A Study of Recombinant Von Willebrand Factor (rVWF) in Pediatric and Adult Participants With Severe Von Willebrand Disease (VWD)

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)

The main aim of the study is to check effectiveness of rVWF (vonicog alfa) prophylaxis based on the annualized bleeding rate (ABR) of spontaneous (not related to trauma) bleeding episodes in pediatric and adult participants during the first 12 months on study treatment.

The participants will be treated with rVWF for a maximum of 3 years. Their von Willebrand Disease will be treated according to Investigational product (IP) dosing directions.

Study Overview

• Status: Recruiting
• Conditions: Von Willebrand Disease (VWD)
• Intervention / Treatment: Biological: rVWF; Biological: rFVIII

• Study Type: Interventional
• Enrollment (Estimated): 71
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Shire Contact; Phone Number: +1 866 842 5335; Email: ClinicalTransparency@takeda.com

Study Locations

• Austria
  • Vienna, Austria
    • Recruiting
    • AKH - Medizinische Universitat Wien
    • Principal Investigator: Male Christoph
    • Contact: Site Contact; Email: christoph.male@meduniwien.ac.at
• France
  • Bron cedex, France, 69677
    • Recruiting
    • Groupement Hospitalier Est- Hôpital Louis Pradel
    • Contact: Site Contact; Email: anne.lienhart@chu-lyon.fr
    • Principal Investigator: Lienhart Anne
  • Gironde, France
    • Completed
    • Groupe Hospitalier Pellegrin - Hôpital Pellegrin
  • Le Kremlin Bicêtre cedex, France, 94270
    • Recruiting
    • Groupement Hospitalier Sud - Hôpital Bicêtre
    • Principal Investigator: D oiron Roseline
    • Contact: Site Contact; Email: roseline.doiron@aphp.fr
  • Nord
    • Lille Cedex, Nord, France
      • Recruiting
      • Hopital Cardiologique - CHU Lille
      • Principal Investigator: Susen Sophie
      • Contact: Site Contact; Email: sophie.susen@chru-lille.fr
  • Paris
    • Paris cedex 15, Paris, France, 75015
      • Recruiting
      • Hopital Necker - Enfants Malades
      • Principal Investigator: Harroche-Angel Annie
      • Contact: Site Contact; Email: annie.harroche@aphp.fr
• Germany
  • Frankfurt, Germany
    • Recruiting
    • Klinikum der Johann Wolfgang Goethe-Universitaet
    • Contact: Site Contact; Email: wolfgang.miesbach@kgu.de
    • Principal Investigator: Miesbach Wolfgang
  • Hannover, Germany
    • Recruiting
    • Werlhof-Institut GmbH
    • Contact: Site Contact; Email: mail@werlhof-institut.de
    • Principal Investigator: von Depka Prondzinski Mario
• Italy
  • Firenze, Italy, 50134
    • Recruiting
    • Azienda Ospedaliera Universitaria Careggi
    • Contact: Site Contact; Email: castaman@aou-careggi.toscana.it
    • Principal Investigator: Giancarlo Castaman, MD
  • Milano, Italy
    • Recruiting
    • Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico
    • Contact: Site Contact; Email: flora.peyvandi@policlinico.mi.it
    • Principal Investigator: Peyvandi Flora
  • Napoli, Italy
    • Recruiting
    • Azienda Ospedaliera Pediatrica Santobono Pausillipon
    • Principal Investigator: Schiavulli Michele
    • Contact: Site Contact; Email: mischiavulli@gmail.com
  • Roma, Italy, 00168
    • Recruiting
    • Fondazione Policlinico Universitario Agostino Gemelli Irccs
    • Contact: Site Contact; Email: raimondo.decristofaro@unicatt.it
    • Principal Investigator: De Cristofaro Raimondo
  • Roma, Italy
    • Recruiting
    • Ospedale Pediatrico Bambino Gesù
    • Principal Investigator: Luciani Matteo
    • Contact: Site Contact; Email: matteo.luciani@opbg.net
  • Roma, Italy, 00185
    • Recruiting
    • Azienda Ospedaliera Universitaria Policlinico Umberto I - Universita di Roma La Sapienza
    • Contact: Site Contact; Email: chistolini@bce.uniroma1.it
    • Principal Investigator: Chistolini Antonio
• Netherlands
  • Rotterdam, Netherlands, 3015 AA
    • Recruiting
    • Erasmus Medisch Centrum
    • Contact: Site contact; Email: f.leebeek@erasmusmc.nl
    • Principal Investigator: Franciscus Leebeek, MD, Ph.D.
  • Rotterdam, Netherlands, 3015 CN
    • Recruiting
    • Erasmus Medisch Centrum
    • Principal Investigator: Marjon Cnossen, MD, Ph.D.
    • Contact: Site contact; Email: m.cnossen@erasmusmc.nl
• Russian Federation
  • Kemerovo, Russian Federation, 650066
    • Completed
    • SAIH "Kemerovo Regional Clinical Hospital"
  • Kirov, Russian Federation, 610017
    • Completed
    • FSBI of Science "Kirov Scientific and Research Institute of Hematology and Blood Transfusion of FMBA
• Spain
  • Alicante, Spain, 03010
    • Recruiting
    • Hospital General Universitario de Alicante
    • Contact: Site Contact; Email: marco_pas@gva.es
    • Principal Investigator: Pascual Marco Vera, MD
  • Madrid, Spain, 28046
    • Recruiting
    • Hospital Universitario La Paz
    • Contact: Site Contact; Email: monicamsalces@gmail.com
    • Principal Investigator: Monica Martin Salces, MD
  • Valencia, Spain, 46026
    • Recruiting
    • Hospital Universitari i Politecnic La Fe
    • Contact: Site contact; Email: cid_ana@gva.es
    • Principal Investigator: Ana Rosa Cid Haro, MD
• Turkey
  • Istanbul, Turkey
    • Recruiting
    • Istanbul University Oncology Institute
    • Principal Investigator: Zulfikar Osman Bulent
    • Contact: Site Contact; Email: bulent.zulfikar@istanbulmedicare.com
  • Izmir, Turkey, 35100
    • Recruiting
    • Ege University Medical Faculty
    • Contact: Site Contact; Email: drcanbalkan@gmail.com
    • Principal Investigator: Can Balkan, MD
  • Izmir, Turkey, 35040
    • Recruiting
    • Ege University Medical Faculty
    • Contact: Site contact; Email: drfahrisahin@gmail.com
    • Principal Investigator: Fahri Sahin, MD
  • Samsun, Turkey, 55139
    • Recruiting
    • Ondokuz Mayis Univ. Med. Fac.
    • Contact: Site Contact; Email: can68ucar@yahoo.com.tr
    • Principal Investigator: Canan Albayrak, MD
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Recruiting
      • Arkansas Children's Hospital Research Institute
      • Contact: Site Contact; Email: stinekimoc@uams.edu
      • Principal Investigator: Stine Kimo
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado Health
      • Contact: Site Contact; Email: michael.wang@ucdenver.edu
      • Principal Investigator: Michael Wang, MD
  • Florida
    • Gainesville, Florida, United States, 32610
      • Recruiting
      • University of Florida College of Medicine
      • Contact: Site Contact; Email: twynn@ufl.edu
      • Principal Investigator: Wynn Tung
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Recruiting
      • Indiana Hemophilia and Thrombosis Center
      • Principal Investigator: Amy Shapiro, MD
      • Contact: Site contact; Email: ashapiro@ihtc.org
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Contact: Site Contact; Phone Number: 513-803-4617; Email: Eric.mullins@cchmc.org
      • Principal Investigator: Mullins Eric, MD
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • Rainbow Babies and Children's Hospital
      • Principal Investigator: Ahuja Sanjay
      • Contact: Site Contact; Email: sanjay.ahuja@uhhospitals.org
    • Columbus, Ohio, United States, 43205
      • Recruiting
      • Nationwide Children's Hospital
      • Principal Investigator: Dunn Amy
      • Contact: Site Contact; Email: amy.dunn@nationwidechildrens.org
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Recruiting
      • Medical University of South Carolina (MUSC)
      • Principal Investigator: Bergmann Shayla
      • Contact: Site Contact; Email: bergmans@musc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 arm treatment 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:

• 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.
• 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:

- Participant has a documented diagnosis of severe von Willebrand disease (VWD) (baseline von Willebrand factor: Ristocetin cofactor (VWF:RCo) <20 International Units per deciliter [IU/dL]) with a history of requiring substitution therapy with von Willebrand factor (vWF) concentrate to control bleeding:

• Type 1 (VWF:RCo <20 IU/dL) or,
• Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2M or,
• Type 3 (Von Willebrand factor antigen (VWF:Ag) less than or equal to (<=) 3 IU/dL).

Diagnosis is confirmed by genetic testing and multimer analysis, documented in participant history or at screening.

• Participant has been receiving OD therapy with VWF products for at least 12 months, and prophylactic treatment is recommended by the investigator.
• Participant has greater than or equal to (>=) 3 documented spontaneous bleeds (not including menorrhagia) requiring VWF treatment during the past 12 months.
• 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.
• Participant is >=12 years old at the time of screening and has a body mass index >=15 but <40 kilogram per meter square (kg/m^2).

Exclusion Criteria:

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

• 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).
• The participant has a history or presence of a VWF inhibitor at screening.
• 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).
• The participant has a known hypersensitivity to any of the components of the study drugs, such as mouse or hamster proteins.
• The participant has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies, or animal allergies.
• The participant has a medical history of a thromboembolic event.
• The participant is human immunodeficiency virus (HIV) positive with an absolute Helper T cell (CD4) count <200/cubic millimeters (mm^3).
• 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.
• The participant has been diagnosed with renal disease, with a serum creatinine (CR) level >=2.5 milligrams per deciliter (mg/dL).
• The participant has a platelet count <100,000/milliliter (mL) at screening.
• 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).
• The participant is pregnant or lactating at the time of enrollment.
• The participant has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, dysplasia).
• 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.
• The participant has a progressive fatal disease and/or life expectancy of less than 15 months.
• For new OD participants, the participant is scheduled for a surgical intervention.
• The participant is identified by the investigator as being unable or unwilling to cooperate with study procedures.
• 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.
• 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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: ADVATE; Octocog alfa
Experimental: Prophylaxis; Participants will receive recombinant von Willebrand factor (rVWF).	Biological: rVWF; Recombinant von Willebrand factor; Other Names: Vonvendi; Vonicog alfa; Biological: rFVIII; Recombinant Factor VIII; Other Names: ADVATE; Octocog alfa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Spontaneous Annualized Bleeding Rate (ABR)	Spontaneous ABR during prophylaxis treatment with rVWF (vonicog alfa)	First 12 months of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events (AEs)/Serious Adverse Events (SAEs)	AEs/ SAEs: incidence, severity, causality	Throughout the study participation period, up to 3 years
Thromboembolic Events	Occurrence of thromboembolic events	Throughout the study participation period, up to 3 years
Hypersensitivity Reactions	Occurrence of hypersensitivity reactions	Throughout the study participation period, up to 3 years
Number of Participants who Develop Neutralizing Antibodies to von Willebrand factor (VWF)	Number of participants who develop neutralizing antibodies (inhibitors) to VWF	Throughout the study participation period, up to 3 years
Number of Participants who Develop Neutralizing Antibodies to Factor VIII (FVIII)	Number of participants who develop neutralizing antibodies (inhibitors) to FVIII	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 VWF	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 total binding antibodies to FVIII	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 CHO proteins	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 mouse IgG	Throughout the study participation period, up to 3 years
Number of Participants who Develop Binding Antibodies to recombinant Furin (rFurin)	Number of participants who develop binding antibodies to rFurin	Throughout the study participation period, up to 3 years
Number of Participants With Clinically Significant Changes in Vital Signs	Clinically significant changes in vital signs (body temperature, blood pressure, respiration and pulse) will be assessed from baseline up to 3 years	Throughout the study participation period, up to 3 years
Number of Participants With Clinically Significant Changes in Laboratory Parameters	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	Throughout the study participation period, up to 3 years
Spontaneous Annualized Bleeding Rate (ABR) Under Prophylactic Treatment	Spontaneous ABR under prophylactic treatment with rVWF (vonicog alfa) while enrolled in the study	Throughout the study participation period, up to 3 years
Categorized Weekly Number of Infusions	Categorized as 1, 2 or >=3 during prophylactic treatment with rVWF (vonicog alfa)	Throughout the study participation period, up to 3 years
Categorized Spontaneous Annualized Bleeding Rate (ABR)	Categorized as 0, 1-2, 3-5, or >5 bleeding episodes during rVWF (vonicog alfa) prophylaxis	Throughout the study participation period, up to 3 years
Time to First Bleeding Event	Under each prophylaxis regimen	Throughout the study participation period, up to 3 years
Spontaneous Annualized Bleeding Rate (ABR) by Location of Bleeding	Gastrointestinal [GI], epistaxis, joint bleeding, menorrhagia, oral, muscle and soft tissue, etc. while on prophylactic treatment with rVWF (vonicog alfa)	Throughout the study participation period, up to 3 years
Total Number of Infusions	Total number of infusions during prophylactic treatment with rVWF (vonicog alfa)	Throughout the study participation period, up to 3 years
Average Number of Infusions	Per week during prophylactic treatment with rVWF (vonicog alfa)	Throughout the study participation period, up to 3 years
Total Weight Adjusted Consumption of recombinant von Willebrand factor (rVWF) (vonicog alfa)	During prophylactic treatment	Throughout the study participation period, up to 3 years
Number of Participants who Achieve Transfusion-free Maintenance of Hemoglobin Levels	Transfusion free maintenance of hemoglobin levels over time	Throughout the study participation period, up to 3 years
Ferritin Levels Over Time	Ferritin levels over time will be reported.	Throughout the study participation period, up to 3 years
Overall Hemostatic Efficacy Rating	At the resolution of bleed with respect to the treatment of bleeding episodes for the initial 12 months of study	Initial 12 months of study
Number of Infusions	Number of infusions of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) utilized to treat bleeding episodes while enrolled in the study	Throughout the study participation period, up to 3 years
Weight-adjusted Consumption	Weight-adjusted consumption of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) per bleeding episode while enrolled in the study	Throughout the study participation period, up to 3 years

Collaborators and Investigators

• Sponsor: Baxalta now part of Shire
• Collaborators: Takeda Development Center Americas, Inc.
• Investigators: Study Director: Study Director, Takeda

Publications and helpful links

Helpful Links

• To obtain more information on the study, click here/on this link

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2019
• Primary Completion (Estimated): March 31, 2025
• Study Completion (Estimated): March 31, 2025

Study Registration Dates

• First Submitted: December 20, 2018
• First Submitted That Met QC Criteria: March 15, 2019
• First Posted (Actual): March 18, 2019

Study Record Updates

• Last Update Posted (Actual): November 15, 2023
• Last Update Submitted That Met QC Criteria: November 14, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Blood Platelet Disorders; Von Willebrand Diseases; Coagulants; Factor VIII
• Other Study ID Numbers: SHP677-304; 2018-003453-16 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No