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| ID | Type | Description | Link |
|---|---|---|---|
| 2014-003575-38 | EudraCT Number |
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The purpose of the study is to assess the efficacy and safety of recombinant von Willebrand factor (rVWF) with or without ADVATE in major and minor elective surgical procedures in adult patients with hereditary severe von Willebrand disease (VWD).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Recombinant von Willebrand Factor (rVWF) | Experimental | Surgery participants treated with Recombinant von Willebrand Factor (rVWF) |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Recombinant von Willebrand Factor (rVWF) | Biological | rVWF will be administered by intravenous bolus infusion. Participants planned for major surgery will undergo a baseline pharmacokinetic assessment prior to surgery. The peri- and postoperative substitution regimen will be individualized according to the PK results, intensity and duration of the hemostatic challenge, and the institution´s standard of care. |
| Measure | Description | Time Frame |
|---|---|---|
| Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician) | Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none. Excellent: Intra-, and postoperative hemostasis achieved with rVWF with our without ADVATE was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal subject. Good: Intra-, and postoperative hemostasis achieved with rVWF with or without ADVATE was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal subject. Moderate: Intra-, and postoperative hemostasis with rVWF with or without ADVATE was clearly less than optimal for the type of procedure performed but was maintained without the need to change the rVWF concentrate. None: Participant experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of rVWF concentrate. | 24 hours after last peri-operative infusion or at completion of Day 14 (± 2 days) visit, whichever occurs earlier |
| Measure | Description | Time Frame |
|---|---|---|
| Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon | The predicted blood loss will be estimated preoperatively by the operating surgeon based on a hemostatically normal individual of the same sex, age, stature and co-morbidities as the participant. The actual blood loss will be assessed consisting of the estimated blood loss, including into swabs, towels and suction during the procedure, per the anesthesiologist's record. |
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Inclusion Criteria:
Diagnosis of severe von Willebrand disease (VWD) as listed below and elective surgical procedure planned
VWD with a history of requiring substitution therapy with von Willebrand factor (VWF) concentrate to control bleeding
If type 3 VWD (VWF Antigen /VWF:Ag ≤ 3 IU/dL), participant has a medical history of at least 20 exposure days to VWF/FVIII coagulation factor concentrates (including cryoprecipitate or fresh frozen plasma)
If type 1 or type 2 VWD, participant has a medical history of 5 exposure days or a past major surgery requiring VWF/FVIII coagulation factor concentrates (including cryoprecipitate or fresh frozen plasma)
Participant is at least 18 years of age
If female of childbearing potential, participant presents with a negative pregnancy test
If applicable, participant agrees to employ adequate birth control measures for the duration of the study
Participant is willing and able to comply with the requirements of the protocol
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Study Director | Takeda | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Colorado Hemophilia & Thrombosis Center | Aurora | Colorado | 80045 | United States | ||
| University of Miami, Jackson Memorial Hospital |
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.
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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.
A total of 24 participants were enrolled (signed informed consent) and screened. Of these, 15 participants were treated with investigational product.
Enrollment was conducted at 14 study sites in 10 countries (USA, Australia, Taiwan, Germany, Russia, Spain, Ukraine, United Kingdom, Italy, Turkey).
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| ID | Title | Description |
|---|---|---|
| FG000 | Recombinant Von Willebrand Factor (rVWF) | Surgery participants treated with Recombinant von Willebrand Factor (rVWF) |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Day 0 (at completion of surgery) |
| Intraoperative Actual Blood Loss Relative to Predicted Blood Loss | Actual blood loss relative to predicted blood loss will be calculated as [Actual Blood loss (mL)] divided by [Predicted Blood Loss (mL) multiplied by 100.](streamdown:incomplete-link) | Day 0 (at completion of surgery) |
| Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon | Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none. Excellent: Intraoperative blood loss was less than or equal to the maximum blood loss expected for the type of procedure performed in a hemostatically normal subject (≤ 100%). Good: Intraoperative blood loss was up to 50% more than the maximum expected blood loss for the type of procedure performed in a hemostatically normal subject (101-150%) Moderate: Intraoperative blood loss was more than 50% of the maximum expected blood loss for the type of procedure performed in a hemostatically normal subject (>150%). None: Uncontrolled hemorrhage that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of clotting factor replacement regimen. | Day 0 (at completion of surgery) |
| Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon | Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none. Excellent: Intraoperative hemostasis achieved with rVWF with our without ADVATE was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal subject. Good: Intraoperative hemostasis achieved with rVWF with or without ADVATE was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal subject. Moderate: Intraoperative hemostasis with rVWF with or without ADVATE was clearly less than optimal for the type of procedure performed but was maintained without the need to change the rVWF concentrate. None: Participant experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of rVWF concentrate. | Day 0 (at completion of surgery) |
| Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE | Daily, from day of surgery through postoperative Day 14 (± 2 days) |
| Occurrence of Adverse Events | Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated. | From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery) |
| Occurrence of Thrombotic Events | Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated for thrombotic events. | From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery) |
| Occurrence of Severe Allergic Reactions (eg, Anaphylaxis) | Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated for severe allergic reactions. | From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery) |
| Number of Participants Who Developed Inhibitory and Total Binding Antibodies to Von Willebrand Factor (VWF) and Inhibitory Antibodies to Factor VIII (FVIII) | Participants were treated with recombinant van Willebrand Factor (rVWF) with or without ADVATE. | Testing occurred throughout the study at screening, prior PK infusion, pre-surgery, post surgery in case of excessive bleeding or unexplained bleeding, at postoperative day 7 and at study completion visit (ie. 14 (± 2) days post surgery). |
| Number of Participants Who Developed Antibodies to Chinese Hamster Ovary (CHO) Proteins, Mouse Immunoglobulin G (IgG) or Recombinant Furin (rFurin) | Participants were treated with recombinant van Willebrand Factor (rVWF) with or without ADVATE. | Testing occurred throughout the study at screening, prior PK infusion, pre-surgery, post surgery in case of excessive bleeding or unexplained bleeding, at postoperative day 7 and at study completion visit (ie. 14 (± 2) days post surgery). |
| Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From 0 to 72 Hours Post-infusion (AUC 0-72 h/Dose) | This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. The area under the plasma concentration/time curve from 0 to 72 hours post-infusion will be computed using the linear trapezoidal rule. For the calculation of AUC(0-72h) the levels at 72 hours will be linearly interpolated/extrapolated from the 2 nearest sampling time points. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac), FVIII Coagulation Activity (FVIII:C) | PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours. |
| Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity (AUC 0-∞ /Dose) | This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. The area under the plasma concentration/time curve from time 0 to infinity and the area under the first moment curve from time 0 to infinity will be calculated as the sum of AUC or AUMC from time 0 to the time of last quantifiable concentration plus a tail area correction calculated as Ct/λz and Ct/λz(t+1/λz), respectively, where Ct is the last quantifiable concentration, t is the time of last quantifiable concentration and λz is the terminal or disposition rate constant. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac), FVIII Coagulation Activity (FVIII:C) | PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours. |
| Pharmacokinetics: Mean Residence Time (MRT) | This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Mean residence time will be calculated as area under the first moment curve from time 0 to infinity divided by the area under the curve time 0 to infinity minus T/2 where T is the duration of the infusion. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac) | PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours. |
| Pharmacokinetics: Clearance (CL) | This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Clearance will be calculated as dose (IU/kg) divided by the area under the curve time 0 to infinity. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac) | PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours. |
| Pharmacokinetics: Incremental Recovery (IR) | This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Incremental recovery will be calculated as (Cmax minus Cpreinfusion) divided by the dose (IU/kg) where kg refers to the body weight at the time of dosing and Cmax is the observed maximum concentration before correction for pre-infusion values. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac) | PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours. |
| Pharmacokinetics: Elimination Phase Half-life (T1/2) | This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Terminal or disposition half-life (T1/2) will be calculated as ln2/λz where λz is the terminal elimination rate constant as calculated in WinNonlin NCA using at least three quantifiable concentrations. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac) | PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours. |
| Pharmacokinetics: Volume of Distribution at Steady State (Vss) | This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Vss will be calculated as the clearance multiplied with the mean residence time. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac) | PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours. |
| Miami |
| Florida |
| 33136 |
| United States |
| Georgia Regents University | Augusta | Georgia | 30912 | United States |
| John Hopkins University | Baltimore | Maryland | 21205 | United States |
| Dana Farber Cancer Institute | Boston | Massachusetts | 02215 | United States |
| Rutgers - Robert Wood Johnson Medical School | New Brunswick | New Jersey | 08901 | United States |
| Duke University Medical Center | Durham | North Carolina | 27705 | United States |
| Case Western Reserve University Hospital | Cleveland | Ohio | 44106 | United States |
| Cleveland Clinic | Cleveland | Ohio | 44195 | United States |
| University of Oklahoma Health Sciences Center | Oklahoma City | Oklahoma | 73104 | United States |
| Medical University of South Carolina (MUSC) | Charleston | South Carolina | 29425 | United States |
| Blood Center of South East Wisconsin | Milwaukee | Wisconsin | 53233 | United States |
| Royal Adelaide Hospital | Adelaide | South Australia | 5000 | Australia |
| The Perth Blood Institute | Nedlands | Western Australia | 6009 | Australia |
| Fiona Stanley Hospital | Perth | Western Australia | 6000 | Australia |
| AKH - Medizinische Universität Wien | Vienna | 1090 | Austria |
| Fakultni nemocnice Ostrava | Ostrava | 70852 | Czechia |
| Universitätsmedizin der Johannes Gutenberg Universität Mainz | Mainz | Rhineland-Palatinate | 55101 | Germany |
| Azienda Ospedaliero - Universitaria Careggi | Firenze (Florence) | 50139 | Italy |
| Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico | Milan | 20122 | Italy |
| Umberto I Policlinico di Roma, Universitá di Roma La Sapienza | Rome | 00144 | Italy |
| Erasmus Medisch Centrum | Rotterdam | 3015 CE | Netherlands |
| Regional Budgetary State Healthcare Institution (SHI) "Regional Clinical Hospital" | Barnaul | 656024 | Russia |
| FSI Kirov Institute of Hematology and Blood Transfusion FMBA | Kirov | 610027 | Russia |
| Complejo Hospitalario Universitario A Coruña | A Coruña | 15006 | Spain |
| Hospital Universitari i Politècnic La Fe | Valencia | 46026 | Spain |
| Taichung Veterans General Hospital | Taichung | 40705 | Taiwan |
| Tri-Service General Hospital | Taipei | 10002 | Taiwan |
| National Taiwan University Hospital | Taipei | 11490 | Taiwan |
| Ege University Medical Faculty | Izmir | 35100 | Turkey (Türkiye) |
| SI Institute of Blood Pathology and Transfusion Medicine of NAMSU | Lviv | 79044 | Ukraine |
| Derriford Hospital | Plymouth | Devon | PL6 8DH | United Kingdom |
| Royal Free Hospital | London | Greater London | NW3 2QG | United Kingdom |
| Churchill Hospital | Oxford | Oxfordshire | OX3 7LJ | United Kingdom |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Recombinant Von Willebrand Factor (rVWF) | Surgery participants treated with Recombinant von Willebrand Factor (rVWF) |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
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| Age, Continuous | Median | Full Range | Years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||
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| Primary | Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician) | Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none. Excellent: Intra-, and postoperative hemostasis achieved with rVWF with our without ADVATE was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal subject. Good: Intra-, and postoperative hemostasis achieved with rVWF with or without ADVATE was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal subject. Moderate: Intra-, and postoperative hemostasis with rVWF with or without ADVATE was clearly less than optimal for the type of procedure performed but was maintained without the need to change the rVWF concentrate. None: Participant experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of rVWF concentrate. | Number of participants with major, minor and oral surgery and number of participant with Von Willebrand Type 1, 2A, 2B, 2M and 3 do sum up to the overall number of participants analyzed. The full analysis data set, including all participants who received investigational product and have at least 1 hemostatic assessment, was used for analysis. | Posted | Count of Participants | Participants | 24 hours after last peri-operative infusion or at completion of Day 14 (± 2 days) visit, whichever occurs earlier |
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| Secondary | Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon | The predicted blood loss will be estimated preoperatively by the operating surgeon based on a hemostatically normal individual of the same sex, age, stature and co-morbidities as the participant. The actual blood loss will be assessed consisting of the estimated blood loss, including into swabs, towels and suction during the procedure, per the anesthesiologist's record. | For predicted blood loss the number of participants analyzed is 14 as for one participant (included in the major surgery reporting group) the predicted blood loss was not collected. The full analysis data set, including all participants who received investigational product and have at least 1 hemostatic assessment, was used for analysis. | Posted | Mean | Standard Deviation | mL | Day 0 (at completion of surgery) |
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| Secondary | Intraoperative Actual Blood Loss Relative to Predicted Blood Loss | Actual blood loss relative to predicted blood loss will be calculated as [Actual Blood loss (mL)] divided by [Predicted Blood Loss (mL) multiplied by 100.](streamdown:incomplete-link) | Number of participants analyzed is 11, as for 3 participants the actual and the predicted blood loss was zero and for 1 participant the predicted blood loss was not collected. Therefore 'actual blood loss relative to predicted blood loss' could not be calculated. The full analysis data set was used for the analysis of this outcome measure. | Posted | Mean | Standard Deviation | Percent | Day 0 (at completion of surgery) |
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| Secondary | Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon | Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none. Excellent: Intraoperative blood loss was less than or equal to the maximum blood loss expected for the type of procedure performed in a hemostatically normal subject (≤ 100%). Good: Intraoperative blood loss was up to 50% more than the maximum expected blood loss for the type of procedure performed in a hemostatically normal subject (101-150%) Moderate: Intraoperative blood loss was more than 50% of the maximum expected blood loss for the type of procedure performed in a hemostatically normal subject (>150%). None: Uncontrolled hemorrhage that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of clotting factor replacement regimen. | Number of participants with major, minor and oral surgery and number of participant with Von Willebrand Type 1, 2A, 2B, 2M and 3 do sum up to the overall number of participants analyzed. The full analysis data set, including all participants who received investigational product and have at least 1 hemostatic assessment, was used for analysis. | Posted | Count of Participants | Participants | Day 0 (at completion of surgery) |
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| Secondary | Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon | Hemostatic efficacy will be rated on a scale of excellent - good - moderate - none. Excellent: Intraoperative hemostasis achieved with rVWF with our without ADVATE was as good or better than that expected for the type of surgical procedure performed in a hemostatically normal subject. Good: Intraoperative hemostasis achieved with rVWF with or without ADVATE was probably as good as that expected for the type of surgical procedure performed in a hemostatically normal subject. Moderate: Intraoperative hemostasis with rVWF with or without ADVATE was clearly less than optimal for the type of procedure performed but was maintained without the need to change the rVWF concentrate. None: Participant experienced uncontrolled bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating a change of rVWF concentrate. | Number of participants with major, minor and oral surgery and number of participant with Von Willebrand Type 1, 2A, 2B, 2M and 3 do sum up to the overall number of participants analyzed. The full analysis data set, including all participants who received investigational product and have at least 1 hemostatic assessment, was used for analysis. | Posted | Count of Participants | Participants | Day 0 (at completion of surgery) |
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| Secondary | Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE | Number of participants analyzed is different for the time points according to individual treatment. The full analysis data set, including all participants who received investigational product and have at least 1 hemostatic assessment, was used for analysis. | Posted | Median | Inter-Quartile Range | IU/kg | Daily, from day of surgery through postoperative Day 14 (± 2 days) |
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| Secondary | Occurrence of Adverse Events | Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated. | The safety analysis data set, including all participants who received any amount of investigational product, was used for analysis of this outcome measure. | Posted | Number | Adverse Events | From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery) |
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| Secondary | Occurrence of Thrombotic Events | Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated for thrombotic events. | The safety analysis data set, including all participants who received any amount of investigational product, was used for analysis of this outcome measure. | Posted | Number | Adverse Events | From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery) |
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| Secondary | Occurrence of Severe Allergic Reactions (eg, Anaphylaxis) | Treatment emergent adverse events (TEAEs) and treatment emergent serious adverse events (TESAEs) will be evaluated for severe allergic reactions. | The safety analysis data set, including all participants who received any amount of investigational product, was used for analysis of this outcome measure. | Posted | Number | Adverse Events | From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery) |
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| Secondary | Number of Participants Who Developed Inhibitory and Total Binding Antibodies to Von Willebrand Factor (VWF) and Inhibitory Antibodies to Factor VIII (FVIII) | Participants were treated with recombinant van Willebrand Factor (rVWF) with or without ADVATE. | The safety analysis data set, including all participants who received any amount of investigational product, was used for analysis of this outcome measure. | Posted | Count of Participants | Participants | Testing occurred throughout the study at screening, prior PK infusion, pre-surgery, post surgery in case of excessive bleeding or unexplained bleeding, at postoperative day 7 and at study completion visit (ie. 14 (± 2) days post surgery). |
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| Secondary | Number of Participants Who Developed Antibodies to Chinese Hamster Ovary (CHO) Proteins, Mouse Immunoglobulin G (IgG) or Recombinant Furin (rFurin) | Participants were treated with recombinant van Willebrand Factor (rVWF) with or without ADVATE. | The safety analysis data set, including all participants who received any amount of investigational product, was used for analysis of this outcome measure. | Posted | Count of Participants | Participants | Testing occurred throughout the study at screening, prior PK infusion, pre-surgery, post surgery in case of excessive bleeding or unexplained bleeding, at postoperative day 7 and at study completion visit (ie. 14 (± 2) days post surgery). |
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| Secondary | Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From 0 to 72 Hours Post-infusion (AUC 0-72 h/Dose) | This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. The area under the plasma concentration/time curve from 0 to 72 hours post-infusion will be computed using the linear trapezoidal rule. For the calculation of AUC(0-72h) the levels at 72 hours will be linearly interpolated/extrapolated from the 2 nearest sampling time points. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac), FVIII Coagulation Activity (FVIII:C) | The PK analysis data set, including all participants who underwent PK assessment with data collected at the relevant time points, was used for analysis of this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours*IU/dL | PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours. |
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| Secondary | Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity (AUC 0-∞ /Dose) | This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. The area under the plasma concentration/time curve from time 0 to infinity and the area under the first moment curve from time 0 to infinity will be calculated as the sum of AUC or AUMC from time 0 to the time of last quantifiable concentration plus a tail area correction calculated as Ct/λz and Ct/λz(t+1/λz), respectively, where Ct is the last quantifiable concentration, t is the time of last quantifiable concentration and λz is the terminal or disposition rate constant. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac), FVIII Coagulation Activity (FVIII:C) | The PK analysis data set, including all participants who underwent PK assessment with data collected at the relevant time points, was used for analysis of this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours*IU/dL | PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours. |
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| Secondary | Pharmacokinetics: Mean Residence Time (MRT) | This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Mean residence time will be calculated as area under the first moment curve from time 0 to infinity divided by the area under the curve time 0 to infinity minus T/2 where T is the duration of the infusion. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac) | The PK analysis data set, including all participants who underwent PK assessment with data collected at the relevant time points, was used for analysis of this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours. |
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| Secondary | Pharmacokinetics: Clearance (CL) | This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Clearance will be calculated as dose (IU/kg) divided by the area under the curve time 0 to infinity. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac) | The PK analysis data set, including all participants who underwent PK assessment with data collected at the relevant time points, was used for analysis of this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | dL/hour/kg | PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours. |
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| Secondary | Pharmacokinetics: Incremental Recovery (IR) | This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Incremental recovery will be calculated as (Cmax minus Cpreinfusion) divided by the dose (IU/kg) where kg refers to the body weight at the time of dosing and Cmax is the observed maximum concentration before correction for pre-infusion values. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac) | The PK analysis data set, including all participants who underwent PK assessment with data collected at the relevant time points, was used for analysis of this outcome measure. | Posted | Mean | Standard Deviation | IU/dL | PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours. |
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| Secondary | Pharmacokinetics: Elimination Phase Half-life (T1/2) | This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Terminal or disposition half-life (T1/2) will be calculated as ln2/λz where λz is the terminal elimination rate constant as calculated in WinNonlin NCA using at least three quantifiable concentrations. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac) | The PK analysis data set, including all participants who underwent PK assessment with data collected at the relevant time points, was used for analysis of this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours. |
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| Secondary | Pharmacokinetics: Volume of Distribution at Steady State (Vss) | This assessment is only required for subjects undergoing major surgery. Subjects will receive a PK infusion at a dose of 50±5 IU/kg rVWF:RCo within 42 days prior to surgery. Vss will be calculated as the clearance multiplied with the mean residence time. PK analysis was performed for the following analytes: VWF Ristocetin Cofactor Activity (VWF:RCo), VWF Antigen Activity (VWF:Ag), VWF Collagen Binding Activity (VWF:CB), VWF Activity Measured INNOVANCE VWF Ac Assay (VWF:Ac) | The PK analysis data set, including all participants who underwent PK assessment with data collected at the relevant time points, was used for analysis of this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | dL/kg | PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours. |
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Throughout the study period (from the first exposure to investigational product until study completion or discontinuation date). Total study duration: 1 year and 3 months. Per participant: up to 58 days.
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Recombinant Von Willebrand Factor (rVWF) | Surgery participants treated with Recombinant von Willebrand Factor (rVWF) | 0 | 15 | 2 | 15 | 6 | 15 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diverticulitis | Infections and infestations | 19.0 | Non-systematic Assessment |
| |
| Deep vein thrombosis | Vascular disorders | 19.0 | Non-systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acne | Skin and subcutaneous tissue disorders | 19.0 | Non-systematic Assessment |
| |
| Dry skin | Skin and subcutaneous tissue disorders | 19.0 | Non-systematic Assessment |
| |
| Iron deficiency anaemia | Blood and lymphatic system disorders | 19.0 | Non-systematic Assessment |
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| Peripheral swelling | General disorders | 19.0 | Non-systematic Assessment |
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| Nasopharyngitis | Infections and infestations | 19.0 | Non-systematic Assessment |
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| Joint swelling | Musculoskeletal and connective tissue disorders | 19.0 | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | 19.0 | Non-systematic Assessment |
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| Headache | Nervous system disorders | 19.0 | Non-systematic Assessment |
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| Pelvic pain | Reproductive system and breast disorders | 19.0 | Non-systematic Assessment |
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| Deep vein thrombosis | Vascular disorders | 19.0 | Non-systematic Assessment |
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Agreements with PIs may vary per requirements of individual PI, but contain common elements. For this study, PIs are restricted from independently publishing results until completion of the multicenter publication or one year after the conclusion of the study at all sites. Baxalta requires a review of results communication (e.g. for confidential information) >= 30 days prior to submission. Baxalta may request an additional delay of <= 6 months (e.g. for intellectual property protection).
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Shire | +1 866 842 5335 | ClinicalTransparency@shire.com |
| ID | Term |
|---|---|
| D014842 | von Willebrand Diseases |
| ID | Term |
|---|---|
| D025861 | Blood Coagulation Disorders, Inherited |
| D001778 | Blood Coagulation Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D020147 | Coagulation Protein Disorders |
| D001791 | Blood Platelet Disorders |
| D006474 | Hemorrhagic Disorders |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
Not provided
Not provided
All participants with von Willebrand Disease Type 3. |
| Good |
|
| Moderate |
|
| None |
|
| OG003 | Oral Surgery | All participants who underwent oral surgery. |
| OG004 | Von Willebrand Disease Type 1 | All participants with von Willebrand Disease Type 1. |
| OG005 | Von Willebrand Disease Type 2A | All participants with von Willebrand Disease Type 2A. |
| OG006 | Von Willebrand Disease Type 2B | All participants with von Willebrand Disease Type 2B. |
| OG007 | Von Willebrand Disease Type 2M | All participants with von Willebrand Disease Type 2M. |
| OG008 | Von Willebrand Disease Type 3 | All participants with von Willebrand Disease Type 3. |
|
|
All participants who underwent oral surgery.
| OG004 | Von Willebrand Disease Type 1 | All participants with von Willebrand Disease Type 1. |
| OG005 | Von Willebrand Disease Type 2A | All participants with von Willebrand Disease Type 2A. |
| OG006 | Von Willebrand Disease Type 2B | All participants with von Willebrand Disease Type 2B. |
| OG007 | Von Willebrand Disease Type 2M | All participants with von Willebrand Disease Type 2M. |
| OG008 | Von Willebrand Disease Type 3 | All participants with von Willebrand Disease Type 3. |
|
|
All participants who underwent minor surgery.
| OG002 | Major Surgery | All participants who underwent major surgery. |
| OG003 | Oral Surgery | All participants who underwent oral surgery. |
| OG004 | Von Willebrand Disease Type 1 | All participants with von Willebrand Disease Type 1. |
| OG005 | Von Willebrand Disease Type 2A | All participants with von Willebrand Disease Type 2A. |
| OG006 | Von Willebrand Disease Type 2B | All participants with von Willebrand Disease Type 2B. |
| OG007 | Von Willebrand Disease Type 2M | All participants with von Willebrand Disease Type 2M. |
| OG008 | Von Willebrand Disease Type 3 | All participants with von Willebrand Disease Type 3. |
|
|
All participants who underwent minor surgery. |
| OG002 | Major Surgery | All participants who underwent major surgery. |
| OG003 | Oral Surgery | All participants who underwent oral surgery. |
| OG004 | Von Willebrand Disease Type 1 | All participants with von Willebrand Disease Type 1. |
| OG005 | Von Willebrand Disease Type 2A | All participants with von Willebrand Disease Type 2A. |
| OG006 | Von Willebrand Disease Type 2B | All participants with von Willebrand Disease Type 2B. |
| OG007 | Von Willebrand Disease Type 2M | All participants with von Willebrand Disease Type 2M. |
| OG008 | Von Willebrand Disease Type 3 | All participants with von Willebrand Disease Type 3. |
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| Participants |
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| Participants |
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