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

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02283268

Enrollment

Registered

2014-11-05

Start date

2015-04-01

Completion date

2016-07-06

Last updated

2021-05-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

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).

Interventions

BIOLOGICALRecombinant 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 design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

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.

Design outcomes

Primary

Measure	Time frame	Description
Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	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.

Secondary

Measure	Time frame	Description
Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	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	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	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	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	Daily, from day of surgery through postoperative Day 14 (± 2 days)	—
Occurrence of Adverse Events	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	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)	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)	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)	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)	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)	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)	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)	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)	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)	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)	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)

Countries

Australia, Austria, Czechia, Germany, Italy, Netherlands, Russia, Spain, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States

Participant flow

Recruitment details

Enrollment was conducted at 14 study sites in 10 countries (USA, Australia, Taiwan, Germany, Russia, Spain, Ukraine, United Kingdom, Italy, Turkey).

Pre-assignment details

A total of 24 participants were enrolled (signed informed consent) and screened. Of these, 15 participants were treated with investigational product.

Participants by arm

Arm	Count
Recombinant Von Willebrand Factor (rVWF) Surgery participants treated with Recombinant von Willebrand Factor (rVWF)	15
Total	15

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Withdrawal by Subject	1

Baseline characteristics

Characteristic	Recombinant Von Willebrand Factor (rVWF)
Age, Continuous	40.0 Years
Sex: Female, Male Female	8 Participants
Sex: Female, Male Male	7 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 15
other Total, other adverse events	6 / 15
serious Total, serious adverse events	2 / 15

Outcome results

Primary

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.

Time frame: 24 hours after last peri-operative infusion or at completion of Day 14 (± 2 days) visit, whichever occurs earlier

Population: Number of participants with major, minor and oral surgery and number of participant with Von Willebrand Type 1, 2A, 2B, 2M and 3 do sum up to the overall number of participants analyzed. The full analysis data set, including all participants who received investigational product and have at least 1 hemostatic assessment, was used for analysis.

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Recombinant Von Willebrand Factor (rVWF)	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Excellent	11 Participants
Recombinant Von Willebrand Factor (rVWF)	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Good	4 Participants
Recombinant Von Willebrand Factor (rVWF)	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Moderate	0 Participants
Recombinant Von Willebrand Factor (rVWF)	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	None	0 Participants
Minor Surgery	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Moderate	0 Participants
Minor Surgery	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	None	0 Participants
Minor Surgery	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Excellent	4 Participants
Minor Surgery	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Good	0 Participants
Major Surgery	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Excellent	7 Participants
Major Surgery	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	None	0 Participants
Major Surgery	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Good	3 Participants
Major Surgery	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Moderate	0 Participants
Oral Surgery	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	None	0 Participants
Oral Surgery	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Moderate	0 Participants
Oral Surgery	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Good	1 Participants
Oral Surgery	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Excellent	0 Participants
Von Willebrand Disease Type 1	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Moderate	0 Participants
Von Willebrand Disease Type 1	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Good	1 Participants
Von Willebrand Disease Type 1	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Excellent	2 Participants
Von Willebrand Disease Type 1	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	None	0 Participants
Von Willebrand Disease Type 2A	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Excellent	1 Participants
Von Willebrand Disease Type 2A	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Good	1 Participants
Von Willebrand Disease Type 2A	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Moderate	0 Participants
Von Willebrand Disease Type 2A	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	None	0 Participants
Von Willebrand Disease Type 2B	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Good	0 Participants
Von Willebrand Disease Type 2B	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	None	0 Participants
Von Willebrand Disease Type 2B	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Excellent	1 Participants
Von Willebrand Disease Type 2B	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Moderate	0 Participants
Von Willebrand Disease Type 2M	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	None	0 Participants
Von Willebrand Disease Type 2M	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Moderate	0 Participants
Von Willebrand Disease Type 2M	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Good	1 Participants
Von Willebrand Disease Type 2M	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Excellent	0 Participants
Von Willebrand Disease Type 3	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Good	1 Participants
Von Willebrand Disease Type 3	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Excellent	7 Participants
Von Willebrand Disease Type 3	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	None	0 Participants
Von Willebrand Disease Type 3	Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)	Moderate	0 Participants

Secondary

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)

Population: Number of participants analyzed is different for the time points according to individual treatment. The full analysis data set, including all participants who received investigational product and have at least 1 hemostatic assessment, was used for analysis.

