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rVWF Pediatric and Adult Study

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ClinicalTrials.gov Identifier: NCT03879135
Recruitment Status : Recruiting
First Posted : March 18, 2019
Last Update Posted : March 16, 2021
Sponsor:
Collaborator:
Baxalta Innovations GmbH, now part of Shire
Information provided by (Responsible Party):
Takeda ( Baxalta now part of Shire )

Tracking Information
First Submitted Date  ICMJE December 20, 2018
First Posted Date  ICMJE March 18, 2019
Last Update Posted Date March 16, 2021
Actual Study Start Date  ICMJE April 1, 2019
Estimated Primary Completion Date March 25, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 15, 2019)
Spontaneous annualized bleeding rate (ABR) [ Time Frame: First 12 months of treatment ]
Spontaneous ABR during prophylaxis treatment with rVWF (vonicog alfa)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 15, 2019)
  • Adverse events (AEs)/serious adverse events (SAEs) [ Time Frame: Throughout the study participation period, up to 3 years ]
    AEs/ SAEs: incidence, severity, causality
  • Thromboembolic events [ Time Frame: Throughout the study participation period, up to 3 years ]
    Occurrence of thromboembolic events
  • Hypersensitivity reactions [ Time Frame: Throughout the study participation period, up to 3 years ]
    Occurrence of hypersensitivity reactions
  • Number of participants who develop neutralizing antibodies to VWF [ Time Frame: Throughout the study participation period, up to 3 years ]
    Number of participants who develop neutralizing antibodies (inhibitors) to von Willebrand factor (VWF)
  • Number of participants who develop neutralizing antibodies to FVIII [ Time Frame: Throughout the study participation period, up to 3 years ]
    Number of participants who develop neutralizing antibodies (inhibitors) to Factor VIII (FVIII)
  • Number of participants who develop total binding antibodies to VWF [ Time Frame: Throughout the study participation period, up to 3 years ]
    Number of participants who develop total binding antibodies to von Willebrand factor (VWF)
  • Number of participants who develop total binding antibodies to FVIII [ Time Frame: Throughout the study participation period, up to 3 years ]
    Number of participants who develop total binding antibodies to Factor VIII (FVIII)
  • Number of participants who develop binding antibodies to CHO proteins [ Time Frame: Throughout the study participation period, up to 3 years ]
    Number of participants who develop binding antibodies to Chinese hamster ovary (CHO) proteins
  • Number of participants who develop binding antibodies to mouse IgG [ Time Frame: Throughout the study participation period, up to 3 years ]
    Number of participants who develop binding antibodies to mouse immunoglobulin G (IgG)
  • Number of participants who develop binding antibodies to rFurin [ Time Frame: Throughout the study participation period, up to 3 years ]
    Number of participants who develop binding antibodies to recombinant Furin (rFurin)
  • Number of Participants with Clinically Significant Changes in Vital Signs Reported as Adverse Events [ Time Frame: Throughout the study participation period, up to 3 years ]
    Clinically significant changes in vital signs (body temperature, blood pressure, respiration and pulse) will be assessed from baseline up to 3 years
  • Number of Participants with Clinically Significant Changes in Laboratory Parameters Reported as Adverse Events [ Time Frame: Throughout the study participation period, up to 3 years ]
    Clinically significant changes in laboratory parameters (clinical chemistry, fasting lipid panel and determination of fat-soluble vitamins, bile acids and other cholestasis biochemical markers) will be assessed from baseline up to 3 years
  • Spontaneous ABR under prophylactic treatment [ Time Frame: Throughout the study participation period, up to 3 years ]
    Spontaneous ABR under prophylactic treatment with rVWF (vonicog alfa) while enrolled in the study
  • Categorized weekly number of infusions [ Time Frame: Throughout the study participation period, up to 3 years ]
    Categorized as 1, 2 or ≥ 3 during prophylactic treatment with rVWF (vonicog alfa)
  • Categorized spontaneous annualized bleeding rate (ABR) [ Time Frame: Throughout the study participation period, up to 3 years ]
    Categorized as 0, 1-2, 3-5, or >5 bleeding episodes during rVWF (vonicog alfa) prophylaxis
  • Time to first bleeding event [ Time Frame: Throughout the study participation period, up to 3 years ]
    Under each prophylaxis regimen
  • Spontaneous ABR by location of bleeding [ Time Frame: Throughout the study participation period, up to 3 years ]
    Gastrointestinal [GI], epistaxis, joint bleeding, menorrhagia, oral, muscle and soft tissue, etc.) while on prophylactic treatment with rVWF (vonicog alfa
  • Total number of infusions [ Time Frame: Throughout the study participation period, up to 3 years ]
    Total number of infusions during prophylactic treatment with rVWF (vonicog alfa)
  • Average number of infusions [ Time Frame: Throughout the study participation period, up to 3 years ]
    Per week during prophylactic treatment with rVWF (vonicog alfa)
  • Total weight adjusted consumption of rVWF (vonicog alfa) [ Time Frame: Throughout the study participation period, up to 3 years ]
    During prophylactic treatment
  • Number of participants who achieve transfusion free maintenance of hemoglobin levels [ Time Frame: Throughout the study participation period, up to 3 years ]
    Transfusion free maintenance of hemoglobin levels over time
  • Duration of transfusion-free maintenance of hemoglobin levels [ Time Frame: Throughout the study participation period, up to 3 years ]
    Length of transfusion-free maintenance of hemoglobin levels
  • Number of participants who achieve transfusion free maintenance of plasma ferritin levels [ Time Frame: Throughout the study participation period, up to 3 years ]
    Transfusion free maintenance of plasma ferritin levels over time
  • Duration of transfusion-free maintenance of plasma ferritin levels [ Time Frame: Throughout the study participation period, up to 3 years ]
    Length of transfusion-free maintenance of plasma ferritin levels
  • Overall hemostatic efficacy rating [ Time Frame: Initial 12 months of study ]
    At the resolution of bleed with respect to the treatment of bleeding episodes for the initial 12 months of study
  • Number of infusions [ Time Frame: Throughout the study participation period, up to 3 years ]
    Number of infusions of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) utilized to treat bleeding episodes while enrolled in the study
  • Weight-adjusted consumption [ Time Frame: Throughout the study participation period, up to 3 years ]
    Weight-adjusted consumption of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) per bleeding episode while enrolled in the study
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE rVWF Pediatric and Adult Study
Official Title  ICMJE A Phase 3b, Prospective, Open-label, Uncontrolled, Multicenter Study on Long-term Safety and Efficacy of rVWF in Pediatric and Adult Subjects With Severe Von Willebrand Disease (VWD)
Brief Summary This study will evaluate the long-term safety and hemostatic efficacy of recombinant von Willebrand factor (rVWF) (vonicog alfa) prophylaxis in adult and pediatric participants (aged 12 to <18 years) with severe von Willebrand disease (VWD) with the option of once weekly dosing, and to further assess the safety and efficacy of rVWF in on-demand (OD) treatment of bleeding episodes, and in perioperative management of surgical bleeding.
Detailed Description 22 JUN 2020: The temporary enrollment stop of new patients into this study due to the COVID-10 pandemic has been lifted in one or more countries/sites, and the study is now again enrolling new patients. However, some countries/sites may still have paused the enrollment of new patients due to the pandemic.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Von Willebrand Disease
Intervention  ICMJE
  • Biological: rVWF
    Recombinant von Willebrand factor
    Other Names:
    • Vonvendi
    • Vonicog alfa
  • Biological: rFVIII
    Recombinant Factor VIII
    Other Names:
    • Octocog alfa
    • ADVATE
Study Arms  ICMJE
  • Experimental: On-Demand
    Participants will receive recombinant von Willebrand factor (rVWF) (with or without ADVATE).
    Interventions:
    • Biological: rVWF
    • Biological: rFVIII
  • Experimental: Prophylaxis
    Participants will receive recombinant von Willebrand factor (rVWF) (with or without ADVATE).
    Interventions:
    • Biological: rVWF
    • Biological: rFVIII
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: March 15, 2019)
64
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 25, 2025
Estimated Primary Completion Date March 25, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

The participant will not be considered eligible for the study without meeting all of the criteria below.

Participants who have completed Study 071301 or Study 071102 (or participants who have completed the surgery in Study 071102 and want to continue to receive on-demand (OD) treatment) and are willing to immediately transition into this study, must meet the following 2 criteria to be eligible for this study:

  1. If female of childbearing potential, has a negative blood/urine pregnancy test at screening and agrees to employ highly effective birth control measures for the duration of the study.
  2. Participant and/or legally authorized representative is willing and able to comply with the requirements of the protocol.

    New participants (Cohort 4) who meet the above 2 and ALL the following additional criteria are eligible for this study:

  3. Participant has a documented diagnosis of severe von Willebrand disease (VWD) (baseline von Willebrand factor: Ristocetin cofactor (VWF:RCo) <20 IU/dL) with a history of requiring substitution therapy with von Willebrand factor (vWF) 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) ≤3 IU/dL). Diagnosis is confirmed by genetic testing and multimer analysis, documented in patient history or at screening.
  4. Participant has been receiving OD therapy with VWF products for at least 12 months, and prophylactic treatment is recommended by the investigator.
  5. Participant has ≥3 documented spontaneous bleeds (not including menorrhagia) requiring VWF treatment during the past 12 months.
  6. Participant has available records that reliably evaluate type, frequency, and treatment of bleeding episodes for at least 12 months preceding enrollment; up to 24 months of retrospective data should be collected if available.
  7. Participant is ≥12 years old at the time of screening and has a body mass index ≥15 but <40 kg/m^2.

Exclusion Criteria:

The participant will be excluded from the study if any of the following exclusion criteria are met.

  1. The participant has been diagnosed with Type 2N 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. The participant has a history or presence of a VWF inhibitor at screening.
  3. 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 ≥0.6 BU (by Bethesda assay).
  4. The participant has a known hypersensitivity to any of the components of the study drugs, such as mouse or hamster proteins.
  5. The participant has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies, or animal allergies.
  6. The participant has a medical history of a thromboembolic event.
  7. The participant is human immunodeficiency virus (HIV) positive with an absolute Helper T cell (CD4) count <200/mm^3.
  8. 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, but not limited to any of the following: serum alanine aminotransferase (ALT) greater than 5 times the upper limit of normal; hypoalbuminemia; portal vein hypertension (eg, presence of otherwise unexplained splenomegaly, history of esophageal varices) or liver cirrhosis classified as Child-Pugh class B or C.
  9. The participant has been diagnosed with renal disease, with a serum creatinine (CR) level ≥2.5 mg/dL.
  10. The participant has a platelet count <100,000/mL at screening.
  11. The participant has been treated with an immunomodulatory drug, excluding topical treatment (eg, ointments, nasal sprays), within 30 days prior to signing the informed consent (or assent, if appropriate).
  12. The participant is pregnant or lactating at the time of enrollment.
  13. The participant has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, dysplasia).
  14. 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.
  15. The participant has a progressive fatal disease and/or life expectancy of less than 15 months.
  16. For new OD subjects, the participant is scheduled for a surgical intervention.
  17. The participant is identified by the investigator as being unable or unwilling to cooperate with study procedures.
  18. 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.
  19. 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.

Delay criteria Only for Cohort 4, if the participant presents with an acute bleeding episodes or acute illness (eg, influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, and non-seasonal asthma) the screening visit will be postponed until the participant has recovered. For all other participants, end of study (EOS) visit for 071102 or 071301 will be completed per protocol and the completed EOS in Study 071102 or 071301 will also serve as the screening visit for this continuation study (SHP677-304).

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Shire Contact +1 866 842 5335 ClinicalTransparency@shire.com
Listed Location Countries  ICMJE France,   Italy,   Netherlands,   Russian Federation,   Spain,   Turkey,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03879135
Other Study ID Numbers  ICMJE SHP677-304
2018-003453-16 ( EudraCT Number )
Has Data Monitoring Committee No
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
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
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: 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/
Responsible Party Takeda ( Baxalta now part of Shire )
Study Sponsor  ICMJE Baxalta now part of Shire
Collaborators  ICMJE Baxalta Innovations GmbH, now part of Shire
Investigators  ICMJE
Study Director: Study Director Shire
PRS Account Takeda
Verification Date March 2021

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