Von Willebrand Disease
Conditions
Brief summary
The purpose of this Phase 3 study is to assess the pharmacokinetics of rVWF:rFVIII and rVWF, and to assess the safety and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding events in subjects with severe hereditary von Willebrand disease (VWD).
Interventions
BIOLOGICALRecombinant von Willebrand factor (rVWF)
Intravenous administration
DRUGPlacebo
Syringe supplied with physiologic saline solution for infusion
BIOLOGICALRecombinant factor VIIII (rFVIII)
Intravenous administration
Sponsors
Baxalta now part of Shire
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Participant has been diagnosed with: 1. Type 1 (Von Willebrand factor: Ristocetin cofactor activity (VWF:RCo) \< 20 IU/dL) or, 2. Type 2A (VWF:RCo \< 20 IU/dL), Type 2B (as diagnosed by genotype), Type 2N (Factor VIII activity (FVIII:C) \<10% and historically documented genetics), Type 2M or, 3. Type 3 ( Von Willebrand factor antigen (VWF:Ag) ≤ 3 IU/dL) or, 4. Severe Von Willebrand disease (VWD) with a history of requiring substitution therapy with von Willebrand factor concentrate to control bleeding * Participant, who participates in the treatment for bleeding episodes, has had a minimum of 1 documented bleed (medical history) requiring VWF coagulation factor replacement therapy during the previous 12 months prior to enrollment. * Participant has a Karnofsky score ≥ 60% * Participant is at least 18 and not older than 65 years of age at enrollment * If female of childbearing potential, participant presents with a negative pregnancy test * Participant agrees to employ adequate birth control measures for the duration of the study * Participant is willing and able to comply with the requirements of the protocol
Exclusion criteria
* Participant has been diagnosed with pseudo VWD or another hereditary or acquired coagulation disorder other than VWD (eg qualitative and quantitative platelet disorders or elevated PT/international normalized ratio \[INR\] \>1.4). * Participant has a documented history of a VWF:RCo half-life of \<6 hours. * Participant has a history or presence of a VWF inhibitor at screening. * Participant has a history or presence of a factor VIII (FVIII) inhibitor with a titer ≥0.4 BU (by Nijmegen assay) or ≥ 0.6 BU (by Bethesda assay). * Participant has a known hypersensitivity to any of the components of the study drugs, such as mouse or hamster proteins. * Participant has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies. * Participant has a medical history of a thromboembolic event. * Participant is HIV positive with an absolute CD4 count \<200/mm3. * Participant has been diagnosed with cardiovascular disease (New York Heart Association \[NYHA\] classes 1-4. * Participant has an acute illness (eg, influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) at screening. * Participant has been diagnosed with significant liver disease as evidenced by any of the following: serum alanine aminotransferase (ALT) 5 times the upper limit of normal; hypoalbuminemia; portal vein hypertension (eg, presence of otherwise unexplained splenomegaly, history of esophageal varices). * Participant has been diagnosed with renal disease, with a serum creatinine level ≥2 mg/dL. * In the judgment of the investigator, the participant has another clinically significant concomitant disease (eg, uncontrolled hypertension) that may pose additional risks for the participant. * Participant has been treated with an immunomodulatory drug, excluding topical treatment (eg, ointments, nasal sprays), within 30 days prior to enrollment * Participant is pregnant or lactating at the time of enrollment. * Participant has participated in another clinical study involving an IP or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an investigational product or investigational device during the course of this study. * Participant has a history of drug or alcohol abuse within the 2 years prior to enrollment. * Participant has a progressive fatal disease and/or life expectancy of less than 3 months. * Participant is identified by the investigator as being unable or unwilling to cooperate with study procedures. * Participant suffers from a mental condition rendering him/her unable to understand the nature, scope and possible consequences of the study and/or evidence of an uncooperative attitude. * Participant is in prison or compulsory detention by regulatory and/or juridical order
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment Success for Treated Bleeding Episodes | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Treated Bleeding Episodes With an Efficacy Rating of Excellent or Good, Excluding Gastrointestinal Bleeds | 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. |
| Number of Infusions of rVWF:rFVIII and/or rVWF Per Bleeding Episode | 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. |
| Number of Units of rVWF:rFVIII and/or rVWF Per Bleeding Episode | 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. |
| Percentage of Participants Who Develop Inhibitory Antibodies to FVIII | 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. |
| Percentage of Participants Who Develop Inhibitory Antibodies to VWF | 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. |
| Percentage of Participants Who Develop Binding Antibodies to VWF | 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. |
| Percentage of Participants Who Develop Binding Antibodies to CHO | 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. |
| Percentage of Participants Who Develop Binding Antibodies to rFurin | 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. |
| Percentage of Participants Who Develop Binding Antibodies to Mouse Immunoglobulin | 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. |
| Percentage of Participants Who Had an Occurrence of Thrombotic Events | After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF | — |
| Number of Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs | 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. |
| Number of Participants With Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs | 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). |
| Number of Adverse Events by Infusion Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs | 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). |
| PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:RCo | 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. |
| PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:RCo | 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. |
| PK50 - Mean Residence Time of VWF:RCo | 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. |
| PK50 - Clearance of VWF:RCo | 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. |
| PK50 - Incremental Recovery of VWF:RCo | 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. |
| PK50 - Elimination Phase Half-Life of VWF:Co | 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. |
| PK50 - Volume of Distribution at Steady State of VWF:RCo | 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. |
| PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:Ag | 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. |
| PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:Ag | 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. |
| PK50 - Mean Residence Time of VWF:Ag | 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. |
| PK50 - Clearance of VWF:Ag | 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. |
| PK50 - Incremental Recovery of VWF:Ag | 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. |
| PK50 - Elimination Phase Half-Life of VWF:Ag | 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 |
| PK50 - Volume of Distribution at Steady State of VWF:Ag | 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. |
| PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:CB | 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. |
| PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:CB | 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. |
| PK50 - Mean Residence Time of VWF:CB | 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. |
| PK50 - Clearance of VWF:CB | 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. |
| PK50 - Incremental Recovery of VWF:CB | 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. |
| PK50 - Elimination Phase Half-Life of VWF:CB | 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. |
| PK50 - Volume of Distribution at Steady State of VWF:CB | 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. |
| PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of FVIII:C | 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. |
| PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of FVIII:C | 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. |
| PK50 - Mean Residence Time of FVIII:C | 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). |
| PK50 - Clearance of FVIII:C | 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). |
| PK50 - Incremental Recovery of FVIII:C | 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). |
| PK50 - Elimination Phase Half-Life of FVIII:C | 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). |
| PK50 - Volume of Distribution at Steady State of FVIII:C | 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). |
| PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:RCo | 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. |
| PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:RCo | 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. |
| PK80 - Mean Residence Time of VWF:RCo | 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. |
| PK80 - Clearance of VWF:RCo | 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. |
| PK80 - Incremental Recovery of VWF:RCo | 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. |
| PK80 - Elimination Phase Half-Life of VWF:Co | 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 |
| PK80 - Volume of Distribution at Steady State of VWF:RCo | 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. |
| PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:Ag | 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. |
| PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:Ag | 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. |
| PK80 - Mean Residence Time of VWF:Ag | 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. |
| PK80 - Clearance of VWF:Ag | 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. |
| PK80 - Incremental Recovery of VWF:Ag | 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. |
| PK80 - Elimination Phase Half-Life of VWF:Ag | 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. |
| PK80 - Volume of Distribution at Steady State of VWF:Ag | 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. |
| PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:CB | 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. |
| PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:CB | 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. |
| Percentage of Treated Bleeding Episodes With an Efficacy Rating of Excellent or Good | 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 |
| PK80 - Clearance of VWF:CB | 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. |
| PK80 - Incremental Recovery of VWF:CB | 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. |
| PK80 - Elimination Phase Half-Life of VWF:CB | 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. |
| PK80 - Volume of Distribution at Steady State of VWF:CB | 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. |
| PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of FVIII:C | 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. |
| PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of FVIII:C | 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. |
| PK80- Ratio of Intra-participant PK of VWF:RCo, VWF:Ag and VWF:CB at Baseline and After 6 Months | 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 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. |
| PK80 - Mean Residence Time of VWF:CB | 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. |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, Germany, India, Italy, Japan, Netherlands, Poland, Russia, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled (signed informed consent) from 30 sites in 15 countries.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| All Subjects Treated With Study Product All subjects treated with study product | 37 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 |
| Overall Study | Met Excl. Criteria After Starting Study | 0 | 0 | 1 | 0 |
| Overall Study | Pregnancy | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | All Subjects Treated With Study Product |
|---|---|
| Age, Continuous | 37 Years |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 14 / 37 |
| serious Total, serious adverse events | 7 / 37 |
Outcome results
Primary
Percentage of Participants With Treatment Success for Treated Bleeding Episodes
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.
Time frame: For 12 months after first infusion of rVWF:rFVIII or rVWF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Full Analysis Set | Percentage of Participants With Treatment Success for Treated Bleeding Episodes | 100.0 Percent of participants |
90% CI: [84.7, 100]Clopper-Pearson
Secondary
Number of Adverse Events by Infusion Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs
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).
Time frame: For 12 months after first infusion of rVWF:rFVIII or rVWF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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
Number of Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs
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.
Time frame: For 12 months after first infusion of rVWF:rFVIII or rVWF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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
Number of Infusions of rVWF:rFVIII and/or rVWF Per Bleeding Episode
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.
Time frame: For 12 months after first infusion of rVWF:rFVIII or rVWF
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Full Analysis Set | Number of Infusions of rVWF:rFVIII and/or rVWF Per Bleeding Episode | 1.0 Number of infusions |
Secondary
Number of Participants With Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs
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).
Time frame: For 12 months after first infusion of rVWF:rFVIII or rVWF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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
Number of Units of rVWF:rFVIII and/or rVWF Per Bleeding Episode
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.
Time frame: For 12 months after first infusion of rVWF:rFVIII or rVWF
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Full Analysis Set | Number of Units of rVWF:rFVIII and/or rVWF Per Bleeding Episode | 48.2 IU/kg |
Secondary
Percentage of Participants Who Develop Binding Antibodies to CHO
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.
Time frame: After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Full Analysis Set | Percentage of Participants Who Develop Binding Antibodies to CHO | Before 1st treatment with study product [N=37] | 0 Percent of participants |
| Full Analysis Set | Percentage of Participants Who Develop Binding Antibodies to CHO | During 1st treatment until study end [N=28] | 0 Percent of participants |
| Full Analysis Set | Percentage of Participants Who Develop Binding Antibodies to CHO | At final study visit [N=24] | 0 Percent of participants |
Secondary
Percentage of Participants Who Develop Binding Antibodies to Mouse Immunoglobulin
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.
Time frame: After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Full Analysis Set | Percentage of Participants Who Develop Binding Antibodies to Mouse Immunoglobulin | Before 1st treatment with study product [N=37] | 2.8 Percent of participants |
| Full Analysis Set | Percentage of Participants Who Develop Binding Antibodies to Mouse Immunoglobulin | During 1st treatment until study end [N=28] | 0 Percent of participants |
| Full Analysis Set | Percentage of Participants Who Develop Binding Antibodies to Mouse Immunoglobulin | At final study visit [N=24] | 0 Percent of participants |
Secondary
Percentage of Participants Who Develop Binding Antibodies to rFurin
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.
Time frame: After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Full Analysis Set | Percentage of Participants Who Develop Binding Antibodies to rFurin | Before 1st treatment with study product [N=37] | 0 Percent of participants |
| Full Analysis Set | Percentage of Participants Who Develop Binding Antibodies to rFurin | During 1st treatment until study end [N=28] | 0 Percent of participants |
| Full Analysis Set | Percentage of Participants Who Develop Binding Antibodies to rFurin | At final study visit [N=24] | 0 Percent of participants |
Secondary
Percentage of Participants Who Develop Binding Antibodies to VWF
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.