Arm	Measure	Group	Value (MEDIAN)
Recombinant Von Willebrand Factor (rVWF)	Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE	intraoperative	18.1 IU/kg
Recombinant Von Willebrand Factor (rVWF)	Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE	postoperative day 1	23.5 IU/kg
Recombinant Von Willebrand Factor (rVWF)	Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE	postoperative day 2	42.3 IU/kg
Recombinant Von Willebrand Factor (rVWF)	Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE	postoperative day 3	28.6 IU/kg
Recombinant Von Willebrand Factor (rVWF)	Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE	postoperative day 4	33.9 IU/kg
Recombinant Von Willebrand Factor (rVWF)	Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE	postoperative day 5	31.5 IU/kg
Recombinant Von Willebrand Factor (rVWF)	Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE	postoperative day 6	23.2 IU/kg
Recombinant Von Willebrand Factor (rVWF)	Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE	postoperative day 7	23.8 IU/kg
Recombinant Von Willebrand Factor (rVWF)	Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE	postoperative day 8	33.9 IU/kg
Recombinant Von Willebrand Factor (rVWF)	Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE	postoperative day 9	23.6 IU/kg
Recombinant Von Willebrand Factor (rVWF)	Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE	postoperative day 10	23.6 IU/kg
Recombinant Von Willebrand Factor (rVWF)	Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE	postoperative day 11	23.6 IU/kg
Recombinant Von Willebrand Factor (rVWF)	Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE	postoperative day 12	29.3 IU/kg
Recombinant Von Willebrand Factor (rVWF)	Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE	postoperative day 13	16.3 IU/kg
Recombinant Von Willebrand Factor (rVWF)	Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE	postoperative day 14	25.5 IU/kg
Recombinant Von Willebrand Factor (rVWF)	Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE	postoperative day 15	16.3 IU/kg

Secondary

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.

Time frame: Day 0 (at completion of surgery)

Population: Number of participants analyzed is 11, as for 3 participants the actual and the predicted blood loss was zero and for 1 participant the predicted blood loss was not collected. Therefore 'actual blood loss relative to predicted blood loss' could not be calculated. The full analysis data set was used for the analysis of this outcome measure.

Arm	Measure	Value (MEAN)	Dispersion
Recombinant Von Willebrand Factor (rVWF)	Intraoperative Actual Blood Loss Relative to Predicted Blood Loss	69.6 Percent	Standard Deviation 44.77
Minor Surgery	Intraoperative Actual Blood Loss Relative to Predicted Blood Loss	0.0 Percent	—
Major Surgery	Intraoperative Actual Blood Loss Relative to Predicted Blood Loss	68.9 Percent	Standard Deviation 34.48
Oral Surgery	Intraoperative Actual Blood Loss Relative to Predicted Blood Loss	145.0 Percent	—
Von Willebrand Disease Type 1	Intraoperative Actual Blood Loss Relative to Predicted Blood Loss	122.5 Percent	Standard Deviation 31.82
Von Willebrand Disease Type 2A	Intraoperative Actual Blood Loss Relative to Predicted Blood Loss	50.0 Percent	—
Von Willebrand Disease Type 2B	Intraoperative Actual Blood Loss Relative to Predicted Blood Loss	100.0 Percent	—
Von Willebrand Disease Type 2M	Intraoperative Actual Blood Loss Relative to Predicted Blood Loss	100.0 Percent	—
Von Willebrand Disease Type 3	Intraoperative Actual Blood Loss Relative to Predicted Blood Loss	45.0 Percent	Standard Deviation 38.92

Secondary

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.

Time frame: Day 0 (at completion of surgery)

Population: For predicted blood loss the number of participants analyzed is 14 as for one participant (included in the major surgery reporting group) the predicted blood loss was not collected. The full analysis data set, including all participants who received investigational product and have at least 1 hemostatic assessment, was used for analysis.

Arm	Measure	Group	Value (MEAN)	Dispersion
Recombinant Von Willebrand Factor (rVWF)	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Actual blood loss	94.3 mL	Standard Deviation 177.88
Recombinant Von Willebrand Factor (rVWF)	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Predicted blood loss	106.1 mL	Standard Deviation 161.82
Minor Surgery	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Actual blood loss	0.0 mL	Standard Deviation 0
Minor Surgery	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Predicted blood loss	2.5 mL	Standard Deviation 5
Major Surgery	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Actual blood loss	127.0 mL	Standard Deviation 209.27
Major Surgery	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Predicted blood loss	152.8 mL	Standard Deviation 186.33
Oral Surgery	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Actual blood loss	145.0 mL	—
Oral Surgery	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Predicted blood loss	100.0 mL	—
Von Willebrand Disease Type 1	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Actual blood loss	115.0 mL	Standard Deviation 103.32
Von Willebrand Disease Type 1	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Predicted blood loss	100.0 mL	Standard Deviation 100
Von Willebrand Disease Type 2A	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Actual blood loss	42.5 mL	Standard Deviation 53.03
Von Willebrand Disease Type 2A	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Predicted blood loss	10.0 mL	—
Von Willebrand Disease Type 2B	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Predicted blood loss	50.0 mL	—
Von Willebrand Disease Type 2B	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Actual blood loss	50.0 mL	—
Von Willebrand Disease Type 2M	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Actual blood loss	50.0 mL	—
Von Willebrand Disease Type 2M	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Predicted blood loss	50.0 mL	—
Von Willebrand Disease Type 3	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Actual blood loss	110.6 mL	Standard Deviation 240.87
Von Willebrand Disease Type 3	Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon	Predicted blood loss	134.4 mL	Standard Deviation 206.46

Secondary

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.

Time frame: Day 0 (at completion of surgery)

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Recombinant Von Willebrand Factor (rVWF)	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Excellent	13 Participants
Recombinant Von Willebrand Factor (rVWF)	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Recombinant Von Willebrand Factor (rVWF)	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	None	0 Participants
Recombinant Von Willebrand Factor (rVWF)	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Good	2 Participants
Minor Surgery	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Good	0 Participants
Minor Surgery	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Excellent	4 Participants
Minor Surgery	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Minor Surgery	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	None	0 Participants
Major Surgery	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Good	2 Participants
Major Surgery	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	None	0 Participants
Major Surgery	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Excellent	8 Participants
Major Surgery	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Oral Surgery	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Oral Surgery	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Excellent	1 Participants
Oral Surgery	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	None	0 Participants
Oral Surgery	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Good	0 Participants
Von Willebrand Disease Type 1	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Excellent	3 Participants
Von Willebrand Disease Type 1	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Good	0 Participants
Von Willebrand Disease Type 1	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Von Willebrand Disease Type 1	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	None	0 Participants
Von Willebrand Disease Type 2A	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	None	0 Participants
Von Willebrand Disease Type 2A	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Excellent	1 Participants
Von Willebrand Disease Type 2A	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Von Willebrand Disease Type 2A	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Good	1 Participants
Von Willebrand Disease Type 2B	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Von Willebrand Disease Type 2B	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	None	0 Participants
Von Willebrand Disease Type 2B	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Good	0 Participants
Von Willebrand Disease Type 2B	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Excellent	1 Participants
Von Willebrand Disease Type 2M	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Good	0 Participants
Von Willebrand Disease Type 2M	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	None	0 Participants
Von Willebrand Disease Type 2M	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Von Willebrand Disease Type 2M	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Excellent	1 Participants
Von Willebrand Disease Type 3	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Excellent	7 Participants
Von Willebrand Disease Type 3	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Good	1 Participants
Von Willebrand Disease Type 3	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Von Willebrand Disease Type 3	Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon	None	0 Participants

Secondary

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.

Time frame: Day 0 (at completion of surgery)

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
Recombinant Von Willebrand Factor (rVWF)	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Recombinant Von Willebrand Factor (rVWF)	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Good	2 Participants
Recombinant Von Willebrand Factor (rVWF)	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	None	0 Participants
Recombinant Von Willebrand Factor (rVWF)	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Excellent	13 Participants
Minor Surgery	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Minor Surgery	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Excellent	4 Participants
Minor Surgery	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	None	0 Participants
Minor Surgery	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Good	0 Participants
Major Surgery	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Major Surgery	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Good	2 Participants
Major Surgery	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Excellent	8 Participants
Major Surgery	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	None	0 Participants
Oral Surgery	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Excellent	1 Participants
Oral Surgery	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Good	0 Participants
Oral Surgery	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	None	0 Participants
Oral Surgery	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Von Willebrand Disease Type 1	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Von Willebrand Disease Type 1	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	None	0 Participants
Von Willebrand Disease Type 1	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Excellent	3 Participants
Von Willebrand Disease Type 1	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Good	0 Participants
Von Willebrand Disease Type 2A	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	None	0 Participants
Von Willebrand Disease Type 2A	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Good	1 Participants
Von Willebrand Disease Type 2A	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Von Willebrand Disease Type 2A	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Excellent	1 Participants
Von Willebrand Disease Type 2B	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	None	0 Participants
Von Willebrand Disease Type 2B	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Good	0 Participants
Von Willebrand Disease Type 2B	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Excellent	1 Participants
Von Willebrand Disease Type 2B	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Von Willebrand Disease Type 2M	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Von Willebrand Disease Type 2M	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	None	0 Participants
Von Willebrand Disease Type 2M	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Good	0 Participants
Von Willebrand Disease Type 2M	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Excellent	1 Participants
Von Willebrand Disease Type 3	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	None	0 Participants
Von Willebrand Disease Type 3	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Moderate	0 Participants
Von Willebrand Disease Type 3	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Good	1 Participants
Von Willebrand Disease Type 3	Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon	Excellent	7 Participants

