A Study of Recombinant Von Willebrand Factor (rVWF) in Pediatric and Adult Participants With Severe Von Willebrand Disease (VWD)
- Conditions
- Von Willebrand Disease (VWD)
- Interventions
- Biological: rFVIII
- Registration Number
- NCT03879135
- Lead Sponsor
- Baxalta now part of Shire
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 38
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).
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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Prophylaxis rFVIII Participants will receive recombinant von Willebrand factor (rVWF). On-Demand rVWF Participants will receive recombinant von Willebrand factor (rVWF) (with or without ADVATE). Prophylaxis rVWF Participants will receive recombinant von Willebrand factor (rVWF). On-Demand rFVIII Participants will receive recombinant von Willebrand factor (rVWF) (with or without ADVATE).
- Primary Outcome Measures
Name Time Method Spontaneous Annualized Bleeding Rate (ABR) First 12 months of treatment Spontaneous ABR during prophylaxis treatment with rVWF (vonicog alfa)
- Secondary Outcome Measures
Name Time Method Ferritin Levels Over Time Throughout the study participation period, up to 3 years Ferritin levels over time will be reported.
Adverse Events (AEs)/Serious Adverse Events (SAEs) Throughout the study participation period, up to 3 years AEs/ SAEs: incidence, severity, causality
Hypersensitivity Reactions Throughout the study participation period, up to 3 years Occurrence of hypersensitivity reactions
Total Number of Infusions Throughout the study participation period, up to 3 years Total number of infusions during prophylactic treatment with rVWF (vonicog alfa)
Total Weight Adjusted Consumption of recombinant von Willebrand factor (rVWF) (vonicog alfa) Throughout the study participation period, up to 3 years During prophylactic treatment
Number of Participants who Achieve Transfusion-free Maintenance of Hemoglobin Levels Throughout the study participation period, up to 3 years Transfusion free maintenance of hemoglobin levels over time
Number of Participants With Clinically Significant Changes in Vital Signs 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 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
Categorized Weekly Number of Infusions Throughout the study participation period, up to 3 years Categorized as 1, 2 or \>=3 during prophylactic treatment with rVWF (vonicog alfa)
Time to First Bleeding Event Throughout the study participation period, up to 3 years Under each prophylaxis regimen
Thromboembolic Events Throughout the study participation period, up to 3 years Occurrence of thromboembolic events
Number of Participants who Develop Neutralizing Antibodies to von Willebrand factor (VWF) Throughout the study participation period, up to 3 years Number of participants who develop neutralizing antibodies (inhibitors) to VWF
Number of Participants who Develop Total Binding Antibodies to von Willebrand factor (VWF) Throughout the study participation period, up to 3 years Number of participants who develop total binding antibodies to VWF
Categorized Spontaneous Annualized Bleeding Rate (ABR) 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
Spontaneous Annualized Bleeding Rate (ABR) by Location of Bleeding 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)
Number of Participants who Develop Neutralizing Antibodies to Factor VIII (FVIII) Throughout the study participation period, up to 3 years Number of participants who develop neutralizing antibodies (inhibitors) to FVIII
Number of Participants who Develop Total Binding Antibodies to Factor VIII (FVIII) Throughout the study participation period, up to 3 years Number of participants who develop total binding antibodies to FVIII
Number of Participants who Develop Binding Antibodies to Chinese hamster ovary (CHO) proteins Throughout the study participation period, up to 3 years Number of participants who develop binding antibodies to CHO proteins
Number of Participants who Develop Binding Antibodies to Mouse Immunoglobulin G (IgG) Throughout the study participation period, up to 3 years Number of participants who develop binding antibodies to mouse IgG
Number of Participants who Develop Binding Antibodies to recombinant Furin (rFurin) Throughout the study participation period, up to 3 years Number of participants who develop binding antibodies to rFurin
Average Number of Infusions Throughout the study participation period, up to 3 years Per week during prophylactic treatment with rVWF (vonicog alfa)
Number of Infusions 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
Spontaneous Annualized Bleeding Rate (ABR) Under Prophylactic Treatment Throughout the study participation period, up to 3 years Spontaneous ABR under prophylactic treatment with rVWF (vonicog alfa) while enrolled in the study
Overall Hemostatic Efficacy Rating 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
Weight-adjusted Consumption 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
Trial Locations
- Locations (31)
Arkansas Children's Hospital Research Institute
🇺🇸Little Rock, Arkansas, United States
University of Colorado Health
🇺🇸Aurora, Colorado, United States
University of Florida College of Medicine
🇺🇸Gainesville, Florida, United States
Indiana Hemophilia and Thrombosis Center
🇺🇸Indianapolis, Indiana, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Rainbow Babies and Children's Hospital
🇺🇸Cleveland, Ohio, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Medical University of South Carolina (MUSC)
🇺🇸Charleston, South Carolina, United States
AKH - Medizinische Universität Wien
🇦🇹Vienna, Austria
Hopital Cardiologique - CHU Lille
🇫🇷Lille Cedex, Nord, France
Hôpital Necker - Enfants Malades
🇫🇷Paris cedex 15, Paris, France
Groupement Hospitalier Est- Hôpital Louis Pradel
🇫🇷Bron cedex, France
Groupe Hospitalier Pellegrin - Hôpital Pellegrin
🇫🇷Gironde, France
Groupement Hospitalier Sud - Hôpital Bicêtre
🇫🇷Le Kremlin Bicêtre cedex, France
Klinikum der Johann Wolfgang Goethe-Universitaet
🇩🇪Frankfurt, Germany
Werlhof-Institut GmbH
🇩🇪Hannover, Germany
Azienda Ospedaliera Universitaria Careggi
🇮🇹Firenze, Italy
Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
🇮🇹Milano, Italy
Azienda Ospedaliera Pediatrica Santobono Pausillipon
🇮🇹Napoli, Italy
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
🇮🇹Roma, Italy
Azienda Ospedaliera Universitaria Policlinico Umberto I - Università di Roma La Sapienza
🇮🇹Roma, Italy
Ospedale Pediatrico Bambino Gesù
🇮🇹Roma, Italy
Erasmus Medisch Centrum
🇳🇱Rotterdam, Netherlands
SAIH "Kemerovo Regional Clinical Hospital"
🇷🇺Kemerovo, Russian Federation
FSBI of Science "Kirov Scientific and Research Institute of Hematology and Blood Transfusion of FMBA
🇷🇺Kirov, Russian Federation
Hospital General Universitario de Alicante
🇪🇸Alicante, Spain
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Hospital Universitari i Politecnic La Fe
🇪🇸Valencia, Spain
Istanbul University Oncology Institute
🇹🇷Istanbul, Turkey
Ege University Medical Faculty
🇹🇷Izmir, Turkey
Ondokuz Mayis Univ. Med. Fac.
🇹🇷Samsun, Turkey