Trial Outcomes & Findings for Pharmacokinetics, Safety and Efficacy of Recombinant Von Willebrand Factor (rVWF) in the Treatment of Bleeding Episodes in Von Willebrand Disease (VWD) (NCT NCT01410227)

Results Overview

Treatment success was defined as the extent of control of bleeding episodes (BEs) using a mean efficacy rating score of \<2.5 for a participant's BEs treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) during the study period. Scores used: Excellent = 1 - actual infusions ≤ estimated number of infusions required to treat BE; no additional VWF required (all BEs); Good = 2 - \>1-2 infusions (minor/moderate BEs) or \<1.5 infusions (major BEs) greater than estimated required to control BE; no additional VWF required (all BEs); Moderate = 3 ≥ 3 infusions (minor/moderate BEs) or ≥ 1.5 infusions (major BEs) greater than estimated required to control BE; no additional VWF required (all BEs); None = 4 - severe uncontrolled bleeding or intensity of bleeding not changed; additional VWF required. Included participants with available primary efficacy rating (prospective-excluding gastrointestinal bleeds) in the Full Analysis Set.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

49 participants

Primary outcome timeframe

For 12 months after first infusion of rVWF:rFVIII or rVWF

Results posted on

2021-05-19

Participant Flow

Participants were enrolled (signed informed consent) from 30 sites in 15 countries.

49 participants provided informed consent and were screened for the study, of which 37 were exposed to study product. Reasons for discontinuation were 6 screen failures, consent withdrawn by 3 participants, 1 physician decision, 1 participant received high doses of rFVIII for oral procedure and arm for which 1 participant was eligible was closed.

Participant milestones

Participant milestones
Measure	Arm 1: PK50 + Treatment In Part A, (pharmacokinetic \[PK\] assessment followed by on-demand treatment for bleeding episodes \[BEs\] for 6 months) participants were initially infused either with 50 IU/kg recombinant von Willebrand Factor:von Willebrand Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) \[rVWF:rFVIII\] or 50 IU/kg rVWF administered together with saline. Participants then crossed over to the alternate infusion after washout (PK). For on-demand treatment, participants received study product \[VWF:rFVIII or rVWF\], where BEs were initially treated with rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels (dose based on previous FVIII levels or if not available from the individual participant's PK data at discretion of investigator). In part, B participants continued to receive on-demand treatment for BEs with study product \[VWF:rFVIII or rVWF\] for a further 6 months.	Arm 2: PK50 Only In Part A, (pharmacokinetic \[PK\] assessment followed by on-demand treatment for bleeding episodes \[BEs\] for 6 months) participants were initially infused either with 50 IU/kg recombinant von Willebrand Factor:von Willebrand Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) \[rVWF:rFVIII\] or 50 IU/kg rVWF administered together with saline. Participants then crossed over to the alternate infusion after washout (PK). For on-demand treatment, participants received study product \[VWF:rFVIII or rVWF\], where BEs were initially treated with rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels (dose based on previous FVIII levels or if not available from the individual participant's PK data at discretion of investigator). Participants then exited the study or could opt to sign informed consent to move to Arm 1 receive treatment for bleeding episodes with study product.	Arm 3: PK80 + Treatment In Part A, participants initially underwent a first PK assessment of an infusion of 80 IU/kg recombinant von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\]. After the first PK assessment participants received on demand treatment for bleeding episodes (BEs) with study product \[VWF:rFVIII or rVWF\], where BEs were initially treated with rVWF:rFVIII and subsequently with rWVF with or without rFVIII, based on FVIII levels. If FVIII levels not available, the individual participant's PK data was used to determine rFVIII dose at discretion of investigator. Participants received on-demand treatment for 6 months after the first study product infusion. After 6 months participants underwent a second PK assessment of an infusion of 80 IU/kg rVWF. In part B, participants continued to receive on-demand treatment for BEs with study product \[VWF:rFVIII or rVWF\] for a further 6 months.	Arm 4: Treatment Only In Part A, participants received on-demand treatment for bleeding episodes (BEs) with study product (recombinant von Willebrand Factor \[rVWF\] administered together with recombinant Factor VIII \[rFVIII\] (rVWF:rFVIII) or rVWF alone), where BEs were initially treated with rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels. If not available, the individual participant's PK data was used to determine rFVIII dose at discretion of investigator. Participants received on-demand treatment for 6 months after the first study product infusion. In part, B participants continued to receive on-demand treatment for BEs with study product \[VWF:rFVIII or rVWF\] for a further 6 months. No pharmacokinetic (PK) assessments were conducted in this arm.
Overall Study STARTED	8	8	15	6
Overall Study COMPLETED	4	8	13	5
Overall Study NOT COMPLETED	4	0	2	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm 1: PK50 + Treatment In Part A, (pharmacokinetic \[PK\] assessment followed by on-demand treatment for bleeding episodes \[BEs\] for 6 months) participants were initially infused either with 50 IU/kg recombinant von Willebrand Factor:von Willebrand Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) \[rVWF:rFVIII\] or 50 IU/kg rVWF administered together with saline. Participants then crossed over to the alternate infusion after washout (PK). For on-demand treatment, participants received study product \[VWF:rFVIII or rVWF\], where BEs were initially treated with rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels (dose based on previous FVIII levels or if not available from the individual participant's PK data at discretion of investigator). In part, B participants continued to receive on-demand treatment for BEs with study product \[VWF:rFVIII or rVWF\] for a further 6 months.	Arm 3: PK80 + Treatment In Part A, participants initially underwent a first PK assessment of an infusion of 80 IU/kg recombinant von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\]. After the first PK assessment participants received on demand treatment for bleeding episodes (BEs) with study product \[VWF:rFVIII or rVWF\], where BEs were initially treated with rVWF:rFVIII and subsequently with rWVF with or without rFVIII, based on FVIII levels. If FVIII levels not available, the individual participant's PK data was used to determine rFVIII dose at discretion of investigator. Participants received on-demand treatment for 6 months after the first study product infusion. After 6 months participants underwent a second PK assessment of an infusion of 80 IU/kg rVWF. In part B, participants continued to receive on-demand treatment for BEs with study product \[VWF:rFVIII or rVWF\] for a further 6 months.	Arm 4: Treatment Only In Part A, participants received on-demand treatment for bleeding episodes (BEs) with study product (recombinant von Willebrand Factor \[rVWF\] administered together with recombinant Factor VIII \[rFVIII\] (rVWF:rFVIII) or rVWF alone), where BEs were initially treated with rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels. If not available, the individual participant's PK data was used to determine rFVIII dose at discretion of investigator. Participants received on-demand treatment for 6 months after the first study product infusion. In part, B participants continued to receive on-demand treatment for BEs with study product \[VWF:rFVIII or rVWF\] for a further 6 months. No pharmacokinetic (PK) assessments were conducted in this arm.
Overall Study Adverse Event	1	0	0
Overall Study Withdrawal by Subject	3	1	0
Overall Study Pregnancy	0	0	1
Overall Study Met Excl. Criteria After Starting Study	0	1	0

