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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 : February 18, 2020
Sponsor:
Collaborator:
Baxalta Innovations GmbH, now part of Shire
Information provided by (Responsible Party):
Shire ( Baxalta now part of Shire )

Study Description
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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.

Condition or disease Intervention/treatment Phase
Von Willebrand Disease Biological: rVWF Biological: rFVIII Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: 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)
Actual Study Start Date : April 1, 2019
Estimated Primary Completion Date : June 30, 2021
Estimated Study Completion Date : June 30, 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: On-Demand
Participants will receive recombinant von Willebrand factor (rVWF) (with or without ADVATE).
 Biological: rVWF
Recombinant von Willebrand factor
Other Names:
  • Vonvendi
  • Vonicog alfa

Biological: rFVIII
Recombinant Factor VIII
Other Names:
  • Octocog alfa
  • ADVATE
Experimental: Prophylaxis
Participants will receive recombinant von Willebrand factor (rVWF) (with or without ADVATE).
 Biological: rVWF
Recombinant von Willebrand factor
Other Names:
  • Vonvendi
  • Vonicog alfa

Biological: rFVIII
Recombinant Factor VIII
Other Names:
  • Octocog alfa
  • ADVATE


Outcome Measures
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Primary Outcome Measures :
  1. Spontaneous annualized bleeding rate (ABR) [ Time Frame: First 12 months of treatment ]
    Spontaneous ABR during prophylaxis treatment with rVWF (vonicog alfa)


Secondary Outcome Measures :
  1. Adverse events (AEs)/serious adverse events (SAEs) [ Time Frame: Throughout the study participation period, up to 3 years ]
    AEs/ SAEs: incidence, severity, causality

  2. Thromboembolic events [ Time Frame: Throughout the study participation period, up to 3 years ]
    Occurrence of thromboembolic events

  3. Hypersensitivity reactions [ Time Frame: Throughout the study participation period, up to 3 years ]
    Occurrence of hypersensitivity reactions

  4. 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)

  5. 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)

  6. 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)

  7. 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)

  8. 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

  9. 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)

  10. 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)

  11. 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

  12. 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

  13. 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

  14. 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)

  15. 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

  16. Time to first bleeding event [ Time Frame: Throughout the study participation period, up to 3 years ]
    Under each prophylaxis regimen

  17. 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

  18. 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)

  19. Average number of infusions [ Time Frame: Throughout the study participation period, up to 3 years ]
    Per week during prophylactic treatment with rVWF (vonicog alfa)

  20. Total weight adjusted consumption of rVWF (vonicog alfa) [ Time Frame: Throughout the study participation period, up to 3 years ]
    During prophylactic treatment

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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


Eligibility Criteria
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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:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).

Contacts and Locations
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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): NCT03879135


Contacts
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Contact: Shire Contact +1 866 842 5335 ClinicalTransparency@shire.com

Locations
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United States, Colorado
University of Colorado Health Recruiting
Loveland, Colorado, United States, 80045
Contact: Site Contact       michael.wang@ucdenver.edu   
Principal Investigator: Michael Wang, MD         
United States, Indiana
Indiana Hemophilia and Thrombosis Center Recruiting
Indianapolis, Indiana, United States, 46260
Contact: Site contact       ashapiro@ihtc.org   
Principal Investigator: Amy Shapiro, MD         
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Site Contact    513-803-4617    Eric.mullins@cchmc.org   
Principal Investigator: Eric Mullins, MD         
France
Groupement Hospitalier Est- Hôpital Louis Pradel Recruiting
Bron cedex, France, 69677
Contact: Site Contact       lucia.rugeri@chu-lyon.fr   
Principal Investigator: Lucia Rugeri, MD         
Italy
Azienda Ospedaliera Universitaria Careggi Recruiting
Firenze, Italy, 50134
Contact: Site Contact       castaman@aou-careggi.toscana.it   
Principal Investigator: Giancarlo Castaman, MD         
Netherlands
Erasmus Medisch Centrum Recruiting
Rotterdam, Netherlands, 3015 AA
Contact: Site contact       f.leebeek@erasmusmc.nl   
Principal Investigator: Franciscus Leebeek, MD, Ph.D.         
Erasmus Medisch Centrum Recruiting
Rotterdam, Netherlands, 3015 CN
Contact: Site contact       m.cnossen@erasmusmc.nl   
Principal Investigator: Marjon Cnossen, MD, Ph.D.         
Russian Federation
SAIH "Kemerovo Regional Clinical Hospital" Recruiting
Kemerovo, Russian Federation, 650066
Contact: Site Contact       mvkosinova@yandex.ru   
Principal Investigator: Marina Kosinova, MD         
FSBI of Science "Kirov Scientific and Research Institute of Hematology and Blood Transfusion of FMBA Recruiting
Kirov, Russian Federation, 610017
Contact: Site Contact       timofeevamargaret@list.ru   
Principal Investigator: Margarita Timofeeva, MD         
Spain
Hospital General Universitario de Alicante Recruiting
Alicante, Spain, 03010
Contact: Site Contact       marco_pas@gva.es   
Principal Investigator: Pascual Marco Vera, MD         
Hospital Universitario La Paz Recruiting
Madrid, Spain, 28046
Contact: Site Contact       monicamsalces@gmail.com   
Principal Investigator: Monica Martin Salces, MD         
Hospital Universitari i Politecnic La Fe Recruiting
Valencia, Spain, 46026
Contact: Site contact       cid_ana@gva.es   
Principal Investigator: Ana Rosa Cid Haro, MD         
Turkey
Ege University Medical Faculty Recruiting
Izmir, Turkey, 35040
Contact: Site contact       fahri.sahin@ege.edu.tr   
Principal Investigator: Fahri Sahin, MD         
Ege University Medical Faculty Recruiting
Izmir, Turkey, 35100
Contact: Site Contact       kaan.kavakli@ege.edu.tr   
Principal Investigator: Can Balkan, MD         
Ondokuz Mayis Univ. Med. Fac. Recruiting
Samsun, Turkey, 55139
Contact: Site Contact       calbayrak@omu.edu.tr   
Principal Investigator: Canan Albayrak, MD         
Sponsors and Collaborators
Baxalta now part of Shire
Baxalta Innovations GmbH, now part of Shire
Investigators
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Study Director: Study Director Shire
More Information
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Responsible Party: Baxalta now part of Shire
ClinicalTrials.gov Identifier: NCT03879135    
Other Study ID Numbers: SHP677-304
2018-003453-16 ( EudraCT Number )
First Posted: March 18, 2019    Key Record Dates
Last Update Posted: February 18, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Shire provides access to the de-identified individual participant data for eligible studies to aid qualified researchers in addressing legitimate scientific objectives. These IPDs will be provided 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 in the Data Sharing section of the www.shiretrials.com website. 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://www.shiretrials.com/en/our-commitment-to-transparency/data-sharing-with-researchers

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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