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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 )

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).

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 22 participants
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 : December 22, 2017
Estimated Primary Completion Date : May 20, 2019
Estimated Study Completion Date : May 20, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: All Study Participants
Participants with severe von Willebrand disease (VWD)
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




Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. 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 ]
  2. Number of participants with zero bleeds during prophylactic treatment with recombinant von Willebrand factor (rVWF) [ Time Frame: Approximately 1 year ]
  3. 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 ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. Incidence of thromboembolic events [ Time Frame: Throughout the study period of approximately 22 months ]
  8. Incidence of severe hypersensitivity reactions [ Time Frame: Throughout the study period of approximately 22 months ]
  9. 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 ]
  10. 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 ]
  11. 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 ]
  12. 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 ]
  13. 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 ]
  14. 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 ]
  15. 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 ]
  16. 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 ]
  17. 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 ]
  18. Pharmacokinetics - Clearance (CL) [ Time Frame: 30 minutes pre-infusion; and post-infusion at 30 minutes and 1, 6, 12, 24. 48, and 72 hours ]
  19. 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 ]
  20. 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 ]
  21. 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 ]
  22. 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 ]
  23. 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

  24. 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

  25. 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

  26. 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

  27. 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



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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) <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.

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


Contacts
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Contact: Sanhita Abrol, PhD +1 617-588-8550 sanhita.abrol1@shire.com

Locations
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United States, Florida
University of Florida College of Medicine Recruiting
Gainesville, Florida, United States, 32610
United States, Illinois
Bleeding and Clotting Disorders Institute Recruiting
Peoria, Illinois, United States, 61615
United States, Indiana
University of Colorado Health Recruiting
Aurora, Indiana, United States, 80045
Indiana Hemophilia and Thrombosis Center Recruiting
Indianapolis, Indiana, United States, 46260
United States, North Carolina
Comprehensive Cancer Center of Wake Forest Unversity Recruiting
Winston-Salem, North Carolina, United States, 27157
France
Hôpital Morvan Recruiting
Brest Cedex, Finistere, France, 29609
Groupement Hospitalier Est- Hôpital Louis Pradel Recruiting
Bron cedex, France, 69677
CHU CAEN - Hôpital de la Côte de Nacre Recruiting
Caen cedex 9, France, 14033
CHU Dijon - Hopital du Bocage Recruiting
Dijon cedex, France, 21079
Hopital Cardiologique - CHU Lille Recruiting
Lille Cedex, France, 59037
Germany
Coagulation Research Centre GmbH Recruiting
Duisburg, Germany, 47051
Werlhof-Institut GmbH Recruiting
Hannover, Germany, 30159
Medizinische Hochschule Hannover Recruiting
Marburg, Germany, 30625
Italy
Ospedale Pediatrico Bambino Gesù Recruiting
Rome, Roma, Italy, 165
Azienda Ospedaliera Universitaria Careggi Recruiting
Firenze, Italy, 50134
Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico Recruiting
Milano, Italy, 20122
Netherlands
Erasmus Medisch Centrum Recruiting
Rotterdam, Netherlands, 3015 CE
Russian Federation
SAIH "Kemerovo Regional Clinical Hospital" Recruiting
Kemerovo, Russian Federation, 650066
FSBI of Science "Kirov Scientific and Research Institute of Hematology and Blood Transfusion of FMBA Recruiting
Kirov, Russian Federation, 610027
Spain
Hospital General Universitario de Alicante Recruiting
Alicante, Spain, 3010
Hospital Universitario La Paz Recruiting
Madrid, Spain, 28046
Hospital Universitari i Politecnic La Fe Recruiting
Valencia, Spain, 46026
Turkey
Istanbul University Cerrahpasa Medical Faculty Recruiting
Istanbul, Turkey, 34098
Ege University Medical Faculty Recruiting
Izmir, Turkey, 35040
Ege University Medical Faculty Recruiting
Izmir, Turkey, 35100
Ondokuz Mayis Univ. Med. Fac. Recruiting
Samsun, Turkey, 55139
Sponsors and Collaborators
Baxalta now part of Shire
Investigators
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Study Director: Arthur Sytkowski, MD Baxalta now part of Shire

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Responsible Party: Baxalta now part of Shire
ClinicalTrials.gov Identifier: NCT02973087     History of Changes
Other Study ID Numbers: 071301
2016-001478-14 ( EudraCT Number )
First Posted: November 25, 2016    Key Record Dates
Last Update Posted: March 6, 2018
Last Verified: March 2018

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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