A Study of Recombinant Von Willebrand Factor (rVWF) With or Without ADVATE in Children With Severe Von Willebrand Disease (VWD)

Von Willebrand Disease Clinical Trial

Official title:

A Phase 3, Prospective, Multicenter, Uncontrolled, Open-Label Clinical Study to Determine the Efficacy, Safety, and Tolerability of rVWF With or Without ADVATE in the Treatment and Control of Bleeding Episodes, the Efficacy and Safety of rVWF in Elective and Emergency Surgeries, and the Pharmacokinetics (PK) of rVWF in Children Diagnosed With Severe Von Willebrand Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02932618
• Other study ID #: 071102
• Secondary ID: 2016-001477-33
• Status: Recruiting
• Phase: Phase 3
• Start date: December 18, 2017
• Est. completion date: January 1, 2025

Study information

• Verified date: November 2023
• Source: Takeda
• Contact: Takeda Contact
• Phone: 1-877-825-3327
• Email: medinfoUS[@]takeda.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The main aim of the study is to check effectiveness, side effects, and tolerability of 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 rVWF 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 34
• Est. completion date: January 1, 2025
• Est. primary completion date: January 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 17 Years

Eligibility

Inclusion Criteria:

• 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.
• If female of childbearing potential, participant presents with a negative serum pregnancy test.
• If applicable, participant agrees to employ adequate birth control measures for the duration of the study.
• 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 or are inadequately responsive to deamino-delta-D-arginine vasopressin (DDAVP).
• 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.

Exclusion Criteria:

• 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. a-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 rVWF 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 rVWF or investigational device during the course of this study.
• Participant's legal representative is a family member or employee of the Investigator.

Related Conditions & MeSH terms

• Von Willebrand Disease
• Von Willebrand Diseases

Intervention

Biological:
• von Willebrand factor (Recombinant)
Lyophilized powder and solvent to prepare solution for injection.
• Antihemophilic Factor (Recombinant)
Packaged in single boxes with 2 glass vials, with one vial containing the lyophilized ADVATE and the second vial containing the diluent.

Locations

Country	Name	City	State
Austria	Medizinische Universität Innsbruck	Innsbruck
Austria	AKH - Medizinische Universität Wien	Vienna
Belgium	UZ Leuven	Leuven
Czechia	Fakultni nemocnice Brno	Brno
France	Groupe Hospitalier Pellegrin - Hôpital Pellegrin	Bordeaux Cedex
France	Hôpital Morvan	Brest	Finistere
France	Groupement Hospitalier Est- Hôpital Louis Pradel	Bron cedex
France	CHU CAEN - Hôpital de la Côte de Nacre	Caen cedex 9
France	Groupement Hospitalier Sud - Hôpital Bicêtre	Le Kremlin-Bicêtre
France	Hopital Cardiologique - CHU Lille	Lille Cedex
France	CHU de Nantes Site Hotel Dieu	Nantes Cedex 1
France	Hôpital Necker - Enfants Malades	Paris cedex 15
Germany	Universitaetsklinikum Hamburg-Eppendorf	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Werlhof-Institut GmbH	Hannover
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze
Italy	Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico	Milano
Italy	Azienda Ospedaliera Pediatrica Santobono Pausillipon	Napoli
Italy	Ospedale Pediatrico Bambino Gesù	Roma
Netherlands	Erasmus Medisch Centrum	Rotterdam
Russian Federation	SBEI HPE Altai State Medical University of MoH and SD	Barnaul
Russian Federation	SAIH "Kemerovo Regional Clinical Hospital"	Kemerovo
Russian Federation	FSBI of Science "Kirov Scientific and Research Institute of Hematology and Blood Transfusion of FMBA	Kirov
Spain	Hospital General Universitario de Alicante	Alicante
Spain	Hospital Universitari i Politecnic La Fe	Valencia
Turkey	Istanbul University Cerrahpasa Medical Faculty	Istanbul
Turkey	Ege University Medical Faculty	Izmir
Turkey	Ondokuz Mayis Univ. Med. Fac.	Samsun
Ukraine	SI Institute of Blood Pathology and Transfusion Medicine of NAMSU	Lviv
United Kingdom	Royal Manchester Children's Hospital	Manchester	Greater Manchester
United States	University of Colorado Hemophilia & Thrombosis Center	Aurora	Colorado
United States	Medical University of South Carolina	Charleston	South Carolina
United States	St. Jude Affiliate Clinic at Novant Health	Charlotte	North Carolina
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	Texas Children's Cancer and Hematology Center	Houston	Texas
United States	Texas Children's Hospital	Houston	Texas
United States	Indiana Hemophilia and Thrombosis Center	Indianapolis	Indiana
United States	University of Florida College of Medicine	Jacksonville	Florida
United States	Comprehensive Center for Bleeding Disorders	Milwaukee	Wisconsin
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Bleeding and Clotting Disorders Institute	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's National Medical Center	Washington	District of Columbia
United States	Comprehensive Cancer Center of Wake Forest Unversity	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Baxalta now part of Shire	Takeda Development Center Americas, Inc.

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Czechia,  France,  Germany,  Italy,  Netherlands,  Russian Federation,  Spain,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hemostatic Efficacy	Treatment success for rVWF-treated nonsurgical bleeding episodes (using a 4-point scale: Excellent, Good, Moderate, None).	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)
Secondary	Number of Treated Nonsurgical Bleeding Episodes With an Efficacy Rating of 'Excellent' or 'Good'	If/when the severity and/or duration of the bleeding requires the infusion of the study drug.	Throughout the study duration of approximately 6.5 years
Secondary	Number of Infusions per Bleeding Episode		Throughout the study duration of approximately 6.5 years
Secondary	Number of Recombinant Von Willebrand Factor (rVWF) Units per Bleeding Episode		Throughout the study duration of approximately 6.5 years
Secondary	Number of ADVATE Units (if needed) per Bleeding Episode		Throughout the study duration of approximately 6.5 years
Secondary	Elective or Emergency Surgery: Assessment of Hemostatic Efficacy - Immediately After Surgery	Assessed by the operating surgeon, based on a 4-point ordinal scale: Excellent, Good, Moderate, None.	Immediately after surgery
Secondary	Elective or Emergency Surgery: Overall Assessment of Hemostatic Efficacy 24 Hours After the Last Perioperative Infusion of rVWF	Assessed by the Investigator (hematologist) on a 4-point ordinal scale: Excellent, Good, Moderate, None.	24 hours after last perioperative rVWF infusion
Secondary	Elective or Emergency surgery: Overall Assessment of Hemostatic Efficacy Day 7 Post-operative	Assessed by the Investigator (hematologist) on a 4-point ordinal scale: Excellent, Good, Moderate, None.	Post-operative Day 7
Secondary	Elective or Emergency surgery: Overall Assessment of Hemostatic Efficacy Day 14 Post-operative	Assessed by the Investigator (hematologist) on a 4-point ordinal scale: Excellent, Good, Moderate, None.	Post-operative Day 14
Secondary	Incidence and Severity of Adverse Events (AEs)		Throughout the study period of approximately 6.5 years
Secondary	Incidence of Thrombotic Events		Throughout the study period of approximately 6.5 years
Secondary	Incidence of Severe Hypersensitivity Reactions		Throughout the study period of approximately 6.5 years
Secondary	Development of Neutralizing Antibodies to von Willebrand Factor (VWF) and Factor VIII (FVIII)		Throughout the study period of approximately 6.5 years
Secondary	Development of Total Binding Antibodies to von Willebrand Factor (VWF)		Throughout the study period of approximately 6.5 years
Secondary	Development of Antibodies to Chinese Hamster Ovary (CHO) Proteins, Murine Immunoglobulin G (IgG), and rFurin		Throughout the study period of approximately 6.5 years
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

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