Secondary

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.

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).

Population: The safety analysis data set, including all participants who received any amount of investigational product, was used for analysis of this outcome measure.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Recombinant Von Willebrand Factor (rVWF)	Number of Participants Who Developed Antibodies to Chinese Hamster Ovary (CHO) Proteins, Mouse Immunoglobulin G (IgG) or Recombinant Furin (rFurin)	0 Participants

Secondary

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.

Population: The safety analysis data set, including all participants who received any amount of investigational product, was used for analysis of this outcome measure.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Recombinant Von Willebrand Factor (rVWF)	Number of Participants Who Developed Inhibitory and Total Binding Antibodies to Von Willebrand Factor (VWF) and Inhibitory Antibodies to Factor VIII (FVIII)	Development of inhibitory antibodies to VWF	0 Participants
Recombinant Von Willebrand Factor (rVWF)	Number of Participants Who Developed Inhibitory and Total Binding Antibodies to Von Willebrand Factor (VWF) and Inhibitory Antibodies to Factor VIII (FVIII)	Development of total binding antibodies to VWF	1 Participants
Recombinant Von Willebrand Factor (rVWF)	Number of Participants Who Developed Inhibitory and Total Binding Antibodies to Von Willebrand Factor (VWF) and Inhibitory Antibodies to Factor VIII (FVIII)	Development of inhibitory antibodies to FVIII	0 Participants

Secondary

Occurrence of Adverse Events

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)

Population: The safety analysis data set, including all participants who received any amount of investigational product, was used for analysis of this outcome measure.

Arm	Measure	Group	Value (NUMBER)
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Adverse Events	TEAEs leading to death	0 Adverse Events
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Adverse Events	Treatment emergent Adverse Events (TEAEs)	12 Adverse Events
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Adverse Events	Severe TEAEs	1 Adverse Events
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Adverse Events	TEAEs related to rVWF	0 Adverse Events
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Adverse Events	TEAEs related to ADVATE	0 Adverse Events
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Adverse Events	TEAEs related to both rVWF and ADVATE	0 Adverse Events
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Adverse Events	Treatment emergent Serious Adverse Events (TESAEs)	2 Adverse Events
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Adverse Events	TESAEs related to rVWF	0 Adverse Events
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Adverse Events	TESAEs related to ADVATE	0 Adverse Events
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Adverse Events	TESAEs related to both rVWF and ADVATE	0 Adverse Events
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Adverse Events	TEAEs leading to discontinuation of rVWF	0 Adverse Events
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Adverse Events	TEAEs leading to discontinuation of ADVATE	0 Adverse Events
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Adverse Events	TEAEs leading to discontinuation of study	0 Adverse Events
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Adverse Events	TEAEs related to study procedure	0 Adverse Events
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Adverse Events	TESAEs related to study procedure	0 Adverse Events

Secondary

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.

Time frame: From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery)

Population: The safety analysis data set, including all participants who received any amount of investigational product, was used for analysis of this outcome measure.

Arm	Measure	Group	Value (NUMBER)
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Severe Allergic Reactions (eg, Anaphylaxis)	Severe allergic reaction TEAEs	0 Adverse Events
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Severe Allergic Reactions (eg, Anaphylaxis)	Severe allergic reaction TESAEs	0 Adverse Events

Secondary

Occurrence of Thrombotic Events

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)

Population: The safety analysis data set, including all participants who received any amount of investigational product, was used for analysis of this outcome measure.

Arm	Measure	Group	Value (NUMBER)
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Thrombotic Events	Thrombotic TEAEs	2 Adverse Events
Recombinant Von Willebrand Factor (rVWF)	Occurrence of Thrombotic Events	Thrombotic TESAEs	1 Adverse Events

Secondary

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)

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.