A Study of Recombinant Von Willebrand Factor (rVWF) With or Without ADVATE in Children With Severe Von Willebrand Disease (VWD)
- Conditions
- Von Willebrand Disease
- Interventions
- Biological: von Willebrand factor (Recombinant)Biological: Antihemophilic Factor (Recombinant)
- Registration Number
- NCT02932618
- Lead Sponsor
- Baxalta now part of Shire
- Brief Summary
The main aim of the study is to check effectiveness, side effects, and tolerability of vonicog alfa (recombinant von Willebrand factor \[rVWF\]), with or without ADVATE, in the treatment and control of nonsurgical bleeding events in pediatric participants (less than (\<)18 years of age) with severe hereditary von Willebrand disease (VWD).
The participants will be treated with vonicog alfa for 12-18 months. Their von Willebrand Disease will be treated by their doctor according to their doctor's usual clinical practice. During the study, participants will be followed up at clinics or over telephone calls.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 31
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Diagnosis of severe von Willebrand disease (VWD) (defined as von Willebrand factor: ristocetin cofactor [VWF:RCo] less than [<] 20 percent [%]):
- Type 1 (VWF:RCo <20 International Units per deciliter [IU/dL]); or
- Type 2A (VWF:RCo <20 IU/dL), Type 2B (as diagnosed by genotype), Type 2N (Factor VIII coagulation activity [FVIII:C] <10 % and historically documented genetics), Type 2M; or
- Type 3 (VWF:Ag less than or equal to [=<] 3 IU/dL).
-
Age 0 to <18 years at the time of Screening.
-
The participant has provided assent (if appropriate) and legally authorized representative(s) has provided informed consent.
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If female of childbearing potential, participant presents with a negative serum pregnancy test.
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If applicable, participant agrees to employ adequate birth control measures for the duration of the study.
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The participant and/or the legally authorized representative are willing and able to comply with the requirements of the protocol, which should also be confirmed based on a pre-screening evaluation held between the Investigator and the Sponsor, to ensure no eminent risk is present that could challenge the participants compliance with the study requirements.
Additional inclusion criteria for both previously treated participants and participants undergoing surgery are as follows:
- Unable to tolerate are inadequately responsive to, or not a good candidate for 1-deamino-8-D-arginine vasopressin (DDAVP). Examples of participants who are not good candidates for DDAVP include participants with type 2B or type 3 VWD.
- The participant has had a minimum of 1 documented bleed requiring VWF coagulation factor replacement therapy (i.e. treatment with a VWF product) during the previous 12 months prior to enrollment and overall historically 3 or more exposure days (EDs) to VWF replacement therapy.
Additional inclusion criterion for previously untreated participants are as follows:
- The participant has not received prior VWF coagulation factor replacement therapy.
- Diagnosis of pseudo-VWD or another hereditary or acquired coagulation disorder (eg, qualitative and quantitative platelet disorders or elevated prothrombin time [PT]/international normalized ratio [INR] greater than [>] 1.4).
- History or presence of a VWF inhibitor at Screening.
- History or presence of a Factor VIII (FVIII) inhibitor with a titer greater than or equal [>=] 0.4 Bethesda units (BU) (by Nijmegen assay) or >=0.6 BU (by Bethesda assay).
- Documented history of a VWF: RCo half-life <6 hours.
- Known hypersensitivity to any of the components of the study drug, such as mouse or hamster proteins.
- Medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis/asthma, food allergies, or animal allergies.
- Medical history of a thromboembolic event.
- Human immunodeficiency virus (HIV) positive, with an absolute CD4 count <200/ cubic millimeter (mm^3).
- In the judgment of the Investigator, the participant has another clinically significant concomitant disease (e.g. uncontrolled hypertension, cancer) that may pose additional risks for the participant.
- Diagnosis of significant liver disease, as evidenced by, but not limited to, any of the following: serum alanine aminotransferase (ALT) of 5 times the upper limit of normal; hypoalbuminemia; portal vein hypertension (e.g. presence of otherwise unexplained splenomegaly, history of esophageal varices) or liver cirrhosis classified as Child B or C.
- Diagnosis of renal disease, with a serum creatinine level >=2.5 milligram per deciliter (mg/dL).
- Immunomodulatory drug treatment other than anti-retroviral chemotherapy (e.g. α-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 milligram per day [mg/day] (excluding topical treatment [e.g. ointments, nasal sprays]), within 30 days prior to signing the informed consent (or assent, if appropriate).
- If female, participant is pregnant or lactating at the time informed consent (or assent, if appropriate) is obtained.
- Participant has participated in another clinical study involving an investigational product (IP), other than vonicog alfa with or without ADVATE, or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP other than vonicog alfa or investigational device during the course of this study.
- Participant's legal representative is a family member or employee of the Investigator.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description On-demand Treatment von Willebrand factor (Recombinant) Participants will receive recombinant von Willebrand factor (rVWF) treatment for non-surgical bleeding episodes over a 12 to 18-month period. On-demand Treatment Antihemophilic Factor (Recombinant) Participants will receive recombinant von Willebrand factor (rVWF) treatment for non-surgical bleeding episodes over a 12 to 18-month period. Elective Surgery von Willebrand factor (Recombinant) 12-24 hours prior to surgery and within 3 hours of surgery. Minor surgery: infuse every 12-24 hours for at least 48 hours based on post-operative dosing. Oral Surgery: infuse at least once within first 8-12 hours post-surgery based on post-operative dosing. Major Surgery: infuse every 12-24 hours for at least first 96 hours post-surgery based on post-operative dosing. Emergency Surgery Antihemophilic Factor (Recombinant) Within 3 hours prior to surgery. Minor surgery: infuse every 12-24 hours for at least 48 hours based on post-operative dosing. Oral Surgery: infuse at least once within first 8-12 hours post-surgery based on post-operative dosing. Major Surgery: infuse every 12-24 hours for at least first 96 hours post-surgery based on post-operative dosing. Elective Surgery Antihemophilic Factor (Recombinant) 12-24 hours prior to surgery and within 3 hours of surgery. Minor surgery: infuse every 12-24 hours for at least 48 hours based on post-operative dosing. Oral Surgery: infuse at least once within first 8-12 hours post-surgery based on post-operative dosing. Major Surgery: infuse every 12-24 hours for at least first 96 hours post-surgery based on post-operative dosing. Emergency Surgery von Willebrand factor (Recombinant) Within 3 hours prior to surgery. Minor surgery: infuse every 12-24 hours for at least 48 hours based on post-operative dosing. Oral Surgery: infuse at least once within first 8-12 hours post-surgery based on post-operative dosing. Major Surgery: infuse every 12-24 hours for at least first 96 hours post-surgery based on post-operative dosing. On-demand Treatment Vonicog alfa Participants will receive vonicog alfa (recombinant von Willebrand factor \[rVWF\]) treatment for non-surgical bleeding episodes over a 12 to 18-month period. On-demand Treatment Antihemophilic Factor (Recombinant) Participants will receive vonicog alfa (recombinant von Willebrand factor \[rVWF\]) treatment for non-surgical bleeding episodes over a 12 to 18-month period. Elective Surgery Vonicog alfa 12-24 hours prior to surgery and within 3 hours of surgery. Minor surgery: infuse every 12-24 hours for at least 48 hours based on post-operative dosing. Oral Surgery: infuse at least once within first 8-12 hours post-surgery based on post-operative dosing. Major Surgery: infuse every 12-24 hours for at least first 96 hours post-surgery based on post-operative dosing. Elective Surgery Antihemophilic Factor (Recombinant) 12-24 hours prior to surgery and within 3 hours of surgery. Minor surgery: infuse every 12-24 hours for at least 48 hours based on post-operative dosing. Oral Surgery: infuse at least once within first 8-12 hours post-surgery based on post-operative dosing. Major Surgery: infuse every 12-24 hours for at least first 96 hours post-surgery based on post-operative dosing. Emergency Surgery Vonicog alfa Within 3 hours prior to surgery. Minor surgery: infuse every 12-24 hours for at least 48 hours based on post-operative dosing. Oral Surgery: infuse at least once within first 8-12 hours post-surgery based on post-operative dosing. Major Surgery: infuse every 12-24 hours for at least first 96 hours post-surgery based on post-operative dosing. Emergency Surgery Antihemophilic Factor (Recombinant) Within 3 hours prior to surgery. Minor surgery: infuse every 12-24 hours for at least 48 hours based on post-operative dosing. Oral Surgery: infuse at least once within first 8-12 hours post-surgery based on post-operative dosing. Major Surgery: infuse every 12-24 hours for at least first 96 hours post-surgery based on post-operative dosing.
- Primary Outcome Measures
Name Time Method Hemostatic Efficacy Within 24 hours after the last infusion of study drug following the onset of the bleeding episode (if/when the severity and/or duration of the bleeding requires the infusion of the study drug) Treatment success for vonicog alfa-treated nonsurgical bleeding episodes (using a 4-point scale: Excellent, Good, Moderate, None).
- Secondary Outcome Measures
Name Time Method Incidence and Severity of Adverse Events (AEs) Throughout the study period of approximately 8.5 years Number of Treated Nonsurgical Bleeding Episodes With an Efficacy Rating of 'Excellent' or 'Good' Throughout the study duration of approximately 8.5 years If/when the severity and/or duration of the bleeding requires the infusion of the study drug.
Number of Infusions per Bleeding Episode Throughout the study duration of approximately 8.5 years Elective or Emergency Surgery: Assessment of Hemostatic Efficacy - Immediately After Surgery Immediately after surgery Assessed by the operating surgeon, based on a 4-point ordinal scale: Excellent, Good, Moderate, None.
Elective or Emergency Surgery: Overall Assessment of Hemostatic Efficacy 24 Hours After the Last Perioperative Infusion of rVWF 24 hours after last perioperative rVWF infusion Assessed by the Investigator (hematologist) on a 4-point ordinal scale: Excellent, Good, Moderate, None.
Elective or Emergency surgery: Overall Assessment of Hemostatic Efficacy Day 7 Post-operative Post-operative Day 7 Assessed by the Investigator (hematologist) on a 4-point ordinal scale: Excellent, Good, Moderate, None.
Elective or Emergency surgery: Overall Assessment of Hemostatic Efficacy Day 14 Post-operative Post-operative Day 14 Assessed by the Investigator (hematologist) on a 4-point ordinal scale: Excellent, Good, Moderate, None.
Area Under the Plasma Concentration/Time Curve From 0 to 96 Hours Post-Infusion (AUC0-96h) for Von Willebrand factor: ristocetin cofactor (VWF:Rco), von Willebrand factor: antigen (VWF:Ag) and von Willebrand factor: collagen binding capacity (VWF:CB) Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-inf) for VWF:RCo, VWF:Ag and VWF:CB Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours Mean Residence Time (MRT) for VWF:RCo, VWF:Ag and VWF:CB Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours Clearance (CL) for VWF:RCo, VWF:Ag and VWF:CB Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours Incremental Recovery (IR) for VWF:RCo, VWF:Ag and VWF:CB Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours In-vivo Recovery (IVR) for VWF:RCo, VWF:Ag and VWF:CB Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours Time to Reach Maximal Plasma Concentration (Tmax) for VWF:RCo, VWF:Ag and VWF:CB Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours Maximal Plasma Concentration (Cmax) for VWF:RCo, VWF:Ag and VWF:CB Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours Elimination Phase Half-life (T1/2) for VWF:RCo, VWF:Ag and VWF:CB Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours Volume of Distribution at Steady State (Vss) for VWF:RCo, VWF:Ag and VWF:CB Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours Area Under the Plasma Concentration/Time Curve From 0 to 96 Hours Post-infusion (AUC0-96h) for Factor VIII (FVIII) Activity Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours Number of Vonicog Alfa Units per Bleeding Episode Throughout the study duration of approximately 8.5 years Number of ADVATE Units (if needed) per Bleeding Episode Throughout the study duration of approximately 8.5 years Incidence of Thromboembolic Events Throughout the study period of approximately 8.5 years Incidence of Severe Hypersensitivity Reactions Throughout the study period of approximately 8.5 years Development of Neutralizing Antibodies to von Willebrand Factor (VWF) and Factor VIII (FVIII) Throughout the study period of approximately 8.5 years Development of Total Binding Antibodies to von Willebrand Factor (VWF) Throughout the study period of approximately 8.5 years Development of Antibodies to Chinese Hamster Ovary (CHO) Proteins, Murine Immunoglobulin G (IgG), and rFurin Throughout the study period of approximately 8.5 years
Trial Locations
- Locations (46)
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
University of Florida College of Medicine
🇺🇸Jacksonville, Florida, United States
Bleeding and Clotting Disorders Institute
🇺🇸Peoria, Illinois, United States
St. Jude Affiliate Clinic at Novant Health
🇺🇸Charlotte, North Carolina, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Fakultni nemocnice Brno
🇨🇿Brno, Czechia
UZ Leuven
🇧🇪Leuven, Belgium
Groupe Hospitalier Pellegrin - Hôpital Pellegrin
🇫🇷Bordeaux Cedex, France
Hôpital Morvan
🇫🇷Brest, Finistere, France
Groupement Hospitalier Est- Hôpital Louis Pradel
🇫🇷Bron cedex, France
Groupement Hospitalier Sud - Hôpital Bicêtre
🇫🇷Le Kremlin-Bicêtre, France
CHU CAEN - Hôpital de la Côte de Nacre
🇫🇷Caen cedex 9, France
CHU de Nantes Site Hotel Dieu
🇫🇷Nantes Cedex 1, France
Hopital Cardiologique - CHU Lille
🇫🇷Lille Cedex, France
Hôpital Necker - Enfants Malades
🇫🇷Paris cedex 15, France
Universitaetsklinikum Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Azienda Ospedaliera Universitaria Careggi
🇮🇹Firenze, Italy
Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
🇮🇹Milano, Italy
Medizinische Hochschule Hannover
🇩🇪Hannover, Germany
Azienda Ospedaliera Pediatrica Santobono Pausillipon
🇮🇹Napoli, Italy
Ospedale Pediatrico Bambino Gesù
🇮🇹Roma, Italy
Erasmus Medisch Centrum
🇳🇱Rotterdam, Netherlands
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 Universitari i Politecnic La Fe
🇪🇸Valencia, Spain
Istanbul University Cerrahpasa Medical Faculty
🇹🇷Istanbul, Turkey
Ondokuz Mayis Univ. Med. Fac.
🇹🇷Samsun, Turkey
Ege University Medical Faculty
🇹🇷Izmir, Turkey
SI Institute of Blood Pathology and Transfusion Medicine of NAMSU
🇺🇦Lviv, Ukraine
Werlhof-Institut GmbH
🇩🇪Hannover, Germany
Comprehensive Center for Bleeding Disorders
🇺🇸Milwaukee, Wisconsin, United States
University of Colorado Hemophilia & Thrombosis Center
🇺🇸Aurora, Colorado, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Royal Manchester Children's Hospital
🇬🇧Manchester, Greater Manchester, United Kingdom
Indiana Hemophilia and Thrombosis Center
🇺🇸Indianapolis, Indiana, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Comprehensive Cancer Center of Wake Forest Unversity
🇺🇸Winston-Salem, North Carolina, United States
Rainbow Babies and Children's Hospital
🇺🇸Cleveland, Ohio, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Texas Children's Hospital
🇺🇸Houston, Texas, United States
Texas Children's Cancer and Hematology Center
🇺🇸Houston, Texas, United States
SAIH "Kemerovo Regional Clinical Hospital"
🇷🇺Kemerovo, Russian Federation
SBEI HPE Altai State Medical University of MoH and SD
🇷🇺Barnaul, Russian Federation
AKH - Medizinische Universität Wien
🇦🇹Vienna, Austria
Medizinische Universität Innsbruck
🇦🇹Innsbruck, Austria