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

This study has been completed.
Sponsor:
Collaborator:
Baxter Innovations GmbH
Information provided by (Responsible Party):
Baxter Healthcare Corporation
ClinicalTrials.gov Identifier:
NCT01410227
First received: August 4, 2011
Last updated: March 10, 2014
Last verified: March 2014
  Purpose

The purpose of this Phase 3 study is to assess the pharmacokinetics of rVWF:rFVIII and rVWF, and to assess the safety and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding events in subjects with severe hereditary von Willebrand disease (VWD).


Condition Intervention Phase
Von Willebrand Disease
Biological: Recombinant von Willebrand factor (rVWF) with or without rFVIII (Advate)
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 3 Clinical Study to Determine the Pharmacokinetics, Safety and Efficacy of Recombinant Von Willebrand Factor : Recombinant Factor VIII (rVWF:rFVIII) and rVWF in the Treatment of Bleeding Episodes in Subjects Diagnosed With Von Willebrand Disease

Resource links provided by NLM:


Further study details as provided by Baxter Healthcare Corporation:

Primary Outcome Measures:
  • Number of participants with treatment success for treated bleeding episodes [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    Treatment success will be defined as a mean efficacy rating score of < 2.5 for a participant´s bleeding episodes treated with the investigational product while in a treatment period. Scores used to assess the extent of control of the bleeding episodes: Excellent = 1, Good = 2, Moderate = 3, None = 4.


Secondary Outcome Measures:
  • Number of treated bleeding episodes with an efficacy rating of "excellent" or "good" [ Time Frame: 12 months ] [ Designated as safety issue: No ]

    Minor and moderate bleeding events:

    Excellent

    • Actual number of infusions ≤ estimated number of infusions required to treat that bleeding episode
    • No additional VWF containing coagulation factor containing product required

    Good

    • 1-2 infusions greater than estimated required to control that bleeding episode
    • No additional VWF containing coagulation factor containing product required

    Major bleeding events:

    Excellent (1)

    • Actual number of infusions ≤ estimated number of infusions required to treat that bleeding episode
    • No additional VWF containing coagulation factor containing product required

    Good (2)

    • <1.5x infusions greater than estimated required to control that bleeding episode
    • No additional VWF containing coagulation factor containing product required

  • Number of infusions and number of units of Recombinant von Willebrand factor (rVWF): recombinant Factor VIII (rFVIII) and/or rVWF per bleeding episode [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Development of inhibitory and total binding anti-Von Willebrand factor (VWF) antibodies [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Development of inhibitory antibodies to Factor VIII (FVIII) [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Development of antibodies to Chinese hamster ovary (CHO) proteins, mouse immunoglobulin G (IgG) or recombinant Furin (rFurin) [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Occurrence of thrombotic events [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Other investigational product (IP) related adverse events (AEs) [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Pharmacokinetics: Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Pharmacokinetics: area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Pharmacokinetics: mean residence time (MRT) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Pharmacokinetics: clearance (CL) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Pharmacokinetics: incremental recovery (IR) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Pharmacokinetics: elimination phase half-life (T1/2) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Pharmacokinetics: volume of distribution at steady state (Vss) of Von Willebrand factor (VWF) Ristocetin cofactor (VWF:RCo), VWF antigen (VWF:Ag), VWF collagen-binding (VWF:CB), and Factor VIII (FVIII) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Pharmacokinetics: In vivo recovery (IVR) of Von Willebrand factor (VWF) Ristocetin cofactor (VWF:RCo); VWF antigen (VWF:Ag); VWF collagen-binding (VWF:CB) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Pharmacokinetics: Comparison of intra-subject PK of Von Willebrand factor (VWF) Ristocetin cofactor (VWF:RCo); VWF collagen-binding (VWF:CB); and VWF antigen (VWF:Ag) [ Time Frame: baseline and after 6 months ] [ Designated as safety issue: No ]

Enrollment: 49
Study Start Date: September 2011
Study Completion Date: February 2014
Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PK 80 Arm (minimum of 22 subjects with severe VWD)
PK assessment (80 IU/kg rVWF) + 12-month treatment period
Biological: Recombinant von Willebrand factor (rVWF) with or without rFVIII (Advate)
Intravenous administration
Experimental: PK 50 Arm (14 subjects with type 3 VWD)
Two single-blinded PK assessments (50 IU/kg rVWF + rFVIII/placebo) + 12-month treatment period
Biological: Recombinant von Willebrand factor (rVWF) with or without rFVIII (Advate)
Intravenous administration
Experimental: PK 50 Only Arm (minimum of 7 subjects with type 3 VWD)
PK assessment (50 IU/kg rVWF) only, no treatment of bleeding episodes
Biological: Recombinant von Willebrand factor (rVWF) with or without rFVIII (Advate)
Intravenous administration
Experimental: Treatment Only (up to 7 subjects independent of VWD subtype)
Treatment of bleeding episodes for a total of 12 months
Biological: Recombinant von Willebrand factor (rVWF) with or without rFVIII (Advate)
Intravenous administration

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participant has been diagnosed with:

    1. Type 1 (Von Willebrand factor: Ristocetin cofactor activity (VWF:RCo) < 20 IU/dL) or,
    2. Type 2A (VWF:RCo < 20 IU/dL), Type 2B (as diagnosed by genotype), Type 2N (Factor VIII activity (FVIII:C) <10% and historically documented genetics), Type 2M or,
    3. Type 3 ( Von Willebrand factor antigen (VWF:Ag) ≤ 3 IU/dL) or,
    4. Severe Von Willebrand disease (VWD) with a history of requiring substitution therapy with von Willebrand factor concentrate to control bleeding
  • Participant, who participates in the treatment for bleeding episodes, has had a minimum of 1 documented bleed (medical history) requiring VWF coagulation factor replacement therapy during the previous 12 months prior to enrollment.
  • Participant has a Karnofsky score ≥ 60%
  • Participant is at least 18 and not older than 65 years of age at enrollment
  • If female of childbearing potential, participant presents with a negative pregnancy test
  • Participant agrees to employ adequate birth control measures for the duration of the study
  • Participant is willing and able to comply with the requirements of the protocol

Exclusion Criteria:

  • Participant has been diagnosed with pseudo VWD or another hereditary or acquired coagulation disorder other than VWD (eg qualitative and quantitative platelet disorders or elevated PT/international normalized ratio [INR] >1.4).
  • Participant has a documented history of a VWF:RCo half-life of <6 hours.
  • Participant has a history or presence of a VWF inhibitor at screening.
  • Participant has a history or presence of a factor VIII (FVIII) inhibitor with a titer ≥0.4 BU (by Nijmegen assay) or ≥ 0.6 BU (by Bethesda assay).
  • Participant has a known hypersensitivity to any of the components of the study drugs, such as mouse or hamster proteins.
  • Participant has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
  • Participant has a medical history of a thromboembolic event.
  • Participant is HIV positive with an absolute CD4 count <200/mm3.
  • Participant has been diagnosed with cardiovascular disease (New York Heart Association [NYHA] classes 1-4.
  • Participant has an acute illness (eg, influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) at screening.
  • Participant has been diagnosed with significant liver disease as evidenced by any of the following: serum alanine aminotransferase (ALT) 5 times the upper limit of normal; hypoalbuminemia; portal vein hypertension (eg, presence of otherwise unexplained splenomegaly, history of esophageal varices).
  • Participant has been diagnosed with renal disease, with a serum creatinine level ≥2 mg/dL.
  • In the judgment of the investigator, the participant has another clinically significant concomitant disease (eg, uncontrolled hypertension) that may pose additional risks for the participant.
  • Participant has been treated with an immunomodulatory drug, excluding topical treatment (eg, ointments, nasal sprays), within 30 days prior to enrollment
  • Participant is pregnant or lactating at the time of enrollment.
  • Participant has participated in another clinical study involving an IP or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an investigational product or investigational device during the course of this study.
  • Participant has a history of drug or alcohol abuse within the 2 years prior to enrollment.
  • Participant has a progressive fatal disease and/or life expectancy of less than 3 months.
  • Participant is identified by the investigator as being unable or unwilling to cooperate with study procedures.
  • Participant suffers from a mental condition rendering him/her unable to understand the nature, scope and possible consequences of the study and/or evidence of an uncooperative attitude.
  • Participant is in prison or compulsory detention by regulatory and/or juridical order
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01410227

  Show 52 Study Locations
Sponsors and Collaborators
Baxter Healthcare Corporation
Baxter Innovations GmbH
Investigators
Study Director: Isabella Presch, MD, MBA Baxter Innovations GmbH
  More Information

No publications provided

Responsible Party: Baxter Healthcare Corporation
ClinicalTrials.gov Identifier: NCT01410227     History of Changes
Other Study ID Numbers: 071001, 2010-024108-84
Study First Received: August 4, 2011
Last Updated: March 10, 2014
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration
Austria: Agency for Health and Food Safety
Belgium: Federal Agency for Medicinal Products and Health Products
Bulgaria: Bulgarian Drug Agency
Canada: Health Canada
Germany: Paul-Ehrlich-Institut
India: Drugs Controller General of India
Italy: The Italian Medicines Agency
Japan: Pharmaceuticals and Medical Devices Agency
Netherlands: Medicines Evaluation Board (MEB)
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Russia: FSI Scientific Center of Expertise of Medical Application
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Sweden: Medical Products Agency
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration

Additional relevant MeSH terms:
Hemorrhage
Von Willebrand Diseases
Pathologic Processes
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Blood Platelet Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn

ClinicalTrials.gov processed this record on April 16, 2014