Time frame: After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Full Analysis Set | Percentage of Participants Who Develop Binding Antibodies to VWF | During 1st treatment until study end [N=28] | 0 Percent of participants |
| Full Analysis Set | Percentage of Participants Who Develop Binding Antibodies to VWF | Before 1st treatment with study product [N=37] | 0 Percent of participants |
| Full Analysis Set | Percentage of Participants Who Develop Binding Antibodies to VWF | At final study visit [N=24] | 0 Percent of participants |
Secondary
Percentage of Participants Who Develop Inhibitory Antibodies to FVIII
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.
Time frame: For 12 months after first infusion of rVWF:rFVIII or rVWF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Full Analysis Set | Percentage of Participants Who Develop Inhibitory Antibodies to FVIII | Before 1st treatment with study product [N=37] | 0 Percent of participants |
| Full Analysis Set | Percentage of Participants Who Develop Inhibitory Antibodies to FVIII | During 1st treatment until study end [N=27] | 0 Percent of participants |
| Full Analysis Set | Percentage of Participants Who Develop Inhibitory Antibodies to FVIII | At final study visit [N=24] | 0 Percent of participants |
Secondary
Percentage of Participants Who Develop Inhibitory Antibodies to VWF
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.
Time frame: After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Full Analysis Set | Percentage of Participants Who Develop Inhibitory Antibodies to VWF | Before 1st treatment with study product [N=37] | 0 Percent of participants |
| Full Analysis Set | Percentage of Participants Who Develop Inhibitory Antibodies to VWF | During 1st treatment until study end [N=27] | 0 Percent of participants |
| Full Analysis Set | Percentage of Participants Who Develop Inhibitory Antibodies to VWF | At final study visit [N=24] | 0 Percent of participants |
Secondary
Percentage of Participants Who Had an Occurrence of Thrombotic Events
Time frame: After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Full Analysis Set | Percentage of Participants Who Had an Occurrence of Thrombotic Events | 0 Percent of participants |
Secondary
Percentage of Treated Bleeding Episodes With an Efficacy Rating of Excellent or Good
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
Time frame: For 12 months after first infusion of rVWF:rFVIII or rVWF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Full Analysis Set | Percentage of Treated Bleeding Episodes With an Efficacy Rating of Excellent or Good | 100.0 Percent of bleeding episodes |
Secondary
Percentage of Treated Bleeding Episodes With an Efficacy Rating of Excellent or Good, Excluding Gastrointestinal Bleeds
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.
Time frame: For 12 months after first infusion of rVWF:rFVIII or rVWF
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Full Analysis Set | Percentage of Treated Bleeding Episodes With an Efficacy Rating of Excellent or Good, Excluding Gastrointestinal Bleeds | 100.0 Percent of bleeding episodes |
Secondary
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of FVIII:C
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | 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) |
| Full Analysis Set | 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) |
Secondary
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:Ag
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.
Time frame: 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
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | 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) |
| Full Analysis Set | 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) |
Secondary
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:CB
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | 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) |
| Full Analysis Set | 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) |
Secondary
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:RCo
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | 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) |
| Full Analysis Set | 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) |
Secondary
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of FVIII:C
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | 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) |
| Full Analysis Set | 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) |
Secondary
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:Ag
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | 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) |
| Full Analysis Set | 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) |
Secondary
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:CB
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | 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) |
| Full Analysis Set | 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) |
Secondary
PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:RCo
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | 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) |
| Full Analysis Set | 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) |
Secondary
PK50 - Clearance of FVIII:C
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).
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Full Analysis Set | PK50 - Clearance of FVIII:C | 0.007 dL/kg/hours |
Secondary
PK50 - Clearance of VWF:Ag
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK50 - Clearance of VWF:Ag | rVWF:rFVIII [N=16] | 0.015 dL/kg/hours |
| Full Analysis Set | PK50 - Clearance of VWF:Ag | rVWF [N=14] | 0.015 dL/kg/hours |
Secondary
PK50 - Clearance of VWF:CB
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK50 - Clearance of VWF:CB | rVWF:rFVIII [N=16] | 0.012 dL/kg/hours |
| Full Analysis Set | PK50 - Clearance of VWF:CB | rVWF [N=14] | 0.012 dL/kg/hours |
Secondary
PK50 - Clearance of VWF:RCo
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK50 - Clearance of VWF:RCo | rVWF:rFVIII [N=16] | 0.031 dL/kg/hours |
| Full Analysis Set | PK50 - Clearance of VWF:RCo | rVWF [N=14] | 0.031 dL/kg/hours |
Secondary
PK50 - Elimination Phase Half-Life of FVIII:C
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).
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Full Analysis Set | PK50 - Elimination Phase Half-Life of FVIII:C | 24.8 hours |
Secondary
PK50 - Elimination Phase Half-Life of VWF:Ag
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
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK50 - Elimination Phase Half-Life of VWF:Ag | rVWF:rFVIII [N=16] | 21.8 hours |
| Full Analysis Set | PK50 - Elimination Phase Half-Life of VWF:Ag | rVWF [N=14] | 25.2 hours |
Secondary
PK50 - Elimination Phase Half-Life of VWF:CB
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK50 - Elimination Phase Half-Life of VWF:CB | rVWF:rFVIII [N=16] | 19.3 hours |
| Full Analysis Set | PK50 - Elimination Phase Half-Life of VWF:CB | rVWF [N=14] | 18.3 hours |
Secondary
PK50 - Elimination Phase Half-Life of VWF:Co
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK50 - Elimination Phase Half-Life of VWF:Co | rVWF:rFVIII [N=16] | 16.6 hours |
| Full Analysis Set | PK50 - Elimination Phase Half-Life of VWF:Co | rVWF [N=14] | 19.4 hours |
Secondary
PK50 - Incremental Recovery of FVIII:C
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).
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Full Analysis Set | PK50 - Incremental Recovery of FVIII:C | 2.3 (U/dL)/(U VWF: RCo/kg) |
Secondary
PK50 - Incremental Recovery of VWF:Ag
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK50 - Incremental Recovery of VWF:Ag | rVWF:rFVIII [N=16] | 2.3 (U/dL)/(U VWF: RCo/kg) |
| Full Analysis Set | PK50 - Incremental Recovery of VWF:Ag | rVWF [N=14] | 2.2 (U/dL)/(U VWF: RCo/kg) |
Secondary
PK50 - Incremental Recovery of VWF:CB
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK50 - Incremental Recovery of VWF:CB | rVWF:rFVIII [N=16] | 3.4 (U/dL)/(U VWF: RCo/kg) |
| Full Analysis Set | PK50 - Incremental Recovery of VWF:CB | rVWF [N=14] | 3.2 (U/dL)/(U VWF: RCo/kg) |
Secondary
PK50 - Incremental Recovery of VWF:RCo
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK50 - Incremental Recovery of VWF:RCo | rVWF:rFVIII [N=16] | 1.8 (U/dL)/(U VWF: RCo/kg) |
| Full Analysis Set | PK50 - Incremental Recovery of VWF:RCo | rVWF [N=14] | 1.8 (U/dL)/(U VWF: RCo/kg) |
Secondary
PK50 - Mean Residence Time of FVIII:C
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).
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Full Analysis Set | PK50 - Mean Residence Time of FVIII:C | 44.0 hours |
Secondary
PK50 - Mean Residence Time of VWF:Ag
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK50 - Mean Residence Time of VWF:Ag | rVWF:rFVIII [N=16] | 32.1 hours |
| Full Analysis Set | PK50 - Mean Residence Time of VWF:Ag | rVWF [N=14] | 34.3 hours |
Secondary
PK50 - Mean Residence Time of VWF:CB
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK50 - Mean Residence Time of VWF:CB | rVWF:rFVIII [N=16] | 27.5 hours |
| Full Analysis Set | PK50 - Mean Residence Time of VWF:CB | rVWF [N=14] | 26.1 hours |
Secondary
PK50 - Mean Residence Time of VWF:RCo
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK50 - Mean Residence Time of VWF:RCo | rVWF:rFVIII [N=16] | 25.2 hours |
| Full Analysis Set | PK50 - Mean Residence Time of VWF:RCo | rVWF [N=14] | 26.7 hours |
Secondary
PK50 - Volume of Distribution at Steady State of FVIII:C
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).
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Full Analysis Set | PK50 - Volume of Distribution at Steady State of FVIII:C | 0.32 dL/kg |
Secondary
PK50 - Volume of Distribution at Steady State of VWF:Ag
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK50 - Volume of Distribution at Steady State of VWF:Ag | rVWF:rFVIII [N=16] | 0.50 dL/kg |
| Full Analysis Set | PK50 - Volume of Distribution at Steady State of VWF:Ag | rVWF [N=14] | 0.49 dL/kg |
Secondary
PK50 - Volume of Distribution at Steady State of VWF:CB
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK50 - Volume of Distribution at Steady State of VWF:CB | rVWF:rFVIII [N=16] | 0.35 dL/kg |
| Full Analysis Set | PK50 - Volume of Distribution at Steady State of VWF:CB | rVWF [N=14] | 0.36 dL/kg |
Secondary
PK50 - Volume of Distribution at Steady State of VWF:RCo
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK50 - Volume of Distribution at Steady State of VWF:RCo | rVWF:rFVIII [N=16] | 0.70 dL/kg |
| Full Analysis Set | PK50 - Volume of Distribution at Steady State of VWF:RCo | rVWF [N=14] | 0.83 dL/kg |
Secondary
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of FVIII:C
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | 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) |
| Full Analysis Set | 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) |
Secondary
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:Ag
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | 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) |
| Full Analysis Set | 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) |
Secondary
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:CB
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | 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) |
| Full Analysis Set | 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) |
Secondary
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:RCo
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | 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) |
| Full Analysis Set | 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) |
Secondary
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of FVIII:C
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | 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) |
| Full Analysis Set | 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) |
Secondary
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:Ag
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | 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) |
| Full Analysis Set | 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) |
Secondary
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:CB
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | 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) |
| Full Analysis Set | 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) |
Secondary
PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:RCo
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | 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) |
| Full Analysis Set | 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) |
Secondary
PK80 - Clearance of VWF:Ag
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK80 - Clearance of VWF:Ag | PK1 of rVWF [N=15] | 0.015 dL/kg/hours |
| Full Analysis Set | PK80 - Clearance of VWF:Ag | PK2 of rVWF [N=13] | 0.012 dL/kg/hours |
Secondary
PK80 - Clearance of VWF:CB
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK80 - Clearance of VWF:CB | PK1 of rVWF [N=15] | 0.014 dL/kg/hours |
| Full Analysis Set | PK80 - Clearance of VWF:CB | PK2 of rVWF [N=13] | 0.011 dL/kg/hours |
Secondary
PK80 - Clearance of VWF:RCo
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK80 - Clearance of VWF:RCo | PK1 of rVWF [N=15] | 0.027 dL/kg/hours |
| Full Analysis Set | PK80 - Clearance of VWF:RCo | PK2 of rVWF [N=13] | 0.026 dL/kg/hours |
Secondary
PK80 - Elimination Phase Half-Life of VWF:Ag
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK80 - Elimination Phase Half-Life of VWF:Ag | PK1 of rVWF [N=15] | 27.5 hours |
| Full Analysis Set | PK80 - Elimination Phase Half-Life of VWF:Ag | PK2 of rVWF [N=13] | 24.8 hours |
Secondary
PK80 - Elimination Phase Half-Life of VWF:CB
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK80 - Elimination Phase Half-Life of VWF:CB | PK1 of rVWF [N=15] | 18.8 hours |
| Full Analysis Set | PK80 - Elimination Phase Half-Life of VWF:CB | PK2 of rVWF [N=13] | 20.9 hours |
Secondary
PK80 - Elimination Phase Half-Life of VWF:Co
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
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK80 - Elimination Phase Half-Life of VWF:Co | PK1 of rVWF [N=15] | 18.4 hours |
| Full Analysis Set | PK80 - Elimination Phase Half-Life of VWF:Co | PK2 of rVWF [N=13] | 19.8 hours |
Secondary
PK80 - Incremental Recovery of VWF:Ag
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK80 - Incremental Recovery of VWF:Ag | PK1 of rVWF [N=15] | 2.2 (U/dL)/(U VWF: RCo/kg) |
| Full Analysis Set | PK80 - Incremental Recovery of VWF:Ag | PK2 of rVWF [N=13] | 2.4 (U/dL)/(U VWF: RCo/kg) |
Secondary
PK80 - Incremental Recovery of VWF:CB
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK80 - Incremental Recovery of VWF:CB | PK1 of rVWF [N=15] | 3.1 (U/dL)/(U VWF: RCo/kg) |
| Full Analysis Set | PK80 - Incremental Recovery of VWF:CB | PK2 of rVWF [N=13] | 3.7 (U/dL)/(U VWF: RCo/kg) |
Secondary
PK80 - Incremental Recovery of VWF:RCo
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK80 - Incremental Recovery of VWF:RCo | PK2 of rVWF [N=13] | 1.8 (U/dL)/(U VWF: RCo/kg) |
| Full Analysis Set | PK80 - Incremental Recovery of VWF:RCo | PK1 of rVWF [N=15] | 1.8 (U/dL)/(U VWF: RCo/kg) |
Secondary
PK80 - Mean Residence Time of VWF:Ag
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK80 - Mean Residence Time of VWF:Ag | PK1 of rVWF [N=15] | 38.4 hours |
| Full Analysis Set | PK80 - Mean Residence Time of VWF:Ag | PK2 of rVWF [N=13] | 36.9 hours |
Secondary
PK80 - Mean Residence Time of VWF:CB
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK80 - Mean Residence Time of VWF:CB | PK1 of rVWF [N=15] | 30.9 hours |
| Full Analysis Set | PK80 - Mean Residence Time of VWF:CB | PK2 of rVWF [N=13] | 28.7 hours |
Secondary
PK80 - Mean Residence Time of VWF:RCo
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK80 - Mean Residence Time of VWF:RCo | PK1 of rVWF [N=15] | 26.4 hours |
| Full Analysis Set | PK80 - Mean Residence Time of VWF:RCo | PK2 of rVWF [N=13] | 26.4 hours |
Secondary
PK80- Ratio of Intra-participant PK of VWF:RCo, VWF:Ag and VWF:CB at Baseline and After 6 Months
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.
Time frame: 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 \[PK2\].
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
| Full Analysis Set | 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 |
Secondary
PK80 - Volume of Distribution at Steady State of VWF:Ag
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK80 - Volume of Distribution at Steady State of VWF:Ag | PK1 of rVWF [N=15] | 0.55 dL/kg |
| Full Analysis Set | PK80 - Volume of Distribution at Steady State of VWF:Ag | PK2 of rVWF [N=13] | 0.50 dL/kg |
Secondary
PK80 - Volume of Distribution at Steady State of VWF:CB
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK80 - Volume of Distribution at Steady State of VWF:CB | PK1 of rVWF [N=15] | 0.39 dL/kg |
| Full Analysis Set | PK80 - Volume of Distribution at Steady State of VWF:CB | PK2 of rVWF [N=13] | 0.36 dL/kg |
Secondary
PK80 - Volume of Distribution at Steady State of VWF:RCo
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Full Analysis Set | PK80 - Volume of Distribution at Steady State of VWF:RCo | PK1 of rVWF [N=15] | 0.78 dL/kg |
| Full Analysis Set | PK80 - Volume of Distribution at Steady State of VWF:RCo | PK2 of rVWF [N=13] | 0.75 dL/kg |