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rVWF IN PROPHYLAXIS

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02973087
Recruitment Status : Completed
First Posted : November 25, 2016
Results First Posted : August 6, 2021
Last Update Posted : August 6, 2021
Sponsor:
Collaborator:
Baxalta Innovations GmbH, now part of Shire
Information provided by (Responsible Party):
Takeda

Brief Summary:
The purpose of this phase 3 study is to investigate the efficacy and safety, including immunogenicity, thrombogenicity and hypersensitivity reactions, as well as pharmacokinetics (PK), health related quality of life (HRQoL) and pharmacoeconomics of prophylactic treatment with recombinant von Willebrand factor (rVWF) (vonicog alfa) in adult participants with severe von Willebrand disease (VWD).

Condition or disease Intervention/treatment Phase
Von Willebrand Disease Biological: von Willebrand factor (Recombinant) Biological: Antihemophilic Factor (Recombinant) Phase 3

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 29 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A PROSPECTIVE, PHASE 3, OPEN-LABEL, INTERNATIONAL MULTICENTER STUDY ON EFFICACY AND SAFETY OF PROPHYLAXIS WITH rVWF IN SEVERE VON WILLEBRAND DISEASE
Actual Study Start Date : November 16, 2017
Actual Primary Completion Date : July 6, 2020
Actual Study Completion Date : July 6, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: All Study Participants
Participants will receive prophylaxis with rVWF in two cohorts: on-demand (OD) cohort (previously treated with OD) and pdVWF switch cohort (participants switching from prophylactic treatment with pdVWF).
Biological: von Willebrand factor (Recombinant)
OD participants will receive intravenous (IV) rVWF:RCo at an initial prophylactic dose of 50 +/- 10 International Unit per Kilogram (IU/kg) twice (two infusions) a week for at least 12 months up to 15 months and may be increased up to 80 IU/kg. pdVWF switch cohort participants will receive rVWF:RCo equivalent (± 10%) to the weekly VWF dose received during prophylactic treatment with pdVWF.
Other Names:
  • BAX 111
  • rVWF
  • VONVENDI
  • vonicog alfa
  • BAX111

Biological: Antihemophilic Factor (Recombinant)
During prophylaxis period any bleeding episodes requiring substitution therapy with VWF concentrate to control bleeding will be treated with rVWF with or without ADVATE. Participants will receive rFVIII IV if necessary for OD treatment of breakthrough bleeds or for peri-operative. The dose will be according to the bleeding type and severity and it will be adjusted to the clinical response.
Other Names:
  • ADVATE
  • Recombinant Factor VIII
  • rFVIII




Primary Outcome Measures :
  1. Ratio of Annualized Bleeding Rate (ABR) for Spontaneous Bleeding Episodes (BEs) (On-study ABR / Historical ABR) Assessed by Investigator During Prophylactic Treatment With rVWF Through Month 12 [ Time Frame: Up to 12 months ]
    ABR for treated spontaneous BEs while on prophylactic treatment with rVWF through month 12 of treatment period/observation period (in years), where an observation period = (date of completion/termination - date of first dose + 1)/365.2425. Bleeds occurred at the same anatomical location with the same etiology within 24 hours after onset of the first bleed were considered a single bleed. Bleeding occurred at multiple locations related to the same injury were considered as a single bleeding episode. Historical observation period for historical BEs was 365 days prior to first dose of study drug. On-study observation period started on the day of first administration of study drug and continuing through the date of completion/discontinuation from study. The comparison of the two ABRs (on-study and historical) for spontaneous bleeding episodes (not related to trauma) during prophylactic treatment with rVWF was reported as a ratio of mean ABRs (on-study ABR:historical ABR).


Secondary Outcome Measures :
  1. Percentage of Prior On-demand Participants Achieved Spontaneous ABR Percent Reduction Success Through Month 12 [ Time Frame: Up to 12 months ]
    For prior on-demand participants, spontaneous ABR percent reduction success was defined as at least 25% reduction of the ABR for treated spontaneous (not related to trauma) BEs during the first 12 months of rVWF (vonicog alfa) prophylaxis relative to the participant's own historical treated spontaneous ABR. Percentage of participants with ABR percent reduction success for on-demand cohort was reported.