Baseline Characteristics

Pharmacokinetics, Safety and Efficacy of Recombinant Von Willebrand Factor (rVWF) in the Treatment of Bleeding Episodes in Von Willebrand Disease (VWD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Subjects Treated With Study Product n=37 Participants All subjects treated with study product
Age, Continuous	37 Years n=5 Participants
Sex: Female, Male Female	20 Participants n=5 Participants
Sex: Female, Male Male	17 Participants n=5 Participants

PRIMARY outcome

Timeframe: For 12 months after first infusion of rVWF:rFVIII or rVWF

Treatment success was defined as the extent of control of bleeding episodes (BEs) using a mean efficacy rating score of \<2.5 for a participant's BEs treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) during the study period. Scores used: Excellent = 1 - actual infusions ≤ estimated number of infusions required to treat BE; no additional VWF required (all BEs); Good = 2 - \>1-2 infusions (minor/moderate BEs) or \<1.5 infusions (major BEs) greater than estimated required to control BE; no additional VWF required (all BEs); Moderate = 3 ≥ 3 infusions (minor/moderate BEs) or ≥ 1.5 infusions (major BEs) greater than estimated required to control BE; no additional VWF required (all BEs); None = 4 - severe uncontrolled bleeding or intensity of bleeding not changed; additional VWF required. Included participants with available primary efficacy rating (prospective-excluding gastrointestinal bleeds) in the Full Analysis Set.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=18 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
Percentage of Participants With Treatment Success for Treated Bleeding Episodes	100.0 Percent of participants Interval 84.7 to 100.0

SECONDARY outcome

Timeframe: For 12 months after first infusion of rVWF:rFVIII or rVWF

Efficacy ratings "excellent" or "good" for the control of bleeding episodes (BEs) with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) are defined as follows: Excellent - actual infusions ≤ estimated number of infusions required to treat BE; no additional von Willebrand Factor (VWF) required (all BEs); Good - \>1-2 infusions (minor/moderate BEs) or \<1.5 infusions (major BEs) greater than estimated required to control BE; no additional VWF required (all BEs). The data set included prospectively estimated BEs treated with study product with an available efficacy rating from participants in the Full Analysis Set

Outcome measures

Outcome measures
Measure	Full Analysis Set n=130 Bleeding episodes Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
Percentage of Treated Bleeding Episodes With an Efficacy Rating of "Excellent" or "Good"	100.0 Percent of bleeding episodes Interval 97.7 to 100.0

SECONDARY outcome

Timeframe: For 12 months after first infusion of rVWF:rFVIII or rVWF

Efficacy ratings of "excellent" or "good" for the control of bleeding episodes (BEs) with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) are defined as follows: Excellent - actual infusions ≤ estimated number of infusions required to treat BE; no additional von Willebrand Factor (VWF) required (all BEs); Good - \>1-2 infusions (minor/moderate BEs) or \<1.5 infusions (major BEs) greater than estimated required to control BE; no additional VWF required (all BEs). The data set included prospectively estimated BEs excluding gastrointestinal (GI) bleeds treated with study product with an available efficacy rating from participants in the Full Analysis Set.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=126 Bleeding episodes Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
Percentage of Treated Bleeding Episodes With an Efficacy Rating of "Excellent" or "Good", Excluding Gastrointestinal Bleeds	100.0 Percent of bleeding episodes Interval 97.7 to 100.0

