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

Tracking Information
First Submitted Date ICMJE	October 27, 2014
First Posted Date ICMJE	November 5, 2014
Results First Submitted Date	July 3, 2017
Results First Posted Date	August 31, 2017
Last Update Posted Date	October 23, 2017
Actual Study Start Date ICMJE	April 1, 2015
Actual Primary Completion Date	July 6, 2016 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: August 30, 2017)	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician) [ Time Frame: 24 hours after last peri-operative infusion or at completion of Day 14 (± 2 days) visit, whichever occurs earlier ]; 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.
Original Primary Outcome Measures ICMJE; (submitted: November 3, 2014)	Hemostatic efficacy as assessed by the investigator (hemophilia physician) [ Time Frame: 24 hours after last peri-operative infusion or at completion of Day 14 visit, whichever occurs earlier ]; Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none.
Change History	Complete list of historical versions of study NCT02283268 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: August 30, 2017)	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon [ Time Frame: Day 0 (at completion of surgery) ]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 [ Time Frame: Day 0 (at completion of surgery) ]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 [ Time Frame: Day 0 (at completion of surgery) ]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 [ Time Frame: Day 0 (at completion of surgery) ]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 [ Time Frame: Daily, from day of surgery through postoperative Day 14 (± 2 days) ]; Occurrence of Adverse Events [ Time Frame: From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery) ]Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated.; Occurrence of Thrombotic Events [ Time Frame: From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery) ]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) [ Time Frame: From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery) ]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) [ 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). ]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) [ 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). ]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) [ 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. ]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) [ 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. ]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) [ 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. ]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) [ 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. ]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) [ 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. ]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) [ 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. ]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) [ 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. ]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)
Original Secondary Outcome Measures ICMJE; (submitted: November 3, 2014)	Intraoperative actual versus predicted blood loss (assessed by the operating surgeon) [ Time Frame: Day 0 (at completion of surgery) ]; Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon [ Time Frame: Day 0 (at completion of surgery) ]Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none.; Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE [ Time Frame: Through postoperative Day 14 ]; Adverse events [ Time Frame: Through study completion (ie, 14 days post surgery) ]; Occurrence of Thrombotic Events [ Time Frame: Through study completion (ie, 14 days post surgery) ]; Occurrence of Severe Allergic Reactions (eg, Anaphylaxis) [ Time Frame: Through study completion (ie, 14 days post surgery) ]; Development of inhibitory and total binding antibodies to VWF [ Time Frame: Through study completion (ie, 14 days post surgery) ]; Development of inhibitory antibodies to Factor VIII (FVIII) [ Time Frame: Through study completion (ie, 14 days post surgery) ]; Development of antibodies to Chinese hamster ovary (CHO) proteins, mouse immunoglobulin G (IgG) or recombinant Furin (rFurin) [ Time Frame: Through study completion (ie, 14 days post surgery) ]; Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From 0 to 72 Hours Post-infusion (AUC 0-72 h/Dose) [ Time Frame: Within 30 minutes pre-infusion and up to 72 (± 2) hours post-infusion ]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.; Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity (AUC 0-∞ /Dose) [ Time Frame: Within 30 minutes pre-infusion and up to 72 (± 2) hours post-infusion ]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.; Pharmacokinetics: Mean Residence Time (MRT) [ Time Frame: Within 30 minutes pre-infusion and up to 72 (± 2) hours post-infusion ]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.; Pharmacokinetics: Clearance (CL) [ Time Frame: Within 30 minutes pre-infusion and up to 72 (± 2) hours post-infusion ]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.; Pharmacokinetics: Incremental Recovery (IR) [ Time Frame: Within 30 minutes pre-infusion and up to 72 (± 2) hours post-infusion ]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.; Pharmacokinetics: Elimination Phase Half-life (T1/2) [ Time Frame: Within 30 minutes pre-infusion and up to 72 (± 2) hours post-infusion ]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.; Pharmacokinetics: Volume of Distribution at Steady State (Vss) [ Time Frame: Within 30 minutes pre-infusion and up to 72 (± 2) hours post-infusion ]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.
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Recombinant Von Willebrand Factor in Subjects With Severe Von Willebrand Disease Undergoing Surgery
Official Title ICMJE	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
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).
Detailed Description	Not Provided
Study Type ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Von Willebrand Disease
Intervention ICMJE	Biological: Recombinant von Willebrand Factor (rVWF); 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.
Study Arms	Experimental: Recombinant von Willebrand Factor (rVWF); Surgery participants treated with Recombinant von Willebrand Factor (rVWF); Intervention: Biological: Recombinant von Willebrand Factor (rVWF)
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: June 22, 2016)	24
Original Estimated Enrollment ICMJE; (submitted: November 3, 2014)	15
Actual Study Completion Date	July 6, 2016
Actual Primary Completion Date	July 6, 2016 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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.
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Australia, Austria, Czechia, Germany, Italy, Netherlands, Russian Federation, Spain, Taiwan, Turkey, Ukraine, United Kingdom, United States
Removed Location Countries	Czech Republic
Administrative Information
NCT Number ICMJE	NCT02283268
Other Study ID Numbers ICMJE	071101; 2014-003575-38 ( EudraCT Number )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Shire ( Baxalta now part of Shire )
Study Sponsor ICMJE	Baxalta now part of Shire
Collaborators ICMJE	Not Provided
Investigators ICMJE	Study Director: Arthur Sytkowski, MD Shire
PRS Account	Shire
Verification Date	July 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP