Primary objective:• Assess the pharmacokinetics (PK) of rVWF:rFVIII and rVWF, and to assess the safety and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding events in subjects with severe hereditary VWDSecundary objectives:• Compare the…
ID
Source
Brief title
Condition
- Coagulopathies and bleeding diatheses (excl thrombocytopenic)
- Blood and lymphatic system disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Number of subjects with a treatment success for treated bleeding episodes
Secondary outcome
Efficacy
• Number of treated bleeding episodes with an efficacy rating of 'excellent' or
'good'
• Number of infusions and rVWF:rFVIII and/or rVWF units per bleeding episode
Safety
• Development of inhibitory and total binding anti-VWF antibodies
• Development of inhibitory antibodies to FVIII
• Development of antibodies to Chinese hamster ovary (CHO) proteins, mouse
immunoglobulin G (IgG) and rFurin
• Occurrence of thrombotic events
• Other IP related AEs, such as clinically significant changes in routine
laboratory parameters (hematology and clinical chemistry) and vital signs
Pharmacokinetics
• Area under the plasma concentration/time curve from time 0 to infinity
(AUC0-*/Dose); area under the plasma concentration/time curve from time 0 to 96
hours (AUC0-96h/Dose); mean residence time (MRT); clearance (CL); incremental
recovery (IR), elimination phase half-life (T1/2); volume of distribution at
steady state (Vss) of VWF Ristocetin cofactor (VWF:RCo), VWF antigen (VWF:Ag),
VWF collagen-binding (VWF:CB), and FVIII.
• In vivo recovery (IVR) of VWF:RCo, VWF:Ag and VWF:CB.
• Comparison of intra-subject PK of VWF:RCo, VWF:CB and VWF:Ag at baseline and
after 6 months in a subset of at least 20 subjects with severe VWD (minimum 6
subjects with type 3 VWD)
Exploratory Endpoints
• Subjective hemostatic efficacy rating
Two instruments to measure Health-related Quality of Life (HRQoL) will be
employed as exploratory endpoints:
• Generic: Physical Component Score (PCS) and Mental Component Score (MCS) of
the Short Form-36 (SF-36)
• Disease-specific: total score of the unvalidated VWD Impact Questionnaire
Background summary
The aim of the studie is assessing the pharmacokinetics (PK) of rVWF:rFVIII and
rVWF, and to assess the safety and efficacy of rVWF:rFVIII and rVWF in the
treatment and prevention of bleeding events in subjects with severe hereditary
VWD.
The benefit for the individual subject is anticipated to be significant during
the Phase 3 clinical study. The subject may benefit from a product combination
that minimizes excessive FVIII administration. Variations in VWF multimeric
composition may lead to variability with respect to treating or preventing
bleeds in VWD patients, especially mucosal bleeds which are especially
problematic. Baxter*s rVWF product consistently contains low ultra-large
molecular weight (ULMW) VWF multimers, which are subsequently cleaved by the
patient*s endogenous ADAMTS13. This may result in improved platelet and
collagen binding and therefore provide more predictable treatment outcomes. By
using a recombinant product, the risk of contamination with viruses or variant
Creutzfeldt-Jakob Disease associated with the use of products of human or
animal origin has been eliminated. At this stage of product development, the
key societal benefit is a better understanding of advanced treatment options
for VWD and enhanced product availability.
Study objective
Primary objective:
• Assess the pharmacokinetics (PK) of rVWF:rFVIII and rVWF, and to assess the
safety and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding events
in subjects with severe hereditary VWD
Secundary objectives:
• Compare the PK parameters of rVWF alone or in combination with rFVIII in
subjects with type 3 VWD
• Examine the PK parameters of rVWF in subjects with severe VWD or type 2N VWD
• Evaluate the hemostatic efficacy, safety, and tolerability of rVWF:rFVIII and
rVWF in subjects with VWD receiving the investigational product for the
treatment of bleeding episodes
• Evaluate tolerability and safety of rVWF including the development of
inhibitory and total binding anti-VWF antibodies and clinically significant
changes in laboratory parameters following drug administration
• Assess changes in health-related quality of life (HRQoL)
Study design
Phase 3, multicenter, open-label clinical study , except for the PK50 arm
(single blinded)
Intervention
• Subjects (type 3 only) participating in the crossover PK arm (PK 50 Arm) will
undergo 2 PK assessments: one following an infusion of 50 IU/kg VWF:RCo rVWF
and an infusion of 38.5 IU/kg FVIII, and the other following an infusion of 50
IU/kg VWF:RCo rVWF and an infusion of saline (placebo). The order in which the
PK assessments will be performed will be randomized and blinded.
• Subjects participating in the PK 80 Arm will receive a single infusion of 80
IU/kg VWF:RCo rVWF at the start of the study and another after at least 6
months on study.
Treatment and Prevention of Bleeding Episodes:
An initial dose of 40-60 IU/kg VWF:RCo (+ 30-45 IU rFVIII/kg) will be infused
to treat/prevent bleeding episodes. Subsequent doses, if necessary, will be
20-60 IU VWF: RCo IU/kg administered up to 24 hours apart to maintain VWF:RCo
and FVIII levels of at least 30 IU/dL for as long as deemed necessary by the
investigator. Additional doses of rFVIII will be administered with the rVWF
product if plasma FVIII levels fall below 30 IU/dL during the treatment period.
Study burden and risks
Please refer to tabel 20.2, 20.4 and 20.5 for an overview of all study visits
and procedures.
Summary of procedures:
- Informed consent: during screening visit
- Physical examination: during all visits
- Vital signs: during all visits
- ECG: during screening visit, baseline visit and PK-infusion visit
- Quality if Life Questionnaires: during baseline and completion visit
- Blood analysis and urinanalysis: during all visits
- Pregnancy test: during screening visit
- Subject diary: during all visits except for screening visit en PK-infusion
visits
The most potential risks in this study are those risks associated with all new
protein therapeutics:
- risk of hypersensitivity reactions (generalized itching, and tightness of the
chest, shortness of breath, low blood pressure, and anaphylaxis)
- risk of formation of antibodies that will inhibit the activity of the study
drug
- risk of thrombogenicity
- possible risk of infectious viruses
- fever
Based in the prior studies of rFVIII, you may experience the following side
effects: a strange taste in your mouth, itching, dizziness, headache,
catheter-related infection, cold shivers, hot flushes, diarrhea, sweating,
nausea, pain in the upper abdomen, chest pain, prolonged bleeding after post
operative drain removal, decreased hematocrit, swelling limbs, swelling of
joints, shortness of breath, fever, decreased FVIII levels and post operative
unspecified blood clot at the site of surgery.
Industriestrasse 67
Vienna 1221
AT
Industriestrasse 67
Vienna 1221
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Listed location countries
Age
Inclusion criteria
The subject has been diagnosed with:
Type 1 (VWF:RCo < 20 IU/dL) or,
Type 2A (VWF:RCo< 20 IU/dL), Type 2B (as diagnosed by genotype), Type 2N
(FVIII:C<10% and historically documented genetics), Type 2M or,
Type 3 (VWF:Ag <= 3 IU/dL) or,
Severe VWD with a history of requiring substitution therapy with von Willebrand factor
concentrate to control bleeding
• The subject, who participates for the treatment for bleeding episodes, has had a minimum of 1 documented bleeds (medical history) requiring VWF coagulation factor replacement therapy during the previous 12 months prior to enrollment.
• The subject has a Karnofsky score >=60.
• The subject is at least 18 and not older than 65 years of age at enrollment.
Exclusion criteria
• The subject has been diagnosed with pseudo VWD or another hereditary or acquired coagulation
disorder other than VWD (eg qualitative and quantitative platelet disorders or elevated PT/
international normalized ratio [INR] >1.4).
• The subject has a documented history of a VWF:RCo half-life of <6 hours.
• The subject has a history or presence of a VWF inhibitor at screening.
• The subject has a history or presence of a factor VIII (FVIII) inhibitor with a titer >=0.4 BU (by Nijmegen assay) or >=0.6 BU (by Bethesda assay).
• The subject has a known hypersensitivity to any of the components of the study drugs, such as to
mouse or hamster proteins.
• The subject has a medical history of immunological disorders, excluding seasonal allergