Clinical trial NCT02283268: Recombinant Von Willebrand Factor in Subjects With Severe Von Willebrand Disease Undergoing Surgery
Official title: A Phase 3, Prospective, Multicenter Study to Evaluate Efficacy and Safety of Recombinant Von Willebrand Factor (rVWF) With or Without ADVATE in Elective Surgical Procedures in Subjects With Severe Von Willebrand Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Von Willebrand Disease
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2014-11-05
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to assess the efficacy and safety of recombinant von Willebrand factor (rVWF) with or without ADVATE in major and minor elective surgical procedures in adult patients with hereditary severe von Willebrand disease (VWD).


Eligibility criteria: Inclusion Criteria:

* Diagnosis of severe von Willebrand disease (VWD) as listed below and elective surgical procedure planned

  1. Type 1 (Von Willebrand factor : Ristocetin cofactor activity (VWF:RCo) \<20 IU/dL), or
  2. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2N (FVIII:C\<10% and historically documented genetics), Type 2M, or
  3. Type 3 (Von Willebrand factor antigen (VWF:Ag) ≤ 3 IU/dL)
* VWD with a history of requiring substitution therapy with von Willebrand factor (VWF) concentrate to control bleeding
* If type 3 VWD (VWF Antigen /VWF:Ag ≤ 3 IU/dL), participant has a medical history of at least 20 exposure days to VWF/FVIII coagulation factor concentrates (including cryoprecipitate or fresh frozen plasma)
* If type 1 or type 2 VWD, participant has a medical history of 5 exposure days or a past major surgery requiring VWF/FVIII coagulation factor concentrates (including cryoprecipitate or fresh frozen plasma)
* Participant is at least 18 years of age
* If female of childbearing potential, participant presents with a negative pregnancy test
* If applicable, participant agrees to employ adequate birth control measures for the duration of the study
* Participant is willing and able to comply with the requirements of the protocol

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 \[INR\] \> 1.4)
* History or presence of a VWF inhibitor at screening
* History or presence of a factor VIII (FVIII) inhibitor with a titer ≥ 0.4 BU (Nijmegen-modified Bethesda assay ) or ≥ 0.6 BU (by Bethesda assay)
* Known hypersensitivity to any of the components of the study drugs, such as to mouse or hamster proteins
* Medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies
* Medical history of a thromboembolic event
* HIV positive with an absolute CD4 count \< 200/mm3
* Platelet count \< 100,000/mL
* Diagnosis of significant liver disease, as evidenced by, but not limited to, any of the following: serum alanine aminotransferase (ALT) 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 B or C
* Diagnosis of renal disease, with a serum creatinine level ≥ 2 .5mg/dL
* Participant has been treated with an immunomodulatory drug, excluding topical treatment (eg, ointments, nasal sprays), within 30 days prior to signing the informed consent
* Participant is pregnant or lactating at the time informed content 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 or investigational device during the course of this study. However, eligible patients participating in the rVWF Prophylaxis Study (071301) may be enrolled.
* Progressive fatal disease and/or life expectancy of less than 3 months
* Participant is identified by the investigator as being unable or unwilling to cooperate with study procedures
* Participant suffers from 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
* Participant is in prison or compulsory detention by regulatory and/or juridical order
* Participant is a member of the study team conducting this study or in a dependent relationship with one of the study team members. Dependent relationships include close relatives (ie, children, partner/spouse, siblings, parents) as well as employees.

Primary outcomes:
measure: Overall Hemostatic Efficacy as Assessed by the Investigator (Hemophilia Physician)
timeFrame: 24 hours after last peri-operative infusion or at completion of Day 14 (± 2 days) visit, whichever occurs earlier
Secondary outcomes:
measure: Intraoperative Actual Versus Predicted Blood Loss as Assessed by the Operating Surgeon
timeFrame: Day 0 (at completion of surgery)
measure: Intraoperative Actual Blood Loss Relative to Predicted Blood Loss
timeFrame: Day 0 (at completion of surgery)
measure: Intraoperative Actual Versus Predicted Blood Loss Score as Assessed by the Operating Surgeon
timeFrame: Day 0 (at completion of surgery)
measure: Intraoperative Hemostatic Efficacy Score as Assessed by the Operating Surgeon
timeFrame: Day 0 (at completion of surgery)
measure: Daily Intra- and Postoperative Weight-adjusted Dose of rVWF With or Without ADVATE
timeFrame: Daily, from day of surgery through postoperative Day 14 (± 2 days)
measure: Occurrence of Adverse Events
timeFrame: From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery)
measure: Occurrence of Thrombotic Events
timeFrame: From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery)
measure: Occurrence of Severe Allergic Reactions (eg, Anaphylaxis)
timeFrame: From first infusion of investigational product through study completion (ie, 14 (± 2) days post surgery)
measure: Number of Participants Who Developed Inhibitory and Total Binding Antibodies to Von Willebrand Factor (VWF) and Inhibitory Antibodies to Factor VIII (FVIII)
timeFrame: Testing occurred throughout the study at screening, prior PK infusion, pre-surgery, post surgery in case of excessive bleeding or unexplained bleeding, at postoperative day 7 and at study completion visit (ie. 14 (± 2) days post surgery).
measure: Number of Participants Who Developed Antibodies to Chinese Hamster Ovary (CHO) Proteins, Mouse Immunoglobulin G (IgG) or Recombinant Furin (rFurin)
timeFrame: Testing occurred throughout the study at screening, prior PK infusion, pre-surgery, post surgery in case of excessive bleeding or unexplained bleeding, at postoperative day 7 and at study completion visit (ie. 14 (± 2) days post surgery).
measure: Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From 0 to 72 Hours Post-infusion (AUC 0-72 h/Dose)
timeFrame: PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
measure: Pharmacokinetics: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Infinity (AUC 0-∞ /Dose)
timeFrame: PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
measure: Pharmacokinetics: Mean Residence Time (MRT)
timeFrame: PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
measure: Pharmacokinetics: Clearance (CL)
timeFrame: PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
measure: Pharmacokinetics: Incremental Recovery (IR)
timeFrame: PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
measure: Pharmacokinetics: Elimination Phase Half-life (T1/2)
timeFrame: PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
measure: Pharmacokinetics: Volume of Distribution at Steady State (Vss)
timeFrame: PK measurements were done within 30 minutes pre-infusion, and post infusion at 30 (± 5) minutes, 60 (± 5) minutes, 6 (± 1) hours, 12 (± 1) hours, 24 (± 2) hours, 48 (± 2) hours and 72 (± 2) hours.
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Hemophilia & Thrombosis Center
state: Colorado
city: Miami
country: United States
facility: University of Miami, Jackson Memorial Hospital
state: Florida
city: Augusta
country: United States
facility: Georgia Regents University
state: Georgia
city: Baltimore
country: United States
facility: John Hopkins University
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: New Brunswick
country: United States
facility: Rutgers - Robert Wood Johnson Medical School
state: New Jersey
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve University Hospital
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Charleston
country: United States
facility: Medical University of South Carolina (MUSC)
state: South Carolina
city: Milwaukee
country: United States
facility: Blood Center of South East Wisconsin
state: Wisconsin
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Nedlands
country: Australia
facility: The Perth Blood Institute
state: Western Australia
city: Perth
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Vienna
country: Austria
facility: AKH - Medizinische Universität Wien
city: Ostrava
country: Czechia
facility: Fakultni nemocnice Ostrava
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg Universität Mainz
state: Rheinland-Pfalz
city: Firenze (Florence)
country: Italy
facility: Azienda Ospedaliero - Universitaria Careggi
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Rome
country: Italy
facility: Umberto I Policlinico di Roma, Universitá di Roma La Sapienza
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum
city: Barnaul
country: Russian Federation
facility: Regional Budgetary State Healthcare Institution (SHI) "Regional Clinical Hospital"
city: Kirov
country: Russian Federation
facility: FSI Kirov Institute of Hematology and Blood Transfusion FMBA
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruña
city: Valencia
country: Spain
facility: Hospital Universitari i Politècnic La Fe
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: Tri-Service General Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Izmir
country: Turkey
facility: Ege University Medical Faculty
city: Lviv
country: Ukraine
facility: SI Institute of Blood Pathology and Transfusion Medicine of NAMSU
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
state: Devon
city: London
country: United Kingdom
facility: Royal Free Hospital
state: Greater London
city: Oxford
country: United Kingdom
facility: Churchill Hospital
state: Oxfordshire
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: