Clinical trial NCT02932618: A Study of Recombinant Von Willebrand Factor (rVWF) With or Without ADVATE in Children With Severe Von Willebrand Disease (VWD)
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Von Willebrand Disease
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Takeda Development Center Americas, Inc.
First posted: 2016-10-13
Enrollment: 31
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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 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.

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. 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.

Primary outcomes:
measure: Hemostatic Efficacy
timeFrame: 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 outcomes:
measure: Number of Treated Nonsurgical Bleeding Episodes With an Efficacy Rating of 'Excellent' or 'Good'
timeFrame: Throughout the study duration of approximately 8.5 years
measure: Number of Infusions per Bleeding Episode
timeFrame: Throughout the study duration of approximately 8.5 years
measure: Number of Vonicog Alfa Units per Bleeding Episode
timeFrame: Throughout the study duration of approximately 8.5 years
measure: Number of ADVATE Units (if needed) per Bleeding Episode
timeFrame: Throughout the study duration of approximately 8.5 years
measure: Elective or Emergency Surgery: Assessment of Hemostatic Efficacy - Immediately After Surgery
timeFrame: Immediately after surgery
measure: Elective or Emergency Surgery: Overall Assessment of Hemostatic Efficacy 24 Hours After the Last Perioperative Infusion of rVWF
timeFrame: 24 hours after last perioperative rVWF infusion
measure: Elective or Emergency surgery: Overall Assessment of Hemostatic Efficacy Day 7 Post-operative
timeFrame: Post-operative Day 7
measure: Elective or Emergency surgery: Overall Assessment of Hemostatic Efficacy Day 14 Post-operative
timeFrame: Post-operative Day 14
measure: Incidence and Severity of Adverse Events (AEs)
timeFrame: Throughout the study period of approximately 8.5 years
measure: Incidence of Thromboembolic Events
timeFrame: Throughout the study period of approximately 8.5 years
measure: Incidence of Severe Hypersensitivity Reactions
timeFrame: Throughout the study period of approximately 8.5 years
measure: Development of Neutralizing Antibodies to von Willebrand Factor (VWF) and Factor VIII (FVIII)
timeFrame: Throughout the study period of approximately 8.5 years
measure: Development of Total Binding Antibodies to von Willebrand Factor (VWF)
timeFrame: Throughout the study period of approximately 8.5 years
measure: Development of Antibodies to Chinese Hamster Ovary (CHO) Proteins, Murine Immunoglobulin G (IgG), and rFurin
timeFrame: Throughout the study period of approximately 8.5 years
measure: 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)
timeFrame: 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
measure: Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-inf) for VWF:RCo, VWF:Ag and VWF:CB
timeFrame: 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
measure: Mean Residence Time (MRT) for VWF:RCo, VWF:Ag and VWF:CB
timeFrame: 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
measure: Time to Reach Maximal Plasma Concentration (Tmax) for VWF:RCo, VWF:Ag and VWF:CB
timeFrame: 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
measure: Maximal Plasma Concentration (Cmax) for VWF:RCo, VWF:Ag and VWF:CB
timeFrame: 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
measure: Clearance (CL) for VWF:RCo, VWF:Ag and VWF:CB
timeFrame: 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
measure: Incremental Recovery (IR) for VWF:RCo, VWF:Ag and VWF:CB
timeFrame: 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
measure: In-vivo Recovery (IVR) for VWF:RCo, VWF:Ag and VWF:CB
timeFrame: 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
measure: Elimination Phase Half-life (T1/2) for VWF:RCo, VWF:Ag and VWF:CB
timeFrame: 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
measure: Volume of Distribution at Steady State (Vss) for VWF:RCo, VWF:Ag and VWF:CB
timeFrame: 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
measure: Area Under the Plasma Concentration/Time Curve From 0 to 96 Hours Post-infusion (AUC0-96h) for Factor VIII (FVIII) Activity
timeFrame: 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
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Hemophilia & Thrombosis Center
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Jacksonville
country: United States
facility: University of Florida College of Medicine
state: Florida
city: Peoria
country: United States
facility: Bleeding and Clotting Disorders Institute
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Hemophilia and Thrombosis Center
state: Indiana
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Charlotte
country: United States
facility: St. Jude Affiliate Clinic at Novant Health
state: North Carolina
city: Winston-Salem
country: United States
facility: Comprehensive Cancer Center of Wake Forest Unversity
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies and Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: Texas Children's Cancer and Hematology Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Milwaukee
country: United States
facility: Comprehensive Center for Bleeding Disorders
state: Wisconsin
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
city: Vienna
country: Austria
facility: AKH - Medizinische Universität Wien
city: Leuven
country: Belgium
facility: UZ Leuven
city: Brno
country: Czechia
facility: Fakultni nemocnice Brno
city: Brest
country: France
facility: Hôpital Morvan
state: Finistere
city: Bordeaux Cedex
country: France
facility: Groupe Hospitalier Pellegrin - Hôpital Pellegrin
city: Bron cedex
country: France
facility: Groupement Hospitalier Est- Hôpital Louis Pradel
city: Caen cedex 9
country: France
facility: CHU CAEN - Hôpital de la Côte de Nacre
city: Le Kremlin-Bicêtre
country: France
facility: Groupement Hospitalier Sud - Hôpital Bicêtre
city: Lille Cedex
country: France
facility: Hopital Cardiologique - CHU Lille
city: Nantes Cedex 1
country: France
facility: CHU de Nantes Site Hotel Dieu
city: Paris cedex 15
country: France
facility: Hôpital Necker - Enfants Malades
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Werlhof-Institut GmbH
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Milano
country: Italy
facility: Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
city: Napoli
country: Italy
facility: Azienda Ospedaliera Pediatrica Santobono Pausillipon
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum
city: Barnaul
country: Russian Federation
facility: SBEI HPE Altai State Medical University of MoH and SD
city: Kemerovo
country: Russian Federation
facility: SAIH "Kemerovo Regional Clinical Hospital"
city: Kirov
country: Russian Federation
facility: FSBI of Science "Kirov Scientific and Research Institute of Hematology and Blood Transfusion of FMBA
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Istanbul
country: Turkey
facility: Istanbul University Cerrahpasa Medical Faculty
city: Izmir
country: Turkey
facility: Ege University Medical Faculty
city: Samsun
country: Turkey
facility: Ondokuz Mayis Univ. Med. Fac.
city: Lviv
country: Ukraine
facility: SI Institute of Blood Pathology and Transfusion Medicine of NAMSU
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
state: Greater Manchester
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: