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

Primary Purpose

Von Willebrand Disease

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Recombinant von Willebrand factor (rVWF)

Placebo

Recombinant factor VIIII (rFVIII)

About this trial

This is an interventional treatment trial for Von Willebrand Disease

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

University of California Davis Cancer Center
University of Miami Miller School of Medicine
University of Illinois College of Medicine at Peoria
Indiana Hemophilia and Thrombosis Center
Newark Beth Israel Medical Center
The Mary M Gooley Hemophilia Center and Rochester General Hospital
University of North Carolina at Chapel Hill
Pennsylvania Hospital
Hemophilia Center of Western Pennsylvania
Blood Center of Wisconsin
Royal Adelaide Hospital
Royal Perth Hospital
Medical University Vienna
Cliniques Universitaires Saint-Luc
UZ Leuven
Specialized Haematological Hospital "Joan Pavel"
Multiprofile Hospital for Active Treatment "Sveta Marina"
University of Alberta Hospital
Vivantes Klinikum im Friedrichshain
Gerinnungszentrum Rhein-Ruhr
Universitätsmedizin der Johannes Gutenberg Universität Mainz
Jehangir Clinical Development Centre Pvt. Ltd.
Sahyadri Speciality Hospital
Christian Medical College
Azienda Ospedaliera Universitaria Careggi
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
Azienda Ospedaliera di Padova
Università degli Studi di Roma "La Sapienza"
Ospedale San Bortolo
Nagoya University Hospital
Tokyo Medical University Hospital
Ogikubo Hospital
Erasmus MC
UMC Utrecht
Hematology and Transplantology Clinic, University Clinic Centre - Medical University Hospital
Nicolaus Copernicus Provincial Specialist Hospital in Lodz Department of Hematology
Institute of Haematology and Transfusion Medicine
Independent Public Clinical Hospital No. 1 in Wroclaw, Department of Hematology, blood cancer and Bone Marrow Transplantation
Regional Pediatric Clinical Hospital #1
Kirov Hematology and Blood Transfusion Research Institute under the Federal Medical and Biological Agency of Russia
Territorial Clinical Hospital
Municipal Policlinic # 37
Hospital Materno Infantil Teresa Herrera
Hospital Universitario La Paz
Hospital Universitario La Paz
Hospital Universitario Marques de Valdecilla
Sahlgrenska Universitetssjukhuset
Skåne University Hospital (SUS)
The Royal London Hospital
Royal Free Hospital
Hammersmith Hospital
Manchester Royal Infirmary

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

PK 80 Arm (minimum of 22 subjects with severe VWD)

PK 50 Arm (14 subjects with type 3 VWD)

PK 50 Only Arm (minimum of 7 subjects with type 3 VWD)

Treatment Only (up to 7 subjects independent of VWD subtype)

Arm Description

PK assessment (80 IU/kg rVWF) + 12-month treatment period

Two single-blinded PK assessments (50 IU/kg rVWF + rFVIII/placebo) + 12-month treatment period

PK assessment (50 IU/kg rVWF) only, no treatment of bleeding episodes

Treatment of bleeding episodes for a total of 12 months

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

Percentage of Participants Who Had an Occurrence of Thrombotic Events

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.

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).

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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).

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).

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).

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).

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT01410227

First Posted

August 4, 2011

Last Updated

April 29, 2021

Sponsor

Baxalta now part of Shire

1. Study Identification

Unique Protocol Identification Number

NCT01410227

Brief Title

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

Official Title

A Phase 3 Clinical Study to Determine the Pharmacokinetics, Safety and Efficacy of Recombinant Von Willebrand Factor : Recombinant Factor VIII (rVWF:rFVIII) and rVWF in the Treatment of Bleeding Episodes in Subjects Diagnosed With Von Willebrand Disease

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Completed

Study Start Date

November 1, 2011 (Actual)

Primary Completion Date

February 1, 2014 (Actual)

Study Completion Date

February 1, 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Baxalta now part of Shire

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of 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).

6. Conditions and Keywords

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

Von Willebrand Disease

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Crossover Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

49 (Actual)

8. Arms, Groups, and Interventions

Arm Title

PK 80 Arm (minimum of 22 subjects with severe VWD)

Arm Type

Experimental

Arm Description

PK assessment (80 IU/kg rVWF) + 12-month treatment period

Arm Title

PK 50 Arm (14 subjects with type 3 VWD)

Arm Type

Experimental

Arm Description

Two single-blinded PK assessments (50 IU/kg rVWF + rFVIII/placebo) + 12-month treatment period

Arm Title

PK 50 Only Arm (minimum of 7 subjects with type 3 VWD)

Arm Type

Experimental

Arm Description

PK assessment (50 IU/kg rVWF) only, no treatment of bleeding episodes

Arm Title

Treatment Only (up to 7 subjects independent of VWD subtype)

Arm Type

Experimental

Arm Description

Treatment of bleeding episodes for a total of 12 months

Intervention Type

Biological

Intervention Name(s)

Recombinant von Willebrand factor (rVWF)

Other Intervention Name(s)

BAX 111, rVWF

Intervention Description

Intravenous administration

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

saline, physiologic saline

Intervention Description

Syringe supplied with physiologic saline solution for infusion

Intervention Type

Biological

Intervention Name(s)

Recombinant factor VIIII (rFVIII)

Other Intervention Name(s)

rFVIII, ADVATE

Intervention Description

Intravenous administration

Primary Outcome Measure Information:

Title

Percentage of Participants With Treatment Success for Treated Bleeding Episodes

Description

Time Frame

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

Secondary Outcome Measure Information:

Title

Percentage of Treated Bleeding Episodes With an Efficacy Rating of "Excellent" or "Good"

Description

Time Frame

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

Title

Percentage of Treated Bleeding Episodes With an Efficacy Rating of "Excellent" or "Good", Excluding Gastrointestinal Bleeds

Description

Time Frame

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

Title

Number of Infusions of rVWF:rFVIII and/or rVWF Per Bleeding Episode

Description

Time Frame

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

Title

Number of Units of rVWF:rFVIII and/or rVWF Per Bleeding Episode

Description

Time Frame

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

Title

Percentage of Participants Who Develop Inhibitory Antibodies to FVIII

Description

Time Frame

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

Title

Percentage of Participants Who Develop Inhibitory Antibodies to VWF

Description

Time Frame

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

Title

Percentage of Participants Who Develop Binding Antibodies to VWF

Description

Time Frame

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

Title

Percentage of Participants Who Develop Binding Antibodies to CHO

Description

Time Frame

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

Title

Percentage of Participants Who Develop Binding Antibodies to rFurin

Description

Time Frame

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

Title

Percentage of Participants Who Develop Binding Antibodies to Mouse Immunoglobulin

Description

Time Frame

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

Title

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

Title

Number of Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs

Description

Time Frame

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

Title

Number of Participants With Adverse Events Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs

Description

Time Frame

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

Title

Number of Adverse Events by Infusion Related to Study Product Including Clinically Significant Changes in Laboratory Parameters and Vital Signs

Description

Time Frame

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

Title

PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:RCo

Description

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.

Title

PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:RCo

Description

Time Frame

Title

PK50 - Mean Residence Time of VWF:RCo

Description

Time Frame

Title

PK50 - Clearance of VWF:RCo

Description

Time Frame

Title

PK50 - Incremental Recovery of VWF:RCo

Description

Time Frame

Title

PK50 - Elimination Phase Half-Life of VWF:Co

Description

Time Frame

Title

PK50 - Volume of Distribution at Steady State of VWF:RCo

Description

Time Frame

Title

PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:Ag

Description

Time Frame

Title

PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:Ag

Description

Time Frame

Title

PK50 - Mean Residence Time of VWF:Ag

Description

Time Frame

Title

PK50 - Clearance of VWF:Ag

Description

Time Frame

Title

PK50 - Incremental Recovery of VWF:Ag

Description

Time Frame

Title

PK50 - Elimination Phase Half-Life of VWF:Ag

Description

Time Frame

Title

PK50 - Volume of Distribution at Steady State of VWF:Ag

Description

Time Frame

Title

PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:CB

Description

Time Frame

Title

PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:CB

Description

Time Frame

Title

PK50 - Mean Residence Time of VWF:CB

Description

Time Frame

Title

PK50 - Clearance of VWF:CB

Description

Time Frame

Title

PK50 - Incremental Recovery of VWF:CB

Description

Time Frame

Title

PK50 - Elimination Phase Half-Life of VWF:CB

Description

Time Frame

Title

PK50 - Volume of Distribution at Steady State of VWF:CB

Description

Time Frame

Title

PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of FVIII:C

Description

Time Frame

Title

PK50 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of FVIII:C

Description

Time Frame

Title

PK50 - Mean Residence Time of FVIII:C

Description

Time Frame

Title

PK50 - Clearance of FVIII:C

Description

Time Frame

Title

PK50 - Incremental Recovery of FVIII:C

Description

Time Frame

Title

PK50 - Elimination Phase Half-Life of FVIII:C

Description

Time Frame

Title

PK50 - Volume of Distribution at Steady State of FVIII:C

Description

Time Frame

Title

PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:RCo

Description

Time Frame

Title

PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:RCo

Description

Time Frame

Title

PK80 - Mean Residence Time of VWF:RCo

Description

Time Frame

Title

PK80 - Clearance of VWF:RCo

Description

Time Frame

Title

PK80 - Incremental Recovery of VWF:RCo

Description

Time Frame

Title

PK80 - Elimination Phase Half-Life of VWF:Co

Description

Time Frame

Title

PK80 - Volume of Distribution at Steady State of VWF:RCo

Description

Time Frame

Title

PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:Ag

Description

Time Frame

Title

PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:Ag

Description

Time Frame

Title

PK80 - Mean Residence Time of VWF:Ag

Description

Time Frame

Title

PK80 - Clearance of VWF:Ag

Description

Time Frame

Title

PK80 - Incremental Recovery of VWF:Ag

Description

Time Frame

Title

PK80 - Elimination Phase Half-Life of VWF:Ag

Description

Time Frame

Title

PK80 - Volume of Distribution at Steady State of VWF:Ag

Description

Time Frame

Title

PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of VWF:CB

Description

Time Frame

Title

PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of VWF:CB

Description

Time Frame

Title

PK80 - Mean Residence Time of VWF:CB

Description

Time Frame

Title

PK80 - Clearance of VWF:CB

Description

Time Frame

Title

PK80 - Incremental Recovery of VWF:CB

Description

Time Frame

Title

PK80 - Elimination Phase Half-Life of VWF:CB

Description

Time Frame

Title

PK80 - Volume of Distribution at Steady State of VWF:CB

Description

Time Frame

Title

PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-∞/Dose) of FVIII:C

Description

Time Frame

Title

PK80 - Area Under the Plasma Concentration/Time Curve From Time 0 to 96 Hours (AUC0-96h/Dose) of FVIII:C

Description

Time Frame

Title

PK80- Ratio of Intra-participant PK of VWF:RCo, VWF:Ag and VWF:CB at Baseline and After 6 Months

Description

Time Frame

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Participant has been diagnosed with: Type 1 (Von Willebrand factor: Ristocetin cofactor activity (VWF:RCo) < 20 IU/dL) or, 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, Type 3 ( Von Willebrand factor antigen (VWF:Ag) ≤ 3 IU/dL) or, 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Study Director

Organizational Affiliation

Takeda

Official's Role

Study Director

Facility Information:

Facility Name

University of California Davis Cancer Center

City

Sacramento

State/Province

California

ZIP/Postal Code

95817

Country

United States

Facility Name

University of Miami Miller School of Medicine

City

Miami

State/Province

Florida

ZIP/Postal Code

33101

Country

United States

Facility Name

University of Illinois College of Medicine at Peoria

City

Peoria

State/Province

Illinois

ZIP/Postal Code

61614

Country

United States

Facility Name

Indiana Hemophilia and Thrombosis Center

City

Indianapolis

State/Province

Indiana

ZIP/Postal Code

46260

Country

United States

Facility Name

Newark Beth Israel Medical Center

City

Newark

State/Province

New Jersey

ZIP/Postal Code

07112

Country

United States

Facility Name

The Mary M Gooley Hemophilia Center and Rochester General Hospital

City

Rochester

State/Province

New York

ZIP/Postal Code

14621

Country

United States

Facility Name

University of North Carolina at Chapel Hill

City

Chapel Hill

State/Province

North Carolina

ZIP/Postal Code

27599

Country

United States

Facility Name

Pennsylvania Hospital

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

Facility Name

Hemophilia Center of Western Pennsylvania

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15213

Country

United States

Facility Name

Blood Center of Wisconsin

City

Milwaukee

State/Province

Wisconsin

ZIP/Postal Code

53226

Country

United States

Facility Name

Royal Adelaide Hospital

City

Adelaide

State/Province

South Australia

ZIP/Postal Code

5000

Country

Australia

Facility Name

Royal Perth Hospital

City

Perth

State/Province

Western Australia

ZIP/Postal Code

6847

Country

Australia

Facility Name

Medical University Vienna

City

Vienna

ZIP/Postal Code

1090

Country

Austria

Facility Name

Cliniques Universitaires Saint-Luc

City

Bruxelles

ZIP/Postal Code

1200

Country

Belgium

Facility Name

UZ Leuven

City

Leuven

ZIP/Postal Code

3000

Country

Belgium

Facility Name

Specialized Haematological Hospital "Joan Pavel"

City

Sofia

ZIP/Postal Code

1233

Country

Bulgaria

Facility Name

Multiprofile Hospital for Active Treatment "Sveta Marina"

City

Varna

ZIP/Postal Code

9010

Country

Bulgaria

Facility Name

University of Alberta Hospital

City

Edmonton

State/Province

Alberta

ZIP/Postal Code

T6G 2H7

Country

Canada

Facility Name

Vivantes Klinikum im Friedrichshain

City

Berlin

ZIP/Postal Code

10249

Country

Germany

Facility Name

Gerinnungszentrum Rhein-Ruhr

City

Duisburg

ZIP/Postal Code

47051

Country

Germany

Facility Name

Universitätsmedizin der Johannes Gutenberg Universität Mainz

City

Mainz

ZIP/Postal Code

55131

Country

Germany

Facility Name

Jehangir Clinical Development Centre Pvt. Ltd.

City

Pune

ZIP/Postal Code

411001

Country

India

Facility Name

Sahyadri Speciality Hospital

City

Pune

ZIP/Postal Code

411004

Country

India

Facility Name

Christian Medical College

City

Vellore

ZIP/Postal Code

632004

Country

India

Facility Name

Azienda Ospedaliera Universitaria Careggi

City

Florence

ZIP/Postal Code

50134

Country

Italy

Facility Name

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico

City

Milano

ZIP/Postal Code

20122

Country

Italy

Facility Name

Azienda Ospedaliera di Padova

City

Padova

ZIP/Postal Code

35128

Country

Italy

Facility Name

Università degli Studi di Roma "La Sapienza"

City

Roma

ZIP/Postal Code

00161

Country

Italy

Facility Name

Ospedale San Bortolo

City

Vicenza

ZIP/Postal Code

36100

Country

Italy

Facility Name

Nagoya University Hospital

City

Nagoya

ZIP/Postal Code

4668560

Country

Japan

Facility Name

Tokyo Medical University Hospital

City

Tokyo

ZIP/Postal Code

1600023

Country

Japan

Facility Name

Ogikubo Hospital

City

Tokyo

ZIP/Postal Code

167-0035

Country

Japan

Facility Name

Erasmus MC

City

Rotterdam

ZIP/Postal Code

3015 CE

Country

Netherlands

Facility Name

UMC Utrecht

City

Utrecht

ZIP/Postal Code

3584 CX

Country

Netherlands

Facility Name

Hematology and Transplantology Clinic, University Clinic Centre - Medical University Hospital

City

Gdansk

ZIP/Postal Code

80-952

Country

Poland

Facility Name

Nicolaus Copernicus Provincial Specialist Hospital in Lodz Department of Hematology

City

Krakow

ZIP/Postal Code

31-501

Country

Poland

Facility Name

Institute of Haematology and Transfusion Medicine

City

Warsaw

ZIP/Postal Code

02-776

Country

Poland

Facility Name

Independent Public Clinical Hospital No. 1 in Wroclaw, Department of Hematology, blood cancer and Bone Marrow Transplantation

City

Wroclaw

ZIP/Postal Code

50-367

Country

Poland

Facility Name

Regional Pediatric Clinical Hospital #1

City

Ekaterinburg

ZIP/Postal Code

620149

Country

Russian Federation

Facility Name

Kirov Hematology and Blood Transfusion Research Institute under the Federal Medical and Biological Agency of Russia

City

Kirov

ZIP/Postal Code

610027

Country

Russian Federation

Facility Name

Territorial Clinical Hospital

City

Krasnoyarsk

ZIP/Postal Code

660022

Country

Russian Federation

Facility Name

Municipal Policlinic # 37

City

St. Petersburg

ZIP/Postal Code

195213

Country

Russian Federation

Facility Name

Hospital Materno Infantil Teresa Herrera

City

a Coruña

State/Province

Galicia

ZIP/Postal Code

15006

Country

Spain

Facility Name

Hospital Universitario La Paz

City

Madrid

ZIP/Postal Code

28046

Country

Spain

Facility Name

Hospital Universitario La Paz

City

Palma de Mallorca

ZIP/Postal Code

07014

Country

Spain

Facility Name

Hospital Universitario Marques de Valdecilla

City

Santander

ZIP/Postal Code

39008

Country

Spain

Facility Name

Sahlgrenska Universitetssjukhuset

City

Gothenburg

ZIP/Postal Code

41345

Country

Sweden

Facility Name

Skåne University Hospital (SUS)

City

Malmö

Country

Sweden

Facility Name

The Royal London Hospital

City

London

ZIP/Postal Code

E1 1BB

Country

United Kingdom

Facility Name

Royal Free Hospital

City

London

ZIP/Postal Code

NW3 2QG

Country

United Kingdom

Facility Name

Hammersmith Hospital

City

London

ZIP/Postal Code

W12 0NN

Country

United Kingdom

Facility Name

Manchester Royal Infirmary

City

Manchester

ZIP/Postal Code

M13 9WL

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

IPD Sharing Access Criteria

IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.

IPD Sharing URL

https://vivli.org/ourmember/takeda/

Citations:

PubMed Identifier

26239086

Citation

Gill JC, Castaman G, Windyga J, Kouides P, Ragni M, Leebeek FW, Obermann-Slupetzky O, Chapman M, Fritsch S, Pavlova BG, Presch I, Ewenstein B. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood. 2015 Oct 22;126(17):2038-46. doi: 10.1182/blood-2015-02-629873. Epub 2015 Aug 3. Erratum In: Blood. 2016 Jun 2;127(22):2777. Blood. 2020 Nov 19;136(21):2479-2480.

Results Reference

result

Learn more about this trial

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

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