIONAL MULTICENTER STUDY ON EFFICACY AND SAFETY OF PROPHYLAXIS WITH rVWF IN SEVERE VON WILLEBRAND DISEASE - rVWF IN PROPHYLAXIS
• Target sample size: 18
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-001478-14
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Canada, Czech Republic, Denmark, Finland, France, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom, United States

Contacts

• Name: Sanhita Abrol
• Affiliation: Baxalta Innovation GmbH

• Name: Sanhita Abrol
• Affiliation: Baxalta Innovation GmbH

Key inclusion & exclusion criteria

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.
Are the trial subjects under 18? no
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 14
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 4

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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Hereditary severe von Willebrand Disease
MedDRA version: 19.0 Level: PT Classification code 10047715 Term: Von Willebrand's disease System Organ Class: 10010331 - Congenital, familial and genetic disorders
MedDRA version: 19.0 Level: LLT Classification code 10055168 Term: Von Willebrand's factor deficiency System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Product Name: Recombinant von Willebrand Factor 650IU
Product Code: BAX 111
Pharmaceutical Form: Powder and solution for solution for injection
INN or Proposed INN: Vonicog alfa
Current Sponsor code: BAX 111
Other descriptive name: HUMAN VON WILLEBRAND FACTOR
Concentration unit: IU international unit(s)
Concentration type: equal
Concentration number: 650-

Product Name: Recombinant von Willebrand Factor 1300IU
Product Code: BAX 111
Pharmaceutical Form: Powder and solution for solution for injection
INN or Proposed INN: Vonicog alfa
Current Sponsor code: BAX111
Other descriptive name: HUMAN VON WILLEBRAND FACTOR
Concentration unit: IU international unit(s)
Concentration type: equal
Concentration number: 1300-

Trade Name: ADVATE 500 IU powder and solvent for solution for injection
Product Name: Advate
Pharmaceutical Form: Powder and solvent for solution for injection
INN or Proposed INN: OCTOCOG ALFA
CAS Number: 139076-62-3
Concentration unit: IU international unit(s)
Concentration type: equal
Concentration number: 500-

Trade Name: ADVATE 1000 IU powder and solvent for solution for injection
Product Name: Advate
Pharmaceutical Form: Powder and solvent for solution for injection
INN or Proposed INN: OCTOCOG ALFA
CAS Number: 139076-62-3
Concentration unit: IU international unit(s)
Concentration type: equal
Concentration number: 1000-

Primary Outcome(s)

Main Objective: 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.

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

Timepoint(s) of evaluation of this end point: On completion of 12 month prophylactic treatment.

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.

Secondary Outcome(s)

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.

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

Secondary ID(s)

071301

Source(s) of Monetary Support

Baxalta Innovations GmbH