  2. Percentage of Switch Participants With Spontaneous ABR Preservation Success Through Month 12 [ Time Frame: Up to 12 months ]
    For switch participants, spontaneous ABR preservation success was defined as achieving an ABR for treated spontaneous BEs during first 12 months of rVWF (vonicog alfa) prophylaxis that was no greater than the participant's own historical ABR for treated spontaneous BEs during prophylactic treatment with pdVWF. Percentage of participants with ABR preservation success in switch cohort was reported.

  3. Number of Participants Based on Categorized Spontaneous ABR (sABR) Through Month 12 [ Time Frame: Baseline through Month 12 ]
    The sABR was the number of spontaneous bleeds divided by the observation period in years, where an observation period = (date of completion/termination-date of first dose+1)/365.2425.sABR was categorized based on number of BEs as 0, greater than (>) 0 through 2,>2 through 5,>5 during the prophylactic treatment with rVWF (vonicog alfa) through 12 months. Bleeding at multiple locations related to the same injury was counted as single bleeding episode. BEs of unknown cause were counted as spontaneous bleeds. Observation period for historical BEs was 365 days prior to first dose of study drug. The baseline sABR for treated BEs was based on historical BE data and on-study sABR was based on treated spontaneous BEs during prophylaxis with rVWF through Month 12. On-study observation period started on the day of first administration of study drug continuing through the date of completion/discontinuation from study. Number of participants based on categorized sABR was calculated and reported.

  4. Total Number of Infusions Administered Per Participant During Prophylactic Treatment With rVWF Through Month 12 [ Time Frame: Up to 12 months ]
    For each participant, the total number of infusions was counted as the total number of unique infusions of rVWF which were administered between the dates of informed consent and termination from the study, inclusive, regardless of the date and time of administration. The total number of infusions administered during the study was entered in electronic case record form (eCRF), and recorded in ERT system. Total number of infusions administered per participant during prophylactic treatment With rVWF through 12 months was calculated.

  5. Average Number of Infusions Per Week Per Participant During Prophylactic Treatment With rVWF Through Month 12 [ Time Frame: Up to 12 months ]
    Average number of infusions per week per participant during prophylactic treatment With rVWF through 12 months was calculated.

  6. Total Weight Adjusted Consumption of rVWF Per Participant During Prophylactic Treatment Through Month 12 [ Time Frame: Up to 12 months ]
    For each participant, the body weight-adjusted dose (IU/kg) was derived as the number of units of rVWF infused (IU) divided by the last available body weight (kilogram [kg]) prior to the infusion. Total weight adjusted consumption of rVWF (vonicog alfa) per participant during prophylactic treatment was reported.

  7. Number of Treated Spontaneous BEs by Location of Bleeding While on Prophylactic Treatment With rVWF Through Month 12 [ Time Frame: Up to 12 months ]
    Number of treated spontaneous BEs by location of bleeding (for example: oral and other mucosa, menorrhagia, hemarthrosis, etc.) while on prophylactic treatment with rVWF was reported.

  8. Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs [ Time Frame: From first dose of study drug up to end of study (approximately 32 months) ]
    An adverse event (AE) is defined as any untoward medical occurrence in a participant administered IP that does not necessarily have a causal relationship with the treatment. TEAEs were events which occurred on or after the date and time of administration of the first dose of study medication. TEAEs included both serious AEs and non-serious AEs. Number of participants with TEAEs and serious TEAEs were reported.

  9. Number of Participants Based on Severity of TEAEs [ Time Frame: From first dose of study drug up to end of study (approximately 32 months) ]
    An AE is defined as any untoward medical occurrence in a participant administered IP that does not necessarily have a causal relationship with the treatment. TEAEs were events which occurred on or after the date and time of administration of the first dose of study medication. TEAEs included both serious AEs and non-serious AEs. Severity of TEAEs was determined by following definitions: Mild: No limitation of usual activities; Moderate: Some limitation of usual activities and may required therapeutic intervention; Severe: Inability to carry out usual activities with sequelae, which required therapeutic intervention. Participants were counted by considering the maximum severity of TEAEs.

  10. Number of Participants With TEAEs Based Causality [ Time Frame: From first dose of study drug up to end of study (approximately 32 months) ]
    An AE was defined as any untoward medical occurrence in a participant administered IP that does not necessarily have a causal relationship with the treatment. TEAEs were events which occurred on or after the date and time of administration of the first dose of study medication. TEAEs included both serious AEs and non-serious AEs. For each AE, the investigator assessed the causal relationship between the IP and the AE based on clinical expertise and judgment according to the following circumstances of the AE: Not related, Unlikely related, Possibly related, or Probably related. A related TEAE was defined as any TEAE indicated as 'possibly related' or 'probably related'. Number of participants with TEAEs based causality was reported.

  11. Number of Participants With Thromboembolic Events [ Time Frame: From first dose of study drug up to end of study (approximately 32 months) ]
    Thromboembolism defined as formation in a blood vessel of a clot (thrombus) that breaks loose and carried by the blood stream and could plug another vessel. Number of participants with thromboembolic events as TEAEs of special interest was reported. A broad standard search query approach was used (broad SMQ) to identify all potential thromboembolic events of interest which were then medically assessed. Number of participants with thromboembolic events as TEAEs of special interest was reported.

  12. Number of Participants With Hypersensitivity Reactions [ Time Frame: From first dose of study drug up to end of study (approximately 32 months) ]
    Hypersensitivity (also called hypersensitivity reaction or intolerance) defined as undesirable reactions produced by the normal immune system, including allergies and autoimmunity. Potential hypersensitivity events were identified by broad search criteria and then medically assessed. Number of participants with hypersensitivity reactions as TEAEs of special interest was calculated.

  13. Number of Participants Who Developed Neutralizing Antibodies to Von Willebrand Factor (rVWF) and Factor VIII (FVIII) [ Time Frame: Baseline through Month 12 ]
    Three functional VWF assays for von Willebrand factor collagen binding (VWF:CB), von Willebrand factor: Ristocetin Cofactor (VWF:RCo) and von Willebrand factor VIII B (VWF:FVIIIB) were used to test the presence of neutralizing anti-VWF antibodies. Neutralizing antibodies to VWF:RCo, VWF:CB and VWF:FVIIIB activities was measured by assays based on the Bethesda assay established for quantitative analysis of FVIII inhibitors (Nijmegen modification of the Bethesda assay). Only confirmed neutralizing anti -VWF antibodies were considered inhibitors. Number of participants who developed neutralizing antibodies to rVWF and FVIII were assessed.

  14. Number of Participants Who Developed of Total Binding Antibodies to Von Willebrand Factor (rVWF) and Factor VIII (FVIII) [ Time Frame: Baseline through Month 12 ]
    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). Binding antibodies against FVIII was analyzed using a proprietary enzyme immunoassay. Number of participants who developed of total binding antibodies to rVWF and FVIII was assessed.

  15. Number of Participants Who Developed Binding Antibodies to Chinese Hamster Ovary (CHO) Proteins, Mouse Immunoglobulin G (IgG) and/or rFurin [ Time Frame: Baseline through Month 12 ]
    Total Ig antibodies (IgG, IgA, IgM) against CHO protein and human furin was analyzed using ELISA. For detection and quantification of IgG antibodies originating from human plasma that were directed against mouse-IgG (HAMA: human anti- mouse antibodies) was assessed using ELISA (Medac, Hamburg, Germany). Number of participants who developed binding antibodies to CHO proteins, Mouse IgG and/or rFurin was assessed.

  16. Number of Participants With Clinically Significant Change From Baseline in Vital Signs [ Time Frame: Baseline up to end of study (approximately 32 months) ]
    Vital signs included blood pressure (systolic and diastolic), pulse rate, respiratory rate and body temperature. Number of participants with clinically significant change from baseline in vital signs was assessed.

  17. Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Parameters [ Time Frame: Baseline up to end of study (approximately 32 months) ]
    Clinical laboratory parameters included hematology and clinical chemistry assessments. Number of participants with clinically significant change from baseline in clinical laboratory parameters was assessed.

  18. Pharmacokinetic (PK) Assessment: Incremental Recovery (IR) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    IR at the maximum plasma concentration of VWF:RCo activity at initial PK assessment was reported. Unit of measure: International Units per deciliter/International Units per kilogram ([IU/dL]/[IU/kg]).

  19. Pharmacokinetic Assessment: Incremental Recovery (IR) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    IR based on VWF:Ag activity at initial PK assessment was reported.

  20. Pharmacokinetic Assessment: Incremental Recovery (IR) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    IR at the maximum plasma concentration of VWF:CB activity at initial PK assessment was reported.

  21. Pharmacokinetic Assessment: Terminal Half-life (T1/2) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    T1/2 defined as the time in hours required for the concentration of the drug to reach half of its original value. T1/2 based on VWF:Rco activity at initial PK assessment was reported.

  22. Pharmacokinetic Assessment: Terminal Half-life (T1/2) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    T1/2 defined as the time in hours required for the concentration of the drug to reach half of its original value. T1/2 based on VWF:Ag activity at initial PK assessment was reported.

  23. Pharmacokinetic Assessment: Terminal Half-life (T1/2) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    T1/2 defined as the time in hours required for the concentration of the drug to reach half of its original value. T1/2 based on VWF:CB activity at initial PK assessment was reported.

  24. Pharmacokinetic Assessment: Mean Residence Time (MRT) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    MRT was calculated as (AUMC0-∞/AUC0-∞) - T1/2 where T1 represented the time duration of infusion, where AUMC represented the area under the first moment curve. MRT based on VWF:Rco activity at initial PK assessment was reported.

  25. Pharmacokinetic Assessment: Mean Residence Time (MRT) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    MRT was calculated as (AUMC0-∞/AUC0-∞) - T1/2 where T1 represented the time duration of infusion, where AUMC represented the area under the first moment curve. MRT based on VWF:Ag activity at initial PK assessment was reported.

  26. Pharmacokinetic Assessment: Mean Residence Time (MRT) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    MRT was calculated as (AUMC0-∞/AUC0-∞) - T1/2 where T1 represented the time duration of infusion, where AUMC represented the area under the first moment curve. MRT based on VWF:CB activity at initial PK assessment was reported.

  27. Pharmacokinetic Assessment: Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    AUC0-∞ based on VWF:Rco activity at initial PK assessment was reported. Unit of measure: International Units*hour per deciliter (IU*h/dL).

  28. Pharmacokinetic Assessment: Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    AUC0-∞ based on VWF:Ag activity at initial PK assessment was reported.

  29. Pharmacokinetic Assessment: Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    AUC0-∞ based on VWF:CB activity at initial PK assessment was reported.

  30. Pharmacokinetic Assessment: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Measurable Concentration (AUC0-tlast) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    AUC0-tlast based on VWF:Rco activity at initial PK assessment was reported.

  31. Pharmacokinetic Assessment: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Measurable Concentration (AUC0-tlast) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    AUC0-tlast based on VWF:Ag activity at initial PK assessment was reported.

  32. Pharmacokinetic Assessment: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Measurable Concentration (AUC0-tlast) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    AUC0-tlast based on VWF:CB activity at initial PK assessment was reported.

  33. Pharmacokinetic Assessment: Maximum Plasma Concentration (Cmax) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Cmax based on VWF:Rco at initial PK assessment was reported. Unit of measure: International Units per deciliter (IU/dL).

  34. Pharmacokinetic Assessment: Maximum Plasma Concentration (Cmax) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Cmax based on VWF:Ag activity at initial PK assessment was reported.

  35. Pharmacokinetic Assessment: Maximum Plasma Concentration (Cmax) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Cmax based on VWF:CB activity at initial PK assessment was reported.

  36. Pharmacokinetic Assessment: Minimum Time to Reach the Maximum Plasma Concentration (Tmax) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Tmax based on VWF:Rco activity at initial PK assessment was reported.

  37. Pharmacokinetic Assessment: Minimum Time to Reach the Maximum Plasma Concentration (Tmax) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Tmax based on VWF:Ag activity at initial PK assessment was reported.

  38. Pharmacokinetic Assessment: Minimum Time to Reach the Maximum Plasma Concentration (Tmax) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Tmax based on VWF:CB activity at initial PK assessment was reported.

  39. Pharmacokinetic Assessment: Volume of Distribution at Steady State (Vss) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss based on VWF:Rco activity at initial assessment was reported.

  40. Pharmacokinetic Assessment: Volume of Distribution at Steady State (Vss) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss based on VWF:Ag activity at initial assessment was reported.

  41. Pharmacokinetic Assessment: Volume of Distribution at Steady State (Vss) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss based on VWF:CB activity at initial assessment was reported.

  42. Pharmacokinetic Assessment: Clearance (CL) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL based on VWF:Rco activity at initial PK assessment was reported. Unit of measure: deciliter per kilogram per hour (dL/kg/h).

  43. Pharmacokinetic Assessment: Clearance (CL) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL based on VWF:Ag activity at initial PK assessment was reported.

  44. Pharmacokinetic Assessment: Clearance (CL) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL based on VWF:CB activity at initial PK assessment was reported.

  45. Pharmacodynamic (PD) Assessment: Maximum Plasma Concentration (Cmax) Based on Factor VIII Clotting (FVIII:C) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Cmax based on FVIII:C activity at initial PD assessment by the 1-stage clotting assay was reported.

  46. Pharmacodynamic Assessment: Minimum Time to Reach the Maximum Plasma Concentration (Tmax) Based on Factor VIII Clotting (FVIII:C) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Tmax based on FVIII:C activity at initial PD assessment by the 1-stage clotting assay was reported.

  47. Pharmacodynamic Assessment: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Measurable Concentration (AUC0-tlast) Based on Factor VIII Clotting (FVIII:C) Activity [ Time Frame: At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    AUC0-tlast based on FVIII:C activity at initial PD assessment by the 1-stage clotting assay was reported.

  48. Pharmacokinetic Assessment at Steady State: Area Under the Plasma Concentration Versus Time Curve From Time 0 to End of the Partial Dosing Interval (AUC0- Tau;ss) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    AUC0-tau;ss based on VWF:Rco activity at steady state during end of study (Month 12) was reported.

  49. Pharmacokinetic Assessment at Steady State: Area Under the Plasma Concentration Versus Time Curve From Time 0 to End of the Partial Dosing Interval (AUC0- Tau;ss) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    AUC0-tau;ss based on VWF:Ag activity at steady state during end of study (Month 12) was reported.

  50. Pharmacokinetic Assessment at Steady State: Area Under the Plasma Concentration Versus Time Curve From Time 0 to End of the Partial Dosing Interval (AUC0- Tau;ss) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    AUC0-tau;ss based on VWF:CB activity at steady state during end of study (Month 12) was reported.

  51. Pharmacokinetics Assessment at Steady State: Maximum Plasma Concentration During the Partial Dosing Interval at Steady State (Cmax;ss) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Cmax;ss based on VWF:Rco activity at steady state during end of study (Month 12) was reported.

  52. Pharmacokinetics Assessment at Steady State: Maximum Plasma Concentration During the Partial Dosing Interval at Steady State (Cmax;ss) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Cmax;ss based on VWF:Ag activity at steady state during end of study (Month 12) was reported.

  53. Pharmacokinetics Assessment at Steady State: Maximum Plasma Concentration During the Partial Dosing Interval at Steady State (Cmax;ss) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Cmax;ss based on VWF:CB activity at steady state during end of study (Month 12) was reported.

  54. Pharmacokinetics Assessment at Steady State: Minimum Time to Reach the Maximum Plasma Concentration at Steady State (Tmax;ss) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Tmax;ss based on VWF:Rco activity at steady state during end of study (Month 12) was reported.

  55. Pharmacokinetics Assessment at Steady State: Minimum Time to Reach the Maximum Plasma Concentration at Steady State (Tmax;ss) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Tmax;ss based on VWF:Ag activity at steady state during end of study (Month 12) was reported.

  56. Pharmacokinetics Assessment at Steady State: Minimum Time to Reach the Maximum Plasma Concentration at Steady State (Tmax;ss) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Tmax;ss based on VWF:CB activity at steady state during end of study (Month 12) was reported.

  57. Pharmacokinetics Assessment at Steady State: Minimum Plasma Concentration During the Partial Dosing Interval at Steady State (Cmin;ss) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Cmin;ss based on VWF:Rco activity at steady state during end of study (Month 12) was reported.

  58. Pharmacokinetics Assessment at Steady State: Minimum Plasma Concentration During the Partial Dosing Interval at Steady State (Cmin;ss) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Cmin;ss based on VWF:Rco activity at steady state during end of study (Month 12) was reported.

  59. Pharmacokinetics Assessment at Steady State: Minimum Plasma Concentration During the Partial Dosing Interval at Steady State (Cmin;ss) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Cmin;ss based on VWF:CB activity at steady state during end of study (Month 12) was reported.

  60. Pharmacodynamic Assessment at Steady State: Area Under the Plasma Concentration Versus Time Curve From Time 0 to End of the Partial Dosing Interval (AUC0- Tau;ss) Based on Factor VIII Clotting (FVIII:C) Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    AUC0-tau;ss based on FVIII:C activity at steady state during end of study (Month 12) was reported.

  61. Pharmacodynamic Assessment at Steady State: Maximum Plasma Concentration During the Partial Dosing Interval at Steady State (Cmax;ss) Based on Factor VIII Clotting (FVIII:C) Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Cmax;ss based on FVIII:C activity was assessed at steady state during end of study (Month 12) was reported.

  62. Pharmacodynamic Assessment at Steady State: Minimum Time to Reach the Maximum Plasma Concentration at Steady State (Tmax;ss) Based on Factor VIII Clotting (FVIII:C) Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Tmax;ss based on FVIII:C activity at steady state during end of study (Month 12) was reported.

  63. Pharmacodynamic Assessment at Steady State: Minimum Plasma Concentration During the Partial Dosing Interval at Steady State (Cmin;ss) Based on Factor VIII Clotting (FVIII:C) Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    Cmin;ss based on FVIII:C activity at steady state during end of study (Month 12) was reported.

  64. Factor VIII (FVIII) Clotting Activity [ Time Frame: At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours ]
    FVIII clotting activity (FVIII:C) levels was assessed and reported as per pre-specified PK time points at Month 12.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Participant has a documented diagnosis of severe von Willebrand disease (VWD) (baseline Von Willebrand factor: Ristocetin cofactor activity (VWF:RCo) less than (<) 20 International Units/Deciliter [IU/dL]) with a history of requiring substitution therapy with von Willebrand factor concentrate to control bleeding

    1. Type 1 (VWF:RCo <20 IU/dL) or,
    2. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2M or,
    3. Type 3 (Von Willebrand factor antigen (VWF:Ag) less than or equal to [< or =] 3 IU/dL).
  2. Diagnosis is confirmed by genetic testing and multimer analysis, documented in patient history or at screening.
  3. For on-demand patient group, participant currently receiving on-demand treatment for whom prophylactic treatment is recommended by the investigator.
  4. For Plasma derived von Willebrand factor (pdVWF) product switch patient group, participant has been receiving prophylactic treatment of pdVWF products for no less than 12 months prior to screening.
  5. For on-demand patient group, participant has greater than or equal to (>or=) 3 documented spontaneous bleeds (not including menorrhagia) requiring von Willebrand factor (VWF) treatment during the past 12 months.
  6. Availability of records to reliably evaluate type, frequency and treatment of bleeding episodes during at least 12 months preceding enrollment. Up to 24 months retrospective data should be collected if available. Availability of dosing and factor consumption during 12 months (up to 24 months) of treatment prior to enrollment is required for pdVWF switch participants and is desired (but not a requirement) for on-demand participants.
  7. Participant is > or = 18 years old at the time of screening and has a body mass index > or = 15 but <40 kilogram per meter square (kg/m^2).
  8. If female of childbearing potential, participant presents with a negative blood/urine pregnancy test at screening and agrees to employ adequate birth control measures for the duration of the study.
  9. Participant is willing and able to comply with the requirements of the protocol.

Exclusion Criteria:

  1. The participant has been diagnosed with Type 2N Von Willebrand disease (VWD), pseudo VWD, or another hereditary or acquired coagulation disorder other than VWD (eg qualitative and quantitative platelet disorders or prothrombin time [PT]/international normalized ratio [INR] greater than [>]1.4).
  2. The participant is currently receiving prophylactic treatment with more than 5 infusions per week.
  3. The participant is currently receiving prophylactic treatment with a weekly dose exceeding 240 IU/kg.
  4. The participant has a history or presence of a VWF inhibitor at screening.
  5. The participant has a history or presence of a Factor VIII (FVIII) inhibitor with a titer ≥0.4 Bethesda units (BU) (by Nijmegen modified Bethesda assay) or > or = 0.6 Bethesda Unit (BU) (by Bethesda assay).
  6. The participant has a known hypersensitivity to any of the components of the study drugs, such as to mouse or hamster proteins.
  7. The participant has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
  8. The participant has a medical history of a thromboembolic event.
  9. The participant is human immunodeficiency virus (HIV) positive with an absolute Helper T cell (CD4) count <200/ cubic millimeter (mm^3).
  10. The participant has been diagnosed with significant liver disease per investigator's medical assessment of the participant's current condition or medical history or as evidenced by any of the following: serum alanine aminotransferase (ALT) greater than 5 times the upper limit of normal; hypoalbuminemia; portal vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal varices).
  11. The participant has been diagnosed with renal disease, with a serum creatinine (CR) level > or = 2.5 milligram per deciliter (mg/dL).
  12. The participant has a platelet count <100,000/ milliliter (mL) at screening.
  13. The participant has been treated with an immunomodulatory drug, excluding topical treatment (e.g., ointments, nasal sprays), within 30 days prior to signing the informed consent.
  14. The participant is pregnant or lactating at the time of enrollment.
  15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, dysplasia).
  16. The participant has participated in another clinical study involving another Investigational product (IP) or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study.
  17. The participant has a progressive fatal disease and/or life expectancy of less than 15 months.
  18. The participant is scheduled for a surgical intervention.
  19. The participant is identified by the investigator as being unable or unwilling to cooperate with study procedures.
  20. The participant has 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.
  21. The participant is in prison or compulsory detention by regulatory and/or juridical order.
  22. The participant is member of the study team or in a dependent relationship with one of the study team members which includes close relatives (i.e., children, partner/spouse, siblings and parents) as well as employees.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02973087


Locations
Show Show 35 study locations
Sponsors and Collaborators
Takeda
Baxalta Innovations GmbH, now part of Shire
Investigators
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Study Director: Study Director Takeda
  Study Documents (Full-Text)

Documents provided by Takeda:
Study Protocol  [PDF] March 12, 2018
Statistical Analysis Plan  [PDF] September 29, 2020

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT02973087    
Other Study ID Numbers: 071301
2016-001478-14 ( EudraCT Number )
First Posted: November 25, 2016    Key Record Dates
Results First Posted: August 6, 2021
Last Update Posted: August 6, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
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.
URL: https://vivli.org/ourmember/takeda/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Von Willebrand Diseases
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Blood Platelet Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII
Coagulants