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Recombinant Von Willebrand Factor in Subjects With Severe Von Willebrand Disease Undergoing Surgery

Primary Purpose

Von Willebrand Disease

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Recombinant von Willebrand Factor (rVWF)
Sponsored by
Baxalta now part of Shire
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Von Willebrand Disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Diagnosis of severe von Willebrand disease (VWD) as listed below and elective surgical procedure planned

    1. Type 1 (Von Willebrand factor : Ristocetin cofactor activity (VWF:RCo) <20 IU/dL), or
    2. 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
    3. Type 3 (Von Willebrand factor antigen (VWF:Ag) ≤ 3 IU/dL)
  • VWD with a history of requiring substitution therapy with von Willebrand factor (VWF) concentrate to control bleeding
  • If type 3 VWD (VWF Antigen /VWF:Ag ≤ 3 IU/dL), participant has a medical history of at least 20 exposure days to VWF/FVIII coagulation factor concentrates (including cryoprecipitate or fresh frozen plasma)
  • If type 1 or type 2 VWD, participant has a medical history of 5 exposure days or a past major surgery requiring VWF/FVIII coagulation factor concentrates (including cryoprecipitate or fresh frozen plasma)
  • Participant is at least 18 years of age
  • If female of childbearing potential, participant presents with a negative pregnancy test
  • If applicable, participant agrees to employ adequate birth control measures for the duration of the study
  • Participant is willing and able to comply with the requirements of the protocol

Exclusion Criteria:

  • Diagnosis of pseudo VWD or another hereditary or acquired coagulation disorder (eg, qualitative and quantitative platelet disorders or elevated prothrombin time [PT] / international normalized ratio [INR] > 1.4)
  • History or presence of a VWF inhibitor at screening
  • 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)
  • Known hypersensitivity to any of the components of the study drugs, such as to mouse or hamster proteins
  • Medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies
  • Medical history of a thromboembolic event
  • HIV positive with an absolute CD4 count < 200/mm3
  • Platelet count < 100,000/mL
  • 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 (eg. presence of otherwise unexplained splenomegaly, history of esophageal varices) or liver cirrhosis classified as Child B or C
  • Diagnosis of renal disease, with a serum creatinine level ≥ 2 .5mg/dL
  • Participant has been treated with an immunomodulatory drug, excluding topical treatment (eg, ointments, nasal sprays), within 30 days prior to signing the informed consent
  • Participant is pregnant or lactating at the time informed content is obtained
  • Participant 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. However, eligible patients participating in the rVWF Prophylaxis Study (071301) may be enrolled.
  • Progressive fatal disease and/or life expectancy of less than 3 months
  • Participant is identified by the investigator as being unable or unwilling to cooperate with study procedures
  • Participant 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
  • Participant is in prison or compulsory detention by regulatory and/or juridical order
  • Participant is a 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 (ie, children, partner/spouse, siblings, parents) as well as employees.

Sites / Locations

  • University of Colorado Hemophilia & Thrombosis Center
  • University of Miami, Jackson Memorial Hospital
  • Georgia Regents University
  • John Hopkins University
  • Dana Farber Cancer Institute
  • Rutgers - Robert Wood Johnson Medical School
  • Duke University Medical Center
  • Case Western Reserve University Hospital
  • Cleveland Clinic
  • University of Oklahoma Health Sciences Center
  • Medical University of South Carolina (MUSC)
  • Blood Center of South East Wisconsin
  • Royal Adelaide Hospital
  • The Perth Blood Institute
  • Fiona Stanley Hospital
  • AKH - Medizinische Universität Wien
  • Fakultni nemocnice Ostrava
  • Universitätsmedizin der Johannes Gutenberg Universität Mainz
  • Azienda Ospedaliero - Universitaria Careggi
  • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
  • Umberto I Policlinico di Roma, Universitá di Roma La Sapienza
  • Erasmus Medisch Centrum
  • Regional Budgetary State Healthcare Institution (SHI) "Regional Clinical Hospital"
  • FSI Kirov Institute of Hematology and Blood Transfusion FMBA
  • Complejo Hospitalario Universitario A Coruña
  • Hospital Universitari i Politècnic La Fe
  • Taichung Veterans General Hospital
  • Tri-Service General Hospital
  • National Taiwan University Hospital
  • Ege University Medical Faculty
  • SI Institute of Blood Pathology and Transfusion Medicine of NAMSU
  • Derriford Hospital
  • Royal Free Hospital
  • Churchill Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Recombinant von Willebrand Factor (rVWF)

Arm Description

Surgery participants treated with Recombinant von Willebrand Factor (rVWF)

Outcomes

Primary Outcome Measures

Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)
Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none. Excellent: Intra-, and postoperative hemostasis achieved with rVWF with our without ADVATE was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal subject. Good: Intra-, and postoperative hemostasis achieved with rVWF with or without ADVATE was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal subject. Moderate: Intra-, and postoperative hemostasis with rVWF with or without ADVATE was clearly less than optimal for the type of procedure performed but was maintained without the need to change the rVWF concentrate. None: Participant experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of rVWF concentrate.

Secondary Outcome Measures

Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon
The predicted blood loss will be estimated preoperatively by the operating surgeon based on a hemostatically normal individual of the same sex, age, stature and co-morbidities as the participant. The actual blood loss will be assessed consisting of the estimated blood loss, including into swabs, towels and suction during the procedure, per the anesthesiologist's record.
Intraoperative Actual Blood Loss Relative to Predicted Blood Loss
Actual blood loss relative to predicted blood loss will be calculated as [Actual Blood loss (mL)] divided by [Predicted Blood Loss (mL) multiplied by 100.
Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon
Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none. Excellent: Intraoperative blood loss was less than or equal to the maximum blood loss expected for the type of procedure performed in a hemostatically normal subject (≤ 100%). Good: Intraoperative blood loss was up to 50% more than the maximum expected blood loss for the type of procedure performed in a hemostatically normal subject (101-150%) Moderate: Intraoperative blood loss was more than 50% of the maximum expected blood loss for the type of procedure performed in a hemostatically normal subject (>150%). None: Uncontrolled hemorrhage that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of clotting factor replacement regimen.
Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon
Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none. Excellent: Intraoperative hemostasis achieved with rVWF with our without ADVATE was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal subject. Good: Intraoperative hemostasis achieved with rVWF with or without ADVATE was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal subject. Moderate: Intraoperative hemostasis with rVWF with or without ADVATE was clearly less than optimal for the type of procedure performed but was maintained without the need to change the rVWF concentrate. None: Participant experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of rVWF concentrate.
Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE
Occurrence of Adverse Events
Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated.
Occurrence of Thrombotic Events
Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated for thrombotic events.
Occurrence of Severe Allergic Reactions (eg, Anaphylaxis)
Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated for severe allergic reactions.
Number of Participants Who Developed Inhibitory and Total Binding Antibodies to Von Willebrand Factor (VWF) and Inhibitory Antibodies to Factor VIII (FVIII)
Participants were treated with recombinant van Willebrand Factor (rVWF) with or without ADVATE.
Number of Participants Who Developed Antibodies to Chinese Hamster Ovary (CHO) Proteins, Mouse Immunoglobulin G (IgG) or Recombinant Furin (rFurin)
Participants were treated with recombinant van Willebrand Factor (rVWF) with or without ADVATE.
Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From 0 to 72 Hours Post-infusion (AUC 0-72 h/Dose)
This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. The area under the plasma concentration/time curve from 0 to 72 hours post-infusion will be computed using the linear trapezoidal rule. For the calculation of AUC(0-72h) the levels at 72 hours will be linearly interpolated/extrapolated from the 2 nearest sampling time points. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac), FVIII Coagulation Activity (FVIII:C)
Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity (AUC 0-∞ /Dose)
This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. The area under the plasma concentration/time curve from time 0 to infinity and the area under the first moment curve from time 0 to infinity will be calculated as the sum of AUC or AUMC from time 0 to the time of last quantifiable concentration plus a tail area correction calculated as Ct/λz and Ct/λz(t+1/λz), respectively, where Ct is the last quantifiable concentration, t is the time of last quantifiable concentration and λz is the terminal or disposition rate constant. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac), FVIII Coagulation Activity (FVIII:C)
Pharmacokinetics: Mean Residence Time (MRT)
This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Mean residence time will be calculated as area under the first moment curve from time 0 to infinity divided by the area under the curve time 0 to infinity minus T/2 where T is the duration of the infusion. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
Pharmacokinetics: Clearance (CL)
This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Clearance will be calculated as dose (IU/kg) divided by the area under the curve time 0 to infinity. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
Pharmacokinetics: Incremental Recovery (IR)
This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Incremental recovery will be calculated as (Cmax minus Cpreinfusion) divided by the dose (IU/kg) where kg refers to the body weight at the time of dosing and Cmax is the observed maximum concentration before correction for pre-infusion values. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
Pharmacokinetics: Elimination Phase Half-life (T1/2)
This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Terminal or disposition half-life (T1/2) will be calculated as ln2/λz where λz is the terminal elimination rate constant as calculated in WinNonlin NCA using at least three quantifiable concentrations. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
Pharmacokinetics: Volume of Distribution at Steady State (Vss)
This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Vss will be calculated as the clearance multiplied with the mean residence time. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)

Full Information

First Posted
October 27, 2014
Last Updated
April 29, 2021
Sponsor
Baxalta now part of Shire
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1. Study Identification

Unique Protocol Identification Number
NCT02283268
Brief Title
Recombinant Von Willebrand Factor in Subjects With Severe Von Willebrand Disease Undergoing Surgery
Official Title
A Phase 3, Prospective, Multicenter Study to Evaluate Efficacy and Safety of Recombinant Von Willebrand Factor (rVWF) With or Without ADVATE in Elective Surgical Procedures in Subjects With Severe Von Willebrand Disease
Study Type
Interventional

2. Study Status

Record Verification Date
April 2021
Overall Recruitment Status
Completed
Study Start Date
April 1, 2015 (Actual)
Primary Completion Date
July 6, 2016 (Actual)
Study Completion Date
July 6, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Baxalta now part of Shire

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of the study is to assess the efficacy and safety of recombinant von Willebrand factor (rVWF) with or without ADVATE in major and minor elective surgical procedures in adult patients with hereditary severe von Willebrand disease (VWD).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Von Willebrand Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Recombinant von Willebrand Factor (rVWF)
Arm Type
Experimental
Arm Description
Surgery participants treated with Recombinant von Willebrand Factor (rVWF)
Intervention Type
Biological
Intervention Name(s)
Recombinant von Willebrand Factor (rVWF)
Intervention Description
rVWF will be administered by intravenous bolus infusion. Participants planned for major surgery will undergo a baseline pharmacokinetic assessment prior to surgery. The peri- and postoperative substitution regimen will be individualized according to the PK results, intensity and duration of the hemostatic challenge, and the institution´s standard of care.
Primary Outcome Measure Information:
Title
Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)
Description
Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none. Excellent: Intra-, and postoperative hemostasis achieved with rVWF with our without ADVATE was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal subject. Good: Intra-, and postoperative hemostasis achieved with rVWF with or without ADVATE was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal subject. Moderate: Intra-, and postoperative hemostasis with rVWF with or without ADVATE was clearly less than optimal for the type of procedure performed but was maintained without the need to change the rVWF concentrate. None: Participant experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of rVWF concentrate.
Time Frame
24 hours after last peri-operative infusion or at completion of Day 14 (± 2 days) visit, whichever occurs earlier
Secondary Outcome Measure Information:
Title
Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon
Description
The predicted blood loss will be estimated preoperatively by the operating surgeon based on a hemostatically normal individual of the same sex, age, stature and co-morbidities as the participant. The actual blood loss will be assessed consisting of the estimated blood loss, including into swabs, towels and suction during the procedure, per the anesthesiologist's record.
Time Frame
Day 0 (at completion of surgery)
Title
Intraoperative Actual Blood Loss Relative to Predicted Blood Loss
Description
Actual blood loss relative to predicted blood loss will be calculated as [Actual Blood loss (mL)] divided by [Predicted Blood Loss (mL) multiplied by 100.
Time Frame
Day 0 (at completion of surgery)
Title
Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon
Description
Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none. Excellent: Intraoperative blood loss was less than or equal to the maximum blood loss expected for the type of procedure performed in a hemostatically normal subject (≤ 100%). Good: Intraoperative blood loss was up to 50% more than the maximum expected blood loss for the type of procedure performed in a hemostatically normal subject (101-150%) Moderate: Intraoperative blood loss was more than 50% of the maximum expected blood loss for the type of procedure performed in a hemostatically normal subject (>150%). None: Uncontrolled hemorrhage that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of clotting factor replacement regimen.
Time Frame
Day 0 (at completion of surgery)
Title
Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon
Description
Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none. Excellent: Intraoperative hemostasis achieved with rVWF with our without ADVATE was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal subject. Good: Intraoperative hemostasis achieved with rVWF with or without ADVATE was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal subject. Moderate: Intraoperative hemostasis with rVWF with or without ADVATE was clearly less than optimal for the type of procedure performed but was maintained without the need to change the rVWF concentrate. None: Participant experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of rVWF concentrate.
Time Frame
Day 0 (at completion of surgery)
Title
Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE
Time Frame
Daily, from day of surgery through postoperative Day 14 (± 2 days)
Title
Occurrence of Adverse Events
Description
Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated.
Time Frame
From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery)
Title
Occurrence of Thrombotic Events
Description
Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated for thrombotic events.
Time Frame
From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery)
Title
Occurrence of Severe Allergic Reactions (eg, Anaphylaxis)
Description
Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated for severe allergic reactions.
Time Frame
From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery)
Title
Number of Participants Who Developed Inhibitory and Total Binding Antibodies to Von Willebrand Factor (VWF) and Inhibitory Antibodies to Factor VIII (FVIII)
Description
Participants were treated with recombinant van Willebrand Factor (rVWF) with or without ADVATE.
Time Frame
Testing occurred throughout the study at screening, prior PK infusion, pre-surgery, post surgery in case of excessive bleeding or unexplained bleeding, at postoperative day 7 and at study completion visit (ie. 14 (± 2) days post surgery).
Title
Number of Participants Who Developed Antibodies to Chinese Hamster Ovary (CHO) Proteins, Mouse Immunoglobulin G (IgG) or Recombinant Furin (rFurin)
Description
Participants were treated with recombinant van Willebrand Factor (rVWF) with or without ADVATE.
Time Frame
Testing occurred throughout the study at screening, prior PK infusion, pre-surgery, post surgery in case of excessive bleeding or unexplained bleeding, at postoperative day 7 and at study completion visit (ie. 14 (± 2) days post surgery).
Title
Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From 0 to 72 Hours Post-infusion (AUC 0-72 h/Dose)
Description
This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. The area under the plasma concentration/time curve from 0 to 72 hours post-infusion will be computed using the linear trapezoidal rule. For the calculation of AUC(0-72h) the levels at 72 hours will be linearly interpolated/extrapolated from the 2 nearest sampling time points. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac), FVIII Coagulation Activity (FVIII:C)
Time Frame
PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
Title
Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity (AUC 0-∞ /Dose)
Description
This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. The area under the plasma concentration/time curve from time 0 to infinity and the area under the first moment curve from time 0 to infinity will be calculated as the sum of AUC or AUMC from time 0 to the time of last quantifiable concentration plus a tail area correction calculated as Ct/λz and Ct/λz(t+1/λz), respectively, where Ct is the last quantifiable concentration, t is the time of last quantifiable concentration and λz is the terminal or disposition rate constant. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac), FVIII Coagulation Activity (FVIII:C)
Time Frame
PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
Title
Pharmacokinetics: Mean Residence Time (MRT)
Description
This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Mean residence time will be calculated as area under the first moment curve from time 0 to infinity divided by the area under the curve time 0 to infinity minus T/2 where T is the duration of the infusion. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
Time Frame
PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
Title
Pharmacokinetics: Clearance (CL)
Description
This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Clearance will be calculated as dose (IU/kg) divided by the area under the curve time 0 to infinity. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
Time Frame
PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
Title
Pharmacokinetics: Incremental Recovery (IR)
Description
This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Incremental recovery will be calculated as (Cmax minus Cpreinfusion) divided by the dose (IU/kg) where kg refers to the body weight at the time of dosing and Cmax is the observed maximum concentration before correction for pre-infusion values. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
Time Frame
PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
Title
Pharmacokinetics: Elimination Phase Half-life (T1/2)
Description
This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Terminal or disposition half-life (T1/2) will be calculated as ln2/λz where λz is the terminal elimination rate constant as calculated in WinNonlin NCA using at least three quantifiable concentrations. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
Time Frame
PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
Title
Pharmacokinetics: Volume of Distribution at Steady State (Vss)
Description
This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Vss will be calculated as the clearance multiplied with the mean residence time. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac)
Time Frame
PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of severe von Willebrand disease (VWD) as listed below and elective surgical procedure planned Type 1 (Von Willebrand factor : Ristocetin cofactor activity (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 (Von Willebrand factor antigen (VWF:Ag) ≤ 3 IU/dL) VWD with a history of requiring substitution therapy with von Willebrand factor (VWF) concentrate to control bleeding If type 3 VWD (VWF Antigen /VWF:Ag ≤ 3 IU/dL), participant has a medical history of at least 20 exposure days to VWF/FVIII coagulation factor concentrates (including cryoprecipitate or fresh frozen plasma) If type 1 or type 2 VWD, participant has a medical history of 5 exposure days or a past major surgery requiring VWF/FVIII coagulation factor concentrates (including cryoprecipitate or fresh frozen plasma) Participant is at least 18 years of age If female of childbearing potential, participant presents with a negative pregnancy test If applicable, participant agrees to employ adequate birth control measures for the duration of the study Participant is willing and able to comply with the requirements of the protocol Exclusion Criteria: Diagnosis of pseudo VWD or another hereditary or acquired coagulation disorder (eg, qualitative and quantitative platelet disorders or elevated prothrombin time [PT] / international normalized ratio [INR] > 1.4) History or presence of a VWF inhibitor at screening 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) Known hypersensitivity to any of the components of the study drugs, such as to mouse or hamster proteins Medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies Medical history of a thromboembolic event HIV positive with an absolute CD4 count < 200/mm3 Platelet count < 100,000/mL 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 (eg. presence of otherwise unexplained splenomegaly, history of esophageal varices) or liver cirrhosis classified as Child B or C Diagnosis of renal disease, with a serum creatinine level ≥ 2 .5mg/dL Participant has been treated with an immunomodulatory drug, excluding topical treatment (eg, ointments, nasal sprays), within 30 days prior to signing the informed consent Participant is pregnant or lactating at the time informed content is obtained Participant 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. However, eligible patients participating in the rVWF Prophylaxis Study (071301) may be enrolled. Progressive fatal disease and/or life expectancy of less than 3 months Participant is identified by the investigator as being unable or unwilling to cooperate with study procedures Participant 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 Participant is in prison or compulsory detention by regulatory and/or juridical order Participant is a 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 (ie, children, partner/spouse, siblings, parents) as well as employees.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Director
Organizational Affiliation
Takeda
Official's Role
Study Director
Facility Information:
Facility Name
University of Colorado Hemophilia & Thrombosis Center
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
University of Miami, Jackson Memorial Hospital
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Georgia Regents University
City
Augusta
State/Province
Georgia
ZIP/Postal Code
30912
Country
United States
Facility Name
John Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Facility Name
Dana Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Rutgers - Robert Wood Johnson Medical School
City
New Brunswick
State/Province
New Jersey
ZIP/Postal Code
08901
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Facility Name
Case Western Reserve University Hospital
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
University of Oklahoma Health Sciences Center
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Facility Name
Medical University of South Carolina (MUSC)
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
Blood Center of South East Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53233
Country
United States
Facility Name
Royal Adelaide Hospital
City
Adelaide
State/Province
South Australia
ZIP/Postal Code
5000
Country
Australia
Facility Name
The Perth Blood Institute
City
Nedlands
State/Province
Western Australia
ZIP/Postal Code
6009
Country
Australia
Facility Name
Fiona Stanley Hospital
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6000
Country
Australia
Facility Name
AKH - Medizinische Universität Wien
City
Vienna
ZIP/Postal Code
1090
Country
Austria
Facility Name
Fakultni nemocnice Ostrava
City
Ostrava
ZIP/Postal Code
70852
Country
Czechia
Facility Name
Universitätsmedizin der Johannes Gutenberg Universität Mainz
City
Mainz
State/Province
Rheinland-Pfalz
ZIP/Postal Code
55101
Country
Germany
Facility Name
Azienda Ospedaliero - Universitaria Careggi
City
Firenze (Florence)
ZIP/Postal Code
50139
Country
Italy
Facility Name
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
City
Milano
ZIP/Postal Code
20122
Country
Italy
Facility Name
Umberto I Policlinico di Roma, Universitá di Roma La Sapienza
City
Rome
ZIP/Postal Code
00144
Country
Italy
Facility Name
Erasmus Medisch Centrum
City
Rotterdam
ZIP/Postal Code
3015 CE
Country
Netherlands
Facility Name
Regional Budgetary State Healthcare Institution (SHI) "Regional Clinical Hospital"
City
Barnaul
ZIP/Postal Code
656024
Country
Russian Federation
Facility Name
FSI Kirov Institute of Hematology and Blood Transfusion FMBA
City
Kirov
ZIP/Postal Code
610027
Country
Russian Federation
Facility Name
Complejo Hospitalario Universitario A Coruña
City
A Coruña
ZIP/Postal Code
15006
Country
Spain
Facility Name
Hospital Universitari i Politècnic La Fe
City
Valencia
ZIP/Postal Code
46026
Country
Spain
Facility Name
Taichung Veterans General Hospital
City
Taichung
ZIP/Postal Code
40705
Country
Taiwan
Facility Name
Tri-Service General Hospital
City
Taipei
ZIP/Postal Code
10002
Country
Taiwan
Facility Name
National Taiwan University Hospital
City
Taipei
ZIP/Postal Code
11490
Country
Taiwan
Facility Name
Ege University Medical Faculty
City
Izmir
ZIP/Postal Code
35100
Country
Turkey
Facility Name
SI Institute of Blood Pathology and Transfusion Medicine of NAMSU
City
Lviv
ZIP/Postal Code
79044
Country
Ukraine
Facility Name
Derriford Hospital
City
Plymouth
State/Province
Devon
ZIP/Postal Code
PL6 8DH
Country
United Kingdom
Facility Name
Royal Free Hospital
City
London
State/Province
Greater London
ZIP/Postal Code
NW3 2QG
Country
United Kingdom
Facility Name
Churchill Hospital
City
Oxford
State/Province
Oxfordshire
ZIP/Postal Code
OX3 7LJ
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
IPD Sharing Access Criteria
IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
IPD Sharing URL
https://vivli.org/ourmember/takeda/

Learn more about this trial

Recombinant Von Willebrand Factor in Subjects With Severe Von Willebrand Disease Undergoing Surgery

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