A study to evaluate the safety and effectiveness of the Recombinant Von Willebrand Factor administred with or without Advate for subjects with severe von Willebrand disease (a hereditary coagulation abnormality) who will undergo major,minor or oral surgery procedures.

• Register: EUCTR
• Last refreshed on: 5 September 2016
• Main ID: EUCTR2014-003575-38-AT
• Date of registration: 10/11/2014
• Prospective Registration: Yes
• Primary sponsor: Baxalta Innovations GmbH
• Public title: A study to evaluate the safety and effectiveness of the Recombinant Von Willebrand Factor administred with or without Advate for subjects with severe von Willebrand disease (a hereditary coagulation abnormality) who will undergo major,minor or oral surgery procedures.
• Scientific title: A PHASE 3 PROSPECTIVE, MULTICENTER STUDY TO EVALUATE EFFICACY AND SAFETY OF rVWF WITH OR WITHOUT ADVATE IN ELECTIVE SURGICAL PROCEDURES IN SUBJECTS WITH SEVERE VON WILLEBRAND DISEASE - rVWF in subjects with severe VWD undergoing surgery
• Date of first enrolment: 07/01/2015
• Target sample size: 15
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-003575-38
• 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

Australia, Austria, Czech Republic, Germany, Italy, Netherlands, Russian Federation, Spain, Taiwan, Turkey, Ukraine, United Kingdom, United States

Contacts

• Name: Fred J. D'Amato
• Affiliation: Baxalta Innovations GmbH

• Name: Fred J. D'Amato
• Affiliation: Baxalta Innovations GmbH

Key inclusion & exclusion criteria

Inclusion criteria:
1. Diagnosis of severe VWD as listed and elective surgical procedure planned:
o VWD with a history of requiring substitution therapy with von Willebrand factor concentrate to control bleeding.
? Type 1 (VWF:RCo < 20 IU/dL) or
? Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2N (FVIII:C<10% and historically documented genetics), Type 2M or
? Type 3 (VWF:Ag = 3 IU/dL)
2. If type 3 VWD (VWF Antigen /VWF:Ag = 3 IU/dL), subject has a medical history of at least 20 EDs to VWF/FVIII coagulation factor concentrates (including cryoprecipitate or fresh frozen plasma)
3. If type 1 or type 2 VWD, subject has a medical history of 5 EDs or a past major surgery requiring VWF/FVIII coagulation factor concentrates (including cryoprecipitate or fresh frozen plasma)
4. At least 18 years of age
5. If female of childbearing potential, subject presents with a negative pregnancy test
6. If applicable, subject agrees to employ adequate birth control measures for the duration of the study
7. 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) no
F.1.3.1 Number of subjects for this age range 1

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 PT/ international normalized ratio [INR] ? 1.4)
2. History or presence of a VWF inhibitor at screening
3. History or presence of a factor VIII (FVIII) inhibitor with a titer = 0.4 BU (Nijmegen-modified Bethesda assay ) or = 0.6 BU (by Bethesda assay)
4. Known hypersensitivity to any of the components of the study drugs, such as to mouse or hamster proteins
5. Medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies
6. Medical history of a thromboembolic event
7. HIV positive with an absolute CD4 count ? 200/mm3
8. Platelet count < 100,000/mL
9. Diagnosis of significant liver disease, as evidenced by, but not limited to, 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) or liver cirrhosis classified as Child B or C
10. Diagnosis of renal disease, with a serum creatinine level = 2 .5mg/dL
11. 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
12. Subject is pregnant or lactating at the time informed content is obtained
13. Subject has participated in another clinical study involving an investigational product (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. (Eligible patients participating in the rVWF Prophy study (071301) may be enrolled).
14. Progressive fatal disease and/or life expectancy of less than 3 months
15. Subject is identified by the investigator as being unable or unwilling to cooperate with study procedures
16. Subject suffers from 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
17. Subject is in prison or compulsory detention by regulatory and/or juridical order
18. Member of the study team conducting this study or in a dependent relationship with one of the study team members. Dependent relationships include close relatives (i.e., children, partner/spouse, siblings, parents) as well as employees



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 adult patients who will undergo major and minor elective surgical procedures
MedDRA version: 18.0 Level: LLT Classification code 10055168 Term: Von Willebrand's factor deficiency System Organ Class: 100000004850

Intervention(s)

Product Name: Recombinant von Willebrand Factor
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: recombinant 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
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: recomibnant human Von Willebrand Factor
Concentration unit: IU international unit(s)
Concentration type: equal
Concentration number: 1300-

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)

Timepoint(s) of evaluation of this end point: 24 hours after last perioperative IP infusion or at completion of day 14 visit, whatever occurs earlier

Primary end point(s): Overall assessment of hemostatic efficacy will be summarized by the percentage of subjects in each efficacy category (“excellent”, “good”, “moderate” and “none”).
Point estimates and corresponding two-sided exact confidence intervals (CIs) at the 90% confidence level will be calculated for the rate of subjects with an overall assessment of hemostatic efficacy of ‘excellent’ or ‘good’ 24 hours after last perioperative IP infusion or at completion of day 14 visit, whatever occurs earlier

Secondary Objective: Efficacy
• Intraoperative actual versus predicted blood loss at completion of surgery
• Intraoperative hemostatic efficacy score on a scale of excellent, good, moderate or none
• Daily intra- and postoperative weight-adjusted dose of rVWF with or without ADVATE through postoperative day 14
2. Safety
• Adverse Events
• Incidence of thrombotic events
• Incidence of severe allergic reactions
• Incidence of development of inhibitory and total binding antibodies to VWF and inhibitory antibodies to FVIII
• Incidence of development of antibodies to Chinese hamster ovary proteins, murine immunoglobulin G and rFurin
3. Pharmacokinetics
• Area under the plasma concentration versus time curve from 0 to 72 hours postinfusion
• Area under the plasma concentration/time curve from time 0 to infinity,mean residence time, clearance, incremental recovery,elimination phase halflife, Volume of distribution at steady state
4. Exploratory Objectives
• Health-related Quality of Life

Main Objective: To evaluate the hemostatic efficacy and safety of rVWF with or without ADVATE in subjects (above 18 years) diagnosed with hereditary severe VWD undergoing major and minor elective surgical procedures

Secondary Outcome(s)

Secondary end point(s): Intraoperative actual versus predicted blood loss as assessed by the surgeon at completion of surgery will be summarized by the percentage of subjects in each efficacy category (“excellent”, “good”, “moderate”
and “none”).

Point estimates and corresponding two-sided exact confidence intervals (CIs) at the 90% confidence level will be calculated for the rate of hemostatic efficacy assessments with excellent/good outcome performed by the surgeon based on the intraoperative actual versus predicted blood loss.

Intraoperative hemostatic efficacy assessed at completion of surgery by the surgeon will be summarized by the percentage of subjects in each efficacy category (“excellent”, “good”, “moderate” and “none”).

Point estimates and corresponding two-sided exact confidence intervals (CIs) at the 90% confidence level will be calculated for the rate of hemostatic efficacy assessments with excellent/good outcome performed by the surgeon at completion of surgery.

Descriptive statistics (median, quartiles and range) will be used to summarize the actual blood loss expressed as a percentage of the estimated blood loss (EBL).

The summary of average daily and total weight-adjusted doses (average through postoperative day 14) of rVWF with or without:ADVATE per subject will be provided using median, quartiles and range.

Timepoint(s) of evaluation of this end point: Intraoperative

The summary of average daily and total weight-adjusted doses (average through postoperative day 14)

Secondary ID(s)

071101

Source(s) of Monetary Support

Baxalta Innovations GmbH