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rVWF IN PROPHYLAXIS

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ClinicalTrials.gov Identifier: NCT02973087
Recruitment Status : Recruiting
First Posted : November 25, 2016
Last Update Posted : March 6, 2018
Sponsor:
Information provided by (Responsible Party):
Shire ( Baxalta now part of Shire )

Tracking Information
First Submitted Date  ICMJE November 22, 2016
First Posted Date  ICMJE November 25, 2016
Last Update Posted Date March 6, 2018
Actual Study Start Date  ICMJE December 22, 2017
Estimated Primary Completion Date May 20, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 22, 2016)
Prospectively recorded annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding episodes during prophylactic treatment with (rVWF) and the participants' historical ABR for spontaneous bleeding episodes during on-demand treatment [ Time Frame: Approximately 1 year ]
recombinant von Willebrand factor (rVWF)
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02973087 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 3, 2018)
  • Number of participants with reduction of annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding episodes during prophylaxis relative to the participants' own historical ABR during on-demand treatment [ Time Frame: Approximately 1 year ]
  • Number of participants with zero bleeds during prophylactic treatment with recombinant von Willebrand factor (rVWF) [ Time Frame: Approximately 1 year ]
  • Number of infusions of recombinant von Willebrand factor (rVWF) and ADVATE per month during prophylactic treatment as well as during on-demand treatment [ Time Frame: Approximately 1 year ]
  • Number of infusions of recombinant von Willebrand factor (rVWF) and ADVATE per year during prophylactic treatment as well as during on-demand treatment [ Time Frame: Approximately 1 year ]
  • Total weight adjusted consumption of recombinant von Willebrand factor (rVWF) and ADVATE per month during prophylactic treatment as well as during on-demand treatment [ Time Frame: Approximately 1 year ]
  • Total weight adjusted consumption of recombinant von Willebrand factor (rVWF) and ADVATE per year during prophylactic treatment as well as during on-demand treatment [ Time Frame: Approximately 1 year ]
  • Incidence of thromboembolic events [ Time Frame: Throughout the study period of approximately 22 months ]
  • Incidence of severe hypersensitivity reactions [ Time Frame: Throughout the study period of approximately 22 months ]
  • Number of participants who develop neutralizing antibodies to recombinant von Willebrand factor (rVWF) and Factor VIII (FVIII) [ Time Frame: Throughout the study period of approximately 22 months ]
  • Number of participants who develop total binding antibodies to recombinant von Willebrand factor (rVWF) and Factor VIII (FVIII) [ Time Frame: Throughout the study period of approximately 22 months ]
  • Number of participants who develop antibodies to Chinese hamster ovary (CHO) proteins, mouse immunoglobulin G (IgG) and rFurin [ Time Frame: Throughout the study period of approximately 22 months ]
  • Pharmacokinetics - Incremental recovery (IR) [ Time Frame: 30 minutes pre-infusion; and post-infusion at 30 minutes and 1, 6, 12, 24. 48, and 72 hours ]
  • Pharmacokinetics - Terminal half-life (T1/2) [ Time Frame: 30 minutes pre-infusion; and post-infusion at 30 minutes and 1, 6, 12, 24. 48, and 72 hours ]
  • Pharmacokinetics - Mean residence time (MRT) [ Time Frame: 30 minutes pre-infusion; and post-infusion at 30 minutes and 1, 6, 12, 24. 48, and 72 hours ]
  • Pharmacokinetics - Area under the curve/dose (AUC/dose) [ Time Frame: 30 minutes pre-infusion; and post-infusion at 30 minutes and 1, 6, 12, 24. 48, and 72 hours ]
  • Pharmacokinetics - Area under moment curve/dose (AUMC/dose) [ Time Frame: 30 minutes pre-infusion; and post-infusion at 30 minutes and 1, 6, 12, 24. 48, and 72 hours ]
  • Pharmacokinetics - Volume of distribution at steady state (Vss) [ Time Frame: 30 minutes pre-infusion; and post-infusion at 30 minutes and 1, 6, 12, 24. 48, and 72 hours ]
  • Pharmacokinetics - Clearance (CL) [ Time Frame: 30 minutes pre-infusion; and post-infusion at 30 minutes and 1, 6, 12, 24. 48, and 72 hours ]
  • Number of infusions of recombinant von Willebrand factor (rVWF) and ADVATE (rFVIII) per spontaneous bleeding episode (BE) [ Time Frame: Throughout the study period, up to approximately 22 months ]
  • Number of infusions of recombinant von Willebrand factor (rVWF) and ADVATE (rFVIII) per traumatic bleeding episode (BE) [ Time Frame: Throughout the study period, up to approximately 22 months ]
  • Weight-adjusted consumption of recombinant von Willebrand factor (rVWF) and ADVATE (rFVIII) per spontaneous bleeding episode (BE) [ Time Frame: Throughout the study period, up to approximately 22 months ]
  • Weight-adjusted consumption of recombinant von Willebrand factor (rVWF) and ADVATE (rFVIII) per traumatic bleeding episode (BE) [ Time Frame: Throughout the study period, up to approximately 22 months ]
  • Overall hemostatic efficacy rating at resolution of bleed [ Time Frame: Throughout the study period, up to approximately 22 months ]
    Using a 4-point scale: Excellent, Good, Moderate, None
  • Intraoperative actual versus predicted blood loss - if surgery is required [ Time Frame: Day 0 (at completion of surgery) ]
    Assessed by the operating surgeon) at completion of surger
  • Intraoperative hemostatic efficacy- if surgery is required [ Time Frame: Day 0 (at completion of surgery) ]
    Score on a scale of excellent, good, moderate or none - assessed by the operating surgeon at completion of surgery
  • For elective surgery: an overall assessment of hemostatic efficacy 24 hours and on Day 7 and Day 14 after the last perioperative infusion of rVWF [ Time Frame: 24 hours and on Day 7 and Day 14 after the last perioperative infusion of rVWF ]
    Score on a scale of excellent, good, moderate or none - assessed by the Investigator
  • Daily intra- and postoperative weight-adjusted dose [ Time Frame: Day 0 (surgery day) through postoperative day 14 ]
    Daily intra- and postoperative weight-adjusted dose of rVWF with or without ADVATE
Original Secondary Outcome Measures  ICMJE
 (submitted: November 22, 2016)
  • Number of participants with reduction of annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding episodes during prophylaxis relative to the participants' own historical ABR during on-demand treatment [ Time Frame: Approximately 1 year ]
  • Number of participants with zero bleeds during prophylactic treatment with recombinant von Willebrand factor (rVWF) [ Time Frame: Approximately 1 year ]
  • Number of infusions of recombinant von Willebrand factor (rVWF) and ADVATE per month during on-demand treatment [ Time Frame: Approximately 1 year ]
  • Number of infusions of recombinant von Willebrand factor (rVWF) and ADVATE per year during on-demand treatment [ Time Frame: Approximately 1 year ]
  • Total weight adjusted consumption of recombinant von Willebrand factor (rVWF) and ADVATE per month on-demand treatment [ Time Frame: Approximately 1 year ]
  • Total weight adjusted consumption of recombinant von Willebrand factor (rVWF) and ADVATE per year on-demand treatment [ Time Frame: Approximately 1 year ]
  • Incidence of thromboembolic events [ Time Frame: Throughout the study period of approximately 22 months ]
  • Incidence of severe hypersensitivity reactions [ Time Frame: Throughout the study period of approximately 22 months ]
  • Number of participants who develop neutralizing antibodies to recombinant von Willebrand factor (rVWF) and Factor VIII (FVIII) [ Time Frame: Throughout the study period of approximately 22 months ]
  • Number of participants who develop total binding antibodies to recombinant von Willebrand factor (rVWF) and Factor VIII (FVIII) [ Time Frame: Throughout the study period of approximately 22 months ]
  • Number of participants who develop antibodies to Chinese hamster ovary (CHO) proteins, mouse immunoglobulin G (IgG) and rFurin [ Time Frame: Throughout the study period of approximately 22 months ]
  • Pharmacokinetics - Incremental recovery (IR) [ Time Frame: 30 minutes pre-infusion; and post-infusion at 30 minutes and 1, 6, 12, 24. 48, and 72 hours ]
  • Pharmacokinetics - Terminal half-life (T1/2) [ Time Frame: 30 minutes pre-infusion; and post-infusion at 30 minutes and 1, 6, 12, 24. 48, and 72 hours ]
  • Pharmacokinetics - Mean residence time (MRT) [ Time Frame: 30 minutes pre-infusion; and post-infusion at 30 minutes and 1, 6, 12, 24. 48, and 72 hours ]
  • Pharmacokinetics - Area under the curve/dose (AUC/dose) [ Time Frame: 30 minutes pre-infusion; and post-infusion at 30 minutes and 1, 6, 12, 24. 48, and 72 hours ]
  • Pharmacokinetics - Area under moment curve/dose (AUMC/dose) [ Time Frame: 30 minutes pre-infusion; and post-infusion at 30 minutes and 1, 6, 12, 24. 48, and 72 hours ]
  • Pharmacokinetics - Volume of distribution at steady state (Vss) [ Time Frame: 30 minutes pre-infusion; and post-infusion at 30 minutes and 1, 6, 12, 24. 48, and 72 hours ]
  • Pharmacokinetics - Clearance (CL) [ Time Frame: 30 minutes pre-infusion; and post-infusion at 30 minutes and 1, 6, 12, 24. 48, and 72 hours ]
  • Number of infusions of recombinant von Willebrand factor (rVWF) and ADVATE (rFVIII) per spontaneous bleeding episode (BE) [ Time Frame: Throughout the study period, up to approximately 22 months ]
  • Number of infusions of recombinant von Willebrand factor (rVWF) and ADVATE (rFVIII) per traumatic bleeding episode (BE) [ Time Frame: Throughout the study period, up to approximately 22 months ]
  • Weight-adjusted consumption of recombinant von Willebrand factor (rVWF) and ADVATE (rFVIII) per spontaneous bleeding episode (BE) [ Time Frame: Throughout the study period, up to approximately 22 months ]
  • Weight-adjusted consumption of recombinant von Willebrand factor (rVWF) and ADVATE (rFVIII) per traumatic bleeding episode (BE) [ Time Frame: Throughout the study period, up to approximately 22 months ]
  • Overall hemostatic efficacy rating at resolution of bleed [ Time Frame: Throughout the study period, up to approximately 22 months ]
    Using a 4-point scale: Excellent, Good, Moderate, None
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE rVWF IN PROPHYLAXIS
Official Title  ICMJE A PROSPECTIVE, PHASE 3, OPEN-LABEL, INTERNATIONAL MULTICENTER STUDY ON EFFICACY AND SAFETY OF PROPHYLAXIS WITH rVWF IN SEVERE VON WILLEBRAND DISEASE
Brief Summary The purpose of this phase 3 study is to investigate the efficacy and safety, including immunogenicity and thrombogenicity of prophylactic treatment with recombinant von Willebrand factor (rVWF) in subjects with severe von Willebrand disease (VWD).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Von Willebrand Disease
Intervention  ICMJE
  • Biological: von Willebrand factor (Recombinant)
    Packaged in boxes with 2 glass vials, one containing the lyophilized rVWF, and the second vial containing the diluent.
    Other Names:
    • VONVENDI
    • BAX111
    • rVWF
    • BAX 111
  • Biological: Antihemophilic Factor (Recombinant)
    Packaged in boxes with 2 glass vials, one containing the lyophilized rFVIII, and the second vial containing the diluent
    Other Names:
    • ADVATE
    • Recombinant Factor VIII
    • rFVIII
Study Arms  ICMJE Experimental: All Study Participants
Participants with severe von Willebrand disease (VWD)
Interventions:
  • Biological: von Willebrand factor (Recombinant)
  • Biological: Antihemophilic Factor (Recombinant)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 24, 2018)
22
Original Estimated Enrollment  ICMJE
 (submitted: November 22, 2016)
18
Estimated Study Completion Date  ICMJE May 20, 2019
Estimated Primary Completion Date May 20, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Participant has a documented diagnosis of severe von Willebrand disease (VWD) (baseline Von Willebrand factor: Ristocetin cofactor activity (VWF:RCo) <20 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 (VWF:Ag ≤3 IU/dL).
  2. Diagnosis is confirmed by genetic testing and multimer analysis, documented in patient history or at screening.
  3. Participant currently receiving on-demand treatment for whom prophylactic treatment is recommended according to standard of care at the center.
  4. Has ≥3 documented spontaneous bleeds requiring von Willebrand factor (VWF) treatment during the past 12 months
  5. Availability of records to reliably evaluate type, frequency and treatment of bleeding episodes during 12 months of on-demand treatment prior to enrollment.
  6. Participant is ≥18 years old at the time of screening and has a body mass index ≥15 but <40 kg/m^2.
  7. 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.
  8. Participant is willing and able to comply with the requirements of the protocol.

Exclusion Criteria:

  1. 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 elevated prothrombin time (PT)/ international normalized ratio (INR) >1.4).
  2. Participant has received prophylaxis treatment in the 12 months prior to screening (including those who received treatment once a month for menorrhagia but were not treated for any other bleeds).
  3. Participant is currently receiving prophylaxis treatment.
  4. Participant has a history or presence of a VWF inhibitor at screening.
  5. Participant has a history or presence of a Factor VIII (FVIII) inhibitor with a titer ≥0.4 BU (by Nijmegen modified Bethesda assay) or ≥0.6 Bethesda Unit (BU) (by Bethesda assay).
  6. Participant has a known hypersensitivity to any of the components of the study drugs, such as to mouse or hamster proteins.
  7. Participant has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
  8. Participant has a medical history of a thromboembolic event.
  9. Participant is human immunodeficiency virus (HIV) positive with an absolute Helper T cell (CD4) count <200/mm^3.
  10. 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 (ULN); hypoalbuminemia; portal vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal varices).
  11. Participant has been diagnosed with renal disease, with a serum creatinine level ≥2.5 mg/dL.
  12. Participant has a platelet count <100,000/mL at screening.
  13. 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. Participant is pregnant or lactating at the time of enrollment.
  15. Participant has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, dysplasia).
  16. 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. Participant has a progressive fatal disease and/or life expectancy of less than 15 months.
  18. Participant is identified by the investigator as being unable or unwilling to cooperate with study procedures.
  19. The subject 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.
  20. Participant is in prison or compulsory detention by regulatory and/or juridical order.
  21. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Sanhita Abrol, PhD +1 617-588-8550 sanhita.abrol1@shire.com
Listed Location Countries  ICMJE France,   Germany,   Italy,   Netherlands,   Russian Federation,   Spain,   Turkey,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02973087
Other Study ID Numbers  ICMJE 071301
2016-001478-14 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Shire ( Baxalta now part of Shire )
Study Sponsor  ICMJE Baxalta now part of Shire
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Arthur Sytkowski, MD Baxalta now part of Shire
PRS Account Shire
Verification Date March 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP