A study to determine the effectiveness, safety, and tolerability of the Recombinant Von Willebrand Factor administered with or without Advate for children diagnosed with Severe von Willebrand Disease who experience bleeding episodes and/or will undergo major, minor or oral surgery procedures.

• Register: EUCTR
• Last refreshed on: 12 March 2018
• Main ID: EUCTR2016-001477-33-IT
• Date of registration: 02/11/2016
• Prospective Registration: Yes
• Primary sponsor: Baxalta Innovations GmbH
• Public title: A study to determine the effectiveness, safety, and tolerability of the Recombinant Von Willebrand Factor administered with or without Advate for children diagnosed with Severe von Willebrand Disease who experience bleeding episodes and/or will undergo major, minor or oral surgery procedures.
• Scientific title: A Phase 3, Prospective, Multicenter, Uncontrolled, Open-Label Clinical Study to Determine the Efficacy, Safety, and Tolerability of rVWF with or without ADVATE in the Treatment and Control of Bleeding Episodes, the Efficacy and Safety of rVWF in Elective and Emergency Surgeries, and the Pharmacokinetics (PK) of rVWF in Children Diagnosed with Severe von Willebrand Disease. PIP decision numbers P/0091/2012 and P/0214/2015 - BAX 111 rVWF in Pediatrics
• Date of first enrolment: 06/02/2017
• Target sample size: 40
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-001477-33
• 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: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Canada, Czech Republic, Finland, France, Germany, Italy, Netherlands, Poland, Russian Federation, Spain, Turkey, Ukraine, 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. Diagnosis of severe VWD (defined as VWF:RCo <20%):
a. Type 1 (VWF:RCo <20 IU/dL); or
b. Type 2A (VWF:RCo <20 IU/dL), Type 2B (as diagnosed by genotype), Type 2N (FVIII:C
<10% and historically documented genetics), Type 2M; or
c. Type 3 (VWF:Ag =3 IU/dL).
2. Age 0 to <18 years at the time of screening
3. The subject has provided assent (if appropriate) and legally authorized representative(s) has
provided informed consent
4. If female of childbearing potential, subject presents with a negative serum pregnancy test
5. If applicable, subject agrees to employ adequate birth control measures for the duration of the study
6. The subject and/or the legal representative is willing and able to comply with the requirements of
the protocol.

Additional inclusion criteria for previously treated subjects and subjects undergoing surgery are as follows:
1. Unable to tolerate or are inadequately responsive to deamino-delta-D-arginine vasopressin
2. The subject has had a minimum of 1 documented bleed requiring VWF coagulation factor
replacement therapy during the previous 12 months prior to enrollment and overall historically
3 or more EDs to plasma-derived VWF.

Additional inclusion criterion for previously untreated subjects are as follows:
1. The subject has not received prior VWF coagulation factor replacement therapy
Are the trial subjects under 18? yes
Number of subjects for this age range: 40
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Subjects who meet ANY of the following criteria are not eligible for this study:
1. Diagnosis of pseudo-VWD or another hereditary or acquired coagulation disorder (eg, qualitative
and quantitative platelet disorders or elevated prothrombin time/international normalized ratio
>1.4)
2. History or presence of a VWF inhibitor at Screening
3. History or presence of a FVIII inhibitor with a titer =0.4 Bethesda units (BU) (by Nijmegen assay)
or =0.6 BU (by Bethesda assay)
4. Documented history of a VWF:RCo half-life <6 hours
5. Known hypersensitivity to any of the components of the study drug, such as mouse or hamster
proteins
6. Medical history of immunological disorders, excluding seasonal allergic rhinitis/ conjunctivitis/
asthma, food allergies, or animal allergies
7. Medical history of a thromboembolic event
8. Human immunodeficiency virus positive, with an absolute CD4 count ?200/mm3
9. In the judgment of the Investigator, the subject has another clinically significant concomitant
disease (eg, uncontrolled hypertension, cancer) that may pose additional risks for the subject
10. Diagnosis of significant liver disease, as evidenced by, but not limited to, any of the following:
serum alanine aminotransferase 5 times the upper limit of normal; hypoalbuminemia; portal vein
hypertension (eg, presence of otherwise unexplained splenomegaly, history of esophageal varices)
or liver cirrhosis classified as Child B or C
11. Diagnosis of renal disease, with a serum creatinine level =2.5 mg/dL
12. Immunomodulatory drug treatment other than anti-retroviral chemotherapy (eg, a-interferon, or
corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day (excluding
topical treatment [eg, ointments, nasal sprays]), within 30 days prior to signing the informed
consent (or assent, if appropriate)
13. If female, subject is pregnant or lactating at the time informed consent (or assent, if appropriate) is
obtained
14. Subject has participated in another clinical study involving an IP, other than rVWF with or
without ADVATE, 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
15. Subject’s legal representative is a family member or employee of the Investigator


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 in children
MedDRA version: 19.0 Level: LLT Classification code 10055168 Term: Von Willebrand's factor deficiency System Organ Class: 100000004850

Intervention(s)

Product Name: Recombinant von Willebrand Factor 650IU
Product Code: BAX111
Pharmaceutical Form: Powder and solvent 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: 650-

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-

Product Name: Recombinant von Willebrand Factor 1300IU
Product Code: BAX111
Pharmaceutical Form: Powder and solvent 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 1000IU 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)

Secondary Objective: 1. Elective or emergency surgery:to evaluate the of hemostatic efficacy after the last perioperative rVWF infusion.
2.To evaluate the safety of Safety of rVWF.
3. To evaluate the PK parameters of rVWF.

Primary end point(s): The primary outcome measure is hemostatic efficacy, defined as the number of pediatric subjects with treatment success for rVWF-treated nonsurgical bleeding episodes (using a 4-point scale). Bleeding episode treatment success is defined as a mean efficacy rating
score of <2.5.

Timepoint(s) of evaluation of this end point: Timepoint of assessment is within 24 hrs after onset of each bleeding episode an infusion of study drug, recording is made after resolution of each bleeding episode.

Main Objective: To evaluate the hemostatic efficacy and safety of rVWF, with or without ADVATE, in the treatment and control of nonsurgical bleeding events in pediatric subjects (<18 years of age) diagnosed with severe, hereditary VWD.

Secondary Outcome(s)

Secondary end point(s): Efficacy
1. Number of treated nonsurgical bleeding episodes with an efficacy rating of ‘excellent’ or ‘good’.
2. Number of infusions, rVWF units, and ADVATE units (if needed), per bleeding episode.
3. For elective surgery: an overall assessment of hemostatic efficacy 24 hours after the last perioperative infusion of rVWF, assessed by the Investigator (hematologist) on a 4-point scale.

Safety
1. Incidence and severity of adverse events (AEs) by system organ class (SOC) and preferred term.
2. Incidence of thrombotic events.
3. Incidence of severe hypersensitivity reactions.
4. Development of neutralizing antibodies to VWF and FVIII.
5. Development of total binding antibodies to VWF.
6. Development of antibodies to CHO proteins, murine IgG, and rFurin.

Pharmacokinetics
1.Area under the plasma concentration/time curve from 0 to 96 hours post-infusion
(AUC0-96h), area under the plasma concentration/time curve from time 0 to infinity
(AUC0-8), mean residence time (MRT), clearance (CL), incremental recovery
(IR), in-vivo recovery (IVR), elimination phase half-life (T1/2), and volume of
distribution at steady state (Vss) for VWF:RCo.
2. Area under the plasma concentration/time curve from 0 to 96 hours post-infusion
(AUC0-96h) for VWF:Ag and VWF:CB. Point estimates per age cohort will be
presented.
3. Area under the plasma concentration/time curve from 0 to 96 hours post-infusion
(AUC0-96h) for FVIII activity. Point estimates per age cohort will be presented.

Timepoint(s) of evaluation of this end point: Hemostatic Efficacy Assessments for surgeries are performed immediately after surgery by operating surgeon and then 24 hours after last perioperative rVWF infusion, Day 7 and Day 14 by the investigator. (See section 11 of protocol for reference)

Secondary ID(s)

071102

2016-001477-33-AT

Source(s) of Monetary Support

Baxalta Innovations GmbH