SECONDARY outcome

Timeframe: For 12 months after first infusion of rVWF:rFVIII or rVWF

The actual number of infusions of recombinant von Willebrand factor:recombinant factor VIII (rVWF:rFVIII) and/or rVWF required to treat a bleeding episode (BE). BEs were to be initially treated with an infusion of rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels, if available. In cases, where no FVIII levels were available, the individual participant's PK data was used to determine the rFVIII dose. The data set included prospectively estimated BEs treated with study product with an available efficacy rating from participants in the Full Analysis Set.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=192 Bleeding episodes Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
Number of Infusions of rVWF:rFVIII and/or rVWF Per Bleeding Episode	1.0 Number of infusions Interval 1.0 to 1.0

SECONDARY outcome

Timeframe: For 12 months after first infusion of rVWF:rFVIII or rVWF

The number of units is provided as the actual dose \[IU/kg\] of recombinant von Willebrand factor:recombinant factor VIII (rVWF:rFVIII) and/or rVWF required to treat a bleeding episode (BE). BEs were to be initially treated with an infusion of rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels, if available. In cases, where no FVIII levels were available, the individual participant's PK data was used to determine the rFVIII dose. The data set included prospectively estimated BEs treated with study product of known lot number with an available efficacy rating from participants in the Full Analysis Set.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=174 Bleeding episodes Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
Number of Units of rVWF:rFVIII and/or rVWF Per Bleeding Episode	48.2 IU/kg Interval 43.9 to 50.2

SECONDARY outcome

Timeframe: For 12 months after first infusion of rVWF:rFVIII or rVWF

Development of neutralizing antibodies (inhibitors) to factor VIII (FVIII) was assessed by the Nijmegen modification of the Bethesda assay. Positive FVIII inhibitor tests were defined as ≥ 0.4 Bethesda units/mL (BU/mL) by the Nijmegen-modified Bethesda assay that is confirmed by a second test performed on an independent sample obtained 2-4 weeks following the first test. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=37 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
Percentage of Participants Who Develop Inhibitory Antibodies to FVIII Before 1st treatment with study product [N=37]	0 Percent of participants
Percentage of Participants Who Develop Inhibitory Antibodies to FVIII During 1st treatment until study end [N=27]	0 Percent of participants
Percentage of Participants Who Develop Inhibitory Antibodies to FVIII At final study visit [N=24]	0 Percent of participants

SECONDARY outcome

Timeframe: After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF

Neutralizing antibodies (inhibitors) to Von Willebrand Factor Ristocetin cofactor (VWF:RCo), VWF collagen binding (VWF:CB) and VWF Factor VIII binding (VWF:FVIIIB) activities were measured using Nijmegen modification of the Bethesda assay. One Bethesda Unit (BU) is thereby defined as the amount of inhibitor that decreased the measured activity in the assays to 50% of that of the negative control samples. The assays were validated using human plasma samples from two type 3 VWD patients with low (1-2 BU/mL) and high (\~10 BU/mL) titer inhibitors and plasma samples from non-human primates immunized with human rVWF (\>100 BU/mL). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=37 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
Percentage of Participants Who Develop Inhibitory Antibodies to VWF Before 1st treatment with study product [N=37]	0 Percent of participants
Percentage of Participants Who Develop Inhibitory Antibodies to VWF During 1st treatment until study end [N=27]	0 Percent of participants
Percentage of Participants Who Develop Inhibitory Antibodies to VWF At final study visit [N=24]	0 Percent of participants

SECONDARY outcome

Timeframe: After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF

The presence of total binding anti-VWF antibodies was determined by an enzyme-linked immunosorbent assay (ELISA) employing polyclonal anti-human immunoglobulin (Ig) antibodies (IgG, IgM and IgA). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=37 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
Percentage of Participants Who Develop Binding Antibodies to VWF Before 1st treatment with study product [N=37]	0 Percent of participants
Percentage of Participants Who Develop Binding Antibodies to VWF During 1st treatment until study end [N=28]	0 Percent of participants
Percentage of Participants Who Develop Binding Antibodies to VWF At final study visit [N=24]	0 Percent of participants

SECONDARY outcome

Timeframe: After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF

The presence of total binding anti-CHO antibodies was determined by measuring total immunoglobulin (Ig) antibodies (IgG, IgA, IgM) against Chinese Hamster Ovary (CHO) protein using an enzyme-linked immunosorbent assay (ELISA). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=37 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
Percentage of Participants Who Develop Binding Antibodies to CHO Before 1st treatment with study product [N=37]	0 Percent of participants
Percentage of Participants Who Develop Binding Antibodies to CHO During 1st treatment until study end [N=28]	0 Percent of participants
Percentage of Participants Who Develop Binding Antibodies to CHO At final study visit [N=24]	0 Percent of participants

SECONDARY outcome

Timeframe: After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF

The presence of total binding anti-rFurin antibodies was determined by measuring total immunoglobulin (Ig) antibodies (IgG, IgA, IgM) against rFurin protein using an enzyme-linked immunosorbent assay (ELISA). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=37 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
Percentage of Participants Who Develop Binding Antibodies to rFurin Before 1st treatment with study product [N=37]	0 Percent of participants
Percentage of Participants Who Develop Binding Antibodies to rFurin During 1st treatment until study end [N=28]	0 Percent of participants
Percentage of Participants Who Develop Binding Antibodies to rFurin At final study visit [N=24]	0 Percent of participants

SECONDARY outcome

Timeframe: After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF

The presence of total binding anti-Murine immunoglobulin (IgG) antibodies was determined using an enzyme-linked immunosorbent assay (ELISA). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=37 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
Percentage of Participants Who Develop Binding Antibodies to Mouse Immunoglobulin Before 1st treatment with study product [N=37]	2.8 Percent of participants
Percentage of Participants Who Develop Binding Antibodies to Mouse Immunoglobulin During 1st treatment until study end [N=28]	0 Percent of participants
Percentage of Participants Who Develop Binding Antibodies to Mouse Immunoglobulin At final study visit [N=24]	0 Percent of participants

SECONDARY outcome

Timeframe: After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF

Outcome measures

Outcome measures
Measure	Full Analysis Set n=37 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
Percentage of Participants Who Had an Occurrence of Thrombotic Events	0 Percent of participants

SECONDARY outcome

Timeframe: For 12 months after first infusion of rVWF:rFVIII or rVWF

Adverse Events (AEs) related to study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) are described. Only laboratory parameters (hematology and clinical chemistry) and vital signs (physical examination, ECG) with clinically significant findings that are recorded as AEs are included. Categories presented as Severity-System Organ Class-Preferred Term Seriousness: serious adverse event (SAE); non serious adverse event (nsAE) System Organ Class: Cardiac disorders (CARD); General disorders and administration site conditions (GEN); Investigations (INV); Nervous system disorders (NERV); Skin and subcutaneous tissue disorders (SKN); Vascular disorders (VAS). Category title includes number of AEs \[N\] for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=125 Adverse Events Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
Number of Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs SAE-GEN-Chest discomfort [N=1]	1 Number of Adverse Events
Number of Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs SAE-INV-Heart rate increased [N=1]	1 Number of Adverse Events
Number of Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-CARD-Tachycardia [N=1]	1 Number of Adverse Events
Number of Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-GEN-Infusion site paraesthesia [N=1]	1 Number of Adverse Events
Number of Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-INV-ECG T wave inversion [N=1]	1 Number of Adverse Events
Number of Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-NERV-Dysgeusia [N=1]	1 Number of Adverse Events
Number of Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-SKN-Pruritus generalized [N=1]	1 Number of Adverse Events
Number of Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-VAS-Hot flush [N=1]	1 Number of Adverse Events

SECONDARY outcome

Timeframe: For 12 months after first infusion of rVWF:rFVIII or rVWF

Number of participants with Adverse Events (AEs) related to study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) are described. Only laboratory parameters (hematology and clinical chemistry) and vital signs (physical examination, ECG) with clinically significant findings that are recorded as AEs are included. Categories presented as Severity-System Organ Class-Preferred Term Seriousness: serious adverse event (SAE); non serious adverse event (nsAE) System Organ Class: Cardiac disorders (CARD); General disorders and administration site conditions (GEN); Investigations (INV); Nervous system disorders (NERV); Skin and subcutaneous tissue disorders (SKN); Vascular disorders (VAS).

Outcome measures

Outcome measures
Measure	Full Analysis Set n=37 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
Number of Participants With Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs SAE-GEN-Chest discomfort	1 Number of participants
Number of Participants With Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs SAE-INV-Heart rate increased	1 Number of participants
Number of Participants With Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-CARD-Tachycardia	1 Number of participants
Number of Participants With Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-GEN-Infusion site paraesthesia	1 Number of participants
Number of Participants With Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-INV-ECG T wave inversion	1 Number of participants
Number of Participants With Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-NERV-Dysgeusia	1 Number of participants
Number of Participants With Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-SKN-Pruritus generalized	1 Number of participants
Number of Participants With Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-VAS-Hot flush	1 Number of participants

SECONDARY outcome

Timeframe: For 12 months after first infusion of rVWF:rFVIII or rVWF

Adverse Events (AEs) by infusion related to study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) are described. Only laboratory parameters (hematology and clinical chemistry) and vital signs (physical examination, ECG) with clinically significant findings that are recorded as AEs are included. Categories presented as Severity-System Organ Class-Preferred Term Seriousness: serious adverse event (SAE); non serious adverse event (nsAE) System Organ Class: Cardiac disorders (CARD); General disorders and administration site conditions (GEN); Investigations (INV); Nervous system disorders (NERV); Skin and subcutaneous tissue disorders (SKN); Vascular disorders (VAS).

Outcome measures

Outcome measures
Measure	Full Analysis Set n=318 Infusions Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
Number of Adverse Events by Infusion Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs SAE-GEN-Chest discomfort	1 Number of Adverse Events
Number of Adverse Events by Infusion Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs SAE-INV-Heart rate increased	1 Number of Adverse Events
Number of Adverse Events by Infusion Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-CARD-Tachycardia	1 Number of Adverse Events
Number of Adverse Events by Infusion Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-GEN-Infusion site paraesthesia	1 Number of Adverse Events
Number of Adverse Events by Infusion Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-INV-ECG T wave inversion	1 Number of Adverse Events
Number of Adverse Events by Infusion Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-NERV-Dysgeusia	1 Number of Adverse Events
Number of Adverse Events by Infusion Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-SKN-Pruritus generalized	1 Number of Adverse Events
Number of Adverse Events by Infusion Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs nsAE-VAS-Hot flush	1 Number of Adverse Events

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:RCo rVWF:rFVIII [N=16]	32.4 (hours*U/dL)/(U VWF: RCo/kg) Interval 27.5 to 40.1
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:RCo rVWF [N=14]	32.7 (hours*U/dL)/(U VWF: RCo/kg) Interval 29.0 to 47.8

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:RCo rVWF:rFVIII [N=16]	31.6 (hours*U/dL)/(U VWF: RCo/kg) Interval 27.3 to 37.3
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:RCo rVWF [N=14]	31.3 (hours*U/dL)/(U VWF: RCo/kg) Interval 28.4 to 43.7

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Mean Residence Time (MRT) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Mean Residence Time of VWF:RCo rVWF:rFVIII [N=16]	25.2 hours Interval 20.0 to 30.1
PK50 - Mean Residence Time of VWF:RCo rVWF [N=14]	26.7 hours Interval 22.7 to 36.0

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Clearance (CL) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Clearance of VWF:RCo rVWF:rFVIII [N=16]	0.031 dL/kg/hours Interval 0.025 to 0.041
PK50 - Clearance of VWF:RCo rVWF [N=14]	0.031 dL/kg/hours Interval 0.021 to 0.035

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Incremental Recovery (IR) at the maximum plasma concentration of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Incremental Recovery of VWF:RCo rVWF:rFVIII [N=16]	1.8 (U/dL)/(U VWF: RCo/kg) Interval 1.6 to 2.4
PK50 - Incremental Recovery of VWF:RCo rVWF [N=14]	1.8 (U/dL)/(U VWF: RCo/kg) Interval 1.5 to 2.2

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Elimination Phase Half-Life (T1/2) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant FVIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Elimination Phase Half-Life of VWF:Co rVWF:rFVIII [N=16]	16.6 hours Interval 14.7 to 20.4
PK50 - Elimination Phase Half-Life of VWF:Co rVWF [N=14]	19.4 hours Interval 15.5 to 31.3

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Volume of Distribution at Steady State (Vss) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Volume of Distribution at Steady State of VWF:RCo rVWF:rFVIII [N=16]	0.70 dL/kg Interval 0.66 to 0.93
PK50 - Volume of Distribution at Steady State of VWF:RCo rVWF [N=14]	0.83 dL/kg Interval 0.7 to 0.97

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:Ag rVWF:rFVIII [N=16]	67.8 (hours*U/dL)/(U VWF: RCo/kg) Interval 55.1 to 81.7
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:Ag rVWF [N=14]	67.1 (hours*U/dL)/(U VWF: RCo/kg) Interval 55.6 to 80.5

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout

Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:Ag rVWF:rFVIII [N=16]	62.1 (hours*U/dL)/(U VWF: RCo/kg) Interval 52.8 to 74.9
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:Ag rVWF [N=14]	62.2 (hours*U/dL)/(U VWF: RCo/kg) Interval 54.7 to 74.5

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Mean Residence Time (MRT) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\] or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Mean Residence Time of VWF:Ag rVWF [N=14]	34.3 hours Interval 30.4 to 41.4
PK50 - Mean Residence Time of VWF:Ag rVWF:rFVIII [N=16]	32.1 hours Interval 29.8 to 41.1

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Clearance (CL) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Clearance of VWF:Ag rVWF:rFVIII [N=16]	0.015 dL/kg/hours Interval 0.013 to 0.018
PK50 - Clearance of VWF:Ag rVWF [N=14]	0.015 dL/kg/hours Interval 0.013 to 0.018

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Incremental Recovery (IR) at the maximum plasma concentration of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Incremental Recovery of VWF:Ag rVWF:rFVIII [N=16]	2.3 (U/dL)/(U VWF: RCo/kg) Interval 2.0 to 2.5
PK50 - Incremental Recovery of VWF:Ag rVWF [N=14]	2.2 (U/dL)/(U VWF: RCo/kg) Interval 1.9 to 2.5

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Elimination Phase Half-Life (T1/2) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant FVIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Elimination Phase Half-Life of VWF:Ag rVWF:rFVIII [N=16]	21.8 hours Interval 19.5 to 27.2
PK50 - Elimination Phase Half-Life of VWF:Ag rVWF [N=14]	25.2 hours Interval 21.9 to 30.3

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Volume of Distribution at Steady State (Vss) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Volume of Distribution at Steady State of VWF:Ag rVWF:rFVIII [N=16]	0.50 dL/kg Interval 0.45 to 0.56
PK50 - Volume of Distribution at Steady State of VWF:Ag rVWF [N=14]	0.49 dL/kg Interval 0.45 to 0.58

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:CB rVWF:rFVIII [N=16]	80.1 (hours*U/dL)/(U VWF: RCo/kg) Interval 68.4 to 95.0
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:CB rVWF [N=14]	81.3 (hours*U/dL)/(U VWF: RCo/kg) Interval 71.2 to 99.8

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:CB rVWF:rFVIII [N=16]	78.7 (hours*U/dL)/(U VWF: RCo/kg) Interval 66.5 to 90.5
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:CB rVWF [N=14]	75.1 (hours*U/dL)/(U VWF: RCo/kg) Interval 69.2 to 97.0

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Mean Residence Time (MRT) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Mean Residence Time of VWF:CB rVWF:rFVIII [N=16]	27.5 hours Interval 22.7 to 32.1
PK50 - Mean Residence Time of VWF:CB rVWF [N=14]	26.1 hours Interval 25.1 to 33.2

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Clearance (CL) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Clearance of VWF:CB rVWF:rFVIII [N=16]	0.012 dL/kg/hours Interval 0.011 to 0.015
PK50 - Clearance of VWF:CB rVWF [N=14]	0.012 dL/kg/hours Interval 0.011 to 0.015

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Incremental Recovery (IR) at the maximum plasma concentration of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Incremental Recovery of VWF:CB rVWF:rFVIII [N=16]	3.4 (U/dL)/(U VWF: RCo/kg) Interval 3.0 to 3.7
PK50 - Incremental Recovery of VWF:CB rVWF [N=14]	3.2 (U/dL)/(U VWF: RCo/kg) Interval 2.8 to 3.7

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Elimination Phase Half-Life (T1/2) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant FVIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Elimination Phase Half-Life of VWF:CB rVWF:rFVIII [N=16]	19.3 hours Interval 14.9 to 23.4
PK50 - Elimination Phase Half-Life of VWF:CB rVWF [N=14]	18.3 hours Interval 17.4 to 24.8

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Volume of Distribution at Steady State (Vss) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants\[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Volume of Distribution at Steady State of VWF:CB rVWF:rFVIII [N=16]	0.35 dL/kg Interval 0.31 to 0.4
PK50 - Volume of Distribution at Steady State of VWF:CB rVWF [N=14]	0.36 dL/kg Interval 0.28 to 0.42

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Area under the plasma concentration curve (AUC) from time 0 to infinity of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of FVIII:C rVWF:rFVIII [N=16]	145.4 hours*U/dL)/(U VWF: RCo/kg) Interval 118.8 to 189.5
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of FVIII:C rVWF [N=14]	113.0 hours*U/dL)/(U VWF: RCo/kg) Interval 93.0 to 167.4

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Area under the plasma concentration curve (AUC) from time 0 to 96 hours of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) \[rVWF\] for participants in the PK50 arms (Arm 1 and Arm 2). Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of FVIII:C rVWF:rFVIII [N=16]	127.8 hours*U/dL)/(U VWF: RCo/kg) Interval 112.3 to 145.1
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of FVIII:C rVWF [N=14]	101.8 hours*U/dL)/(U VWF: RCo/kg) Interval 74.4 to 124.4

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Mean Residence Time (MRT) of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\] for participants in the PK50 arms (Arm 1 and Arm 2).

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Mean Residence Time of FVIII:C	44.0 hours Interval 38.0 to 75.0

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Clearance (CL) of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\] for participants in the PK50 arms (Arm 1 and Arm 2).

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Clearance of FVIII:C	0.007 dL/kg/hours Interval 0.006 to 0.009

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Incremental Recovery (IR) at the maximum plasma concentration of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\] for participants in the PK50 arms (Arm 1 and Arm 2).

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Incremental Recovery of FVIII:C	2.3 (U/dL)/(U VWF: RCo/kg) Interval 1.9 to 2.7

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Elimination Phase Half-Life (T1/2) of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant FVIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\] for participants in the PK50 arms (Arm 1 and Arm 2).

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Elimination Phase Half-Life of FVIII:C	24.8 hours Interval 20.1 to 50.5

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Volume of Distribution at Steady State (Vss) of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) \[rVWF:rFVIII\] for participants in the PK50 arms (Arm 1 and Arm 2).

Outcome measures

Outcome measures
Measure	Full Analysis Set n=16 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK50 - Volume of Distribution at Steady State of FVIII:C	0.32 dL/kg Interval 0.29 to 0.44

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:RCo PK1 of rVWF [N=15]	36.9 (hours*U/dL)/(U VWF: RCo/kg) Interval 29.2 to 41.7
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:RCo PK2 of rVWF [N=13]	38.9 (hours*U/dL)/(U VWF: RCo/kg) Interval 28.1 to 43.3

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:RCo PK1 of rVWF [N=15]	35.6 (hours*U/dL)/(U VWF: RCo/kg) Interval 28.9 to 41.2
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:RCo PK2 of rVWF [N=13]	37.9 (hours*U/dL)/(U VWF: RCo/kg) Interval 25.9 to 41.8

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Mean Residence Time (MRT) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Mean Residence Time of VWF:RCo PK1 of rVWF [N=15]	26.4 hours Interval 20.9 to 31.1
PK80 - Mean Residence Time of VWF:RCo PK2 of rVWF [N=13]	26.4 hours Interval 23.7 to 32.8

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Clearance (CL) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Clearance of VWF:RCo PK1 of rVWF [N=15]	0.027 dL/kg/hours Interval 0.024 to 0.034
PK80 - Clearance of VWF:RCo PK2 of rVWF [N=13]	0.026 dL/kg/hours Interval 0.023 to 0.036

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Incremental Recovery (IR) at the maximum plasma concentration Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Incremental Recovery of VWF:RCo PK1 of rVWF [N=15]	1.8 (U/dL)/(U VWF: RCo/kg) Interval 1.7 to 2.2
PK80 - Incremental Recovery of VWF:RCo PK2 of rVWF [N=13]	1.8 (U/dL)/(U VWF: RCo/kg) Interval 1.6 to 2.0

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Elimination Phase Half-Life (T1/2) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Elimination Phase Half-Life of VWF:Co PK1 of rVWF [N=15]	18.4 hours Interval 16.4 to 22.1
PK80 - Elimination Phase Half-Life of VWF:Co PK2 of rVWF [N=13]	19.8 hours Interval 15.2 to 23.6

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Volume of Distribution at Steady State (Vss) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study. PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Volume of Distribution at Steady State of VWF:RCo PK1 of rVWF [N=15]	0.78 dL/kg Interval 0.58 to 0.86
PK80 - Volume of Distribution at Steady State of VWF:RCo PK2 of rVWF [N=13]	0.75 dL/kg Interval 0.58 to 1.01

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:Ag PK1 of rVWF [N=15]	66.6 (hours*U/dL)/(U VWF: RCo/kg) Interval 50.4 to 89.4
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:Ag PK2 of rVWF [N=13]	86.9 (hours*U/dL)/(U VWF: RCo/kg) Interval 54.9 to 100.5

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:Ag PK1 of rVWF [N=15]	61.3 (hours*U/dL)/(U VWF: RCo/kg) Interval 48.8 to 73.7
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:Ag PK2 of rVWF [N=13]	77.4 (hours*U/dL)/(U VWF: RCo/kg) Interval 53.0 to 87.6

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Mean Residence Time (MRT) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Mean Residence Time of VWF:Ag PK1 of rVWF [N=15]	38.4 hours Interval 31.9 to 48.1
PK80 - Mean Residence Time of VWF:Ag PK2 of rVWF [N=13]	36.9 hours Interval 30.0 to 50.8

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Clearance (CL) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Clearance of VWF:Ag PK1 of rVWF [N=15]	0.015 dL/kg/hours Interval 0.011 to 0.02
PK80 - Clearance of VWF:Ag PK2 of rVWF [N=13]	0.012 dL/kg/hours Interval 0.01 to 0.018

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Incremental Recovery (IR) at the maximum plasma concentration Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Incremental Recovery of VWF:Ag PK1 of rVWF [N=15]	2.2 (U/dL)/(U VWF: RCo/kg) Interval 1.9 to 2.6
PK80 - Incremental Recovery of VWF:Ag PK2 of rVWF [N=13]	2.4 (U/dL)/(U VWF: RCo/kg) Interval 2.0 to 2.9

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Elimination Phase Half-Life (T1/2) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Elimination Phase Half-Life of VWF:Ag PK1 of rVWF [N=15]	27.5 hours Interval 22.5 to 34.0
PK80 - Elimination Phase Half-Life of VWF:Ag PK2 of rVWF [N=13]	24.8 hours Interval 21.1 to 37.7

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Volume of Distribution at Steady State (Vss) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Volume of Distribution at Steady State of VWF:Ag PK1 of rVWF [N=15]	0.55 dL/kg Interval 0.46 to 0.61
PK80 - Volume of Distribution at Steady State of VWF:Ag PK2 of rVWF [N=13]	0.50 dL/kg Interval 0.41 to 0.57

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:CB PK1 of rVWF [N=15]	73.9 (hours*U/dL)/(U VWF: RCo/kg) Interval 57.3 to 96.2
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:CB PK2 of rVWF [N=13]	90.8 (hours*U/dL)/(U VWF: RCo/kg) Interval 66.0 to 105.2

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participatns from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:CB PK1 of rVWF [N=15]	71.9 (hours*U/dL)/(U VWF: RCo/kg) Interval 57.0 to 89.8
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:CB PK2 of rVWF [N=13]	88.1 (hours*U/dL)/(U VWF: RCo/kg) Interval 63.8 to 96.3

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Mean Residence Time (MRT) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Mean Residence Time of VWF:CB PK1 of rVWF [N=15]	30.9 hours Interval 24.3 to 35.0
PK80 - Mean Residence Time of VWF:CB PK2 of rVWF [N=13]	28.7 hours Interval 25.6 to 37.2

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Clearance (CL) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Clearance of VWF:CB PK1 of rVWF [N=15]	0.014 dL/kg/hours Interval 0.01 to 0.017
PK80 - Clearance of VWF:CB PK2 of rVWF [N=13]	0.011 dL/kg/hours Interval 0.01 to 0.015

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Incremental Recovery (IR) at the maximum plasma concentration Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Incremental Recovery of VWF:CB PK1 of rVWF [N=15]	3.1 (U/dL)/(U VWF: RCo/kg) Interval 2.8 to 3.6
PK80 - Incremental Recovery of VWF:CB PK2 of rVWF [N=13]	3.7 (U/dL)/(U VWF: RCo/kg) Interval 2.7 to 4.0

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Elimination Phase Half-Life (T1/2) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Elimination Phase Half-Life of VWF:CB PK1 of rVWF [N=15]	18.8 hours Interval 16.6 to 24.9
PK80 - Elimination Phase Half-Life of VWF:CB PK2 of rVWF [N=13]	20.9 hours Interval 17.8 to 23.5

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Volume of Distribution at Steady State (Vss) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Volume of Distribution at Steady State of VWF:CB PK1 of rVWF [N=15]	0.39 dL/kg Interval 0.34 to 0.46
PK80 - Volume of Distribution at Steady State of VWF:CB PK2 of rVWF [N=13]	0.36 dL/kg Interval 0.33 to 0.4

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Area under the plasma concentration curve (AUC) from time 0 to infinity of Factor VIII activity (FVIII:C) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of FVIII:C PK1 of rVWF [N=15]	96.8 (hours*U/dL)/(U VWF: RCo/kg) Interval 64.0 to 126.5
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of FVIII:C PK2 of rVWF [N=13]	94.8 (hours*U/dL)/(U VWF: RCo/kg) Interval 60.4 to 106.5

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Area under the plasma concentration curve (AUC) from time 0 to 96 hours of Factor VIII activity (FVIII:C) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. Category title includes number of participants \[N\] who provided data for the category.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=15 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of FVIII:C PK1 of rVWF [N=15]	81.7 (hours*U/dL)/(U VWF: RCo/kg) Interval 54.7 to 104.3
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of FVIII:C PK2 of rVWF [N=13]	71.8 (hours*U/dL)/(U VWF: RCo/kg) Interval 49.6 to 89.2

SECONDARY outcome

Timeframe: PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.

Population: Participants from the PK80 Arm who had pharmacokinetic (PK) data available after both the first infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] \[PK1\] and the second infusion of 80 IU/kg rVWF \[PK2\].

Area under the plasma concentration curve (AUC) from time 0 to infinity per dose (AUC0-∞/dose) for von Willebrand Factor Ristocetin cofactor (VWF:RCo), von Willebrand Factor Antigen (VWF:Ag) and von Willebrand Factor Collagen Binding (VWF:CB). Each parameter was compared between the two PK assessments after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) \[rVWF\] for participants in the PK80 arm (participants from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF \[PK1\] and the second infusion of 80 IU/kg rVWF after participants were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product \[PK2\]. 13 participants had data available for this endpoint i.e. data for PK1 and PK2.

Outcome measures

Outcome measures
Measure	Full Analysis Set n=13 Participants Comprises of participants treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) for whom at least one efficacy rating scale was available.
PK80- Ratio of Intra-participant PK of VWF:RCo, VWF:Ag and VWF:CB at Baseline and After 6 Months AUC0-∞/dose - VWF:RCo	0.9587 ratio of AUC0-∞/dose Interval 0.8466 to 1.0857
PK80- Ratio of Intra-participant PK of VWF:RCo, VWF:Ag and VWF:CB at Baseline and After 6 Months AUC0-∞/dose - VWF:Ag	1.0914 ratio of AUC0-∞/dose Interval 1.0132 to 1.1757
PK80- Ratio of Intra-participant PK of VWF:RCo, VWF:Ag and VWF:CB at Baseline and After 6 Months AUC0-∞/dose - VWF:CB	1.0666 ratio of AUC0-∞/dose Interval 1.0004 to 1.1372

Adverse Events

Safety Analysis Set

Serious events: 7 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Safety Analysis Set n=37 participants at risk Comprises of participants who were treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) at least once during the study.
Gastrointestinal disorders Constipation	2.7% 1/37 • Number of events 1 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Gastrointestinal disorders Gastrointestinal haemorrhage	2.7% 1/37 • Number of events 1 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Gastrointestinal disorders Haemorrhoids	2.7% 1/37 • Number of events 1 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Gastrointestinal disorders Mesenteric haematoma	2.7% 1/37 • Number of events 1 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
General disorders Chest discomfort	2.7% 1/37 • Number of events 1 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Infections and infestations Osteomyelitis	2.7% 1/37 • Number of events 1 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Infections and infestations Heart rate increased	2.7% 1/37 • Number of events 1 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	2.7% 1/37 • Number of events 1 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Reproductive system and breast disorders Uterine polyp	2.7% 1/37 • Number of events 1 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)

Other adverse events

Other adverse events
Measure	Safety Analysis Set n=37 participants at risk Comprises of participants who were treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) at least once during the study.
Blood and lymphatic system disorders Anaemia	5.4% 2/37 • Number of events 2 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Blood and lymphatic system disorders Iron deficiency anaemia	8.1% 3/37 • Number of events 4 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Ear and labyrinth disorders Vertigo	5.4% 2/37 • Number of events 3 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Gastrointestinal disorders Nausea	5.4% 2/37 • Number of events 2 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Gastrointestinal disorders Vomiting	8.1% 3/37 • Number of events 4 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
General disorders Infusion site paraesthesia	5.4% 2/37 • Number of events 2 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Infections and infestations Upper respiratory tract infection	8.1% 3/37 • Number of events 5 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Injury, poisoning and procedural complications Contusion	5.4% 2/37 • Number of events 2 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Injury, poisoning and procedural complications Laceration	5.4% 2/37 • Number of events 4 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Musculoskeletal and connective tissue disorders Arthralgia	8.1% 3/37 • Number of events 16 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Musculoskeletal and connective tissue disorders Back pain	5.4% 2/37 • Number of events 3 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
Nervous system disorders Headache	10.8% 4/37 • Number of events 12 • For 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Baxter's agreements with PIs may vary per requirements of individual PI, but contain common elements. For this study, PIs are restricted from independently publishing results until the earlier of the primary multicenter publication or ≥12 months after study completion. Baxter requires a review of results communications (e.g., for confidential information) ≥40 days prior to submission or communication. Baxter may request an additional delay of ≤45 days eg, for intellectual property protection.
Publication restrictions are in place

Restriction type: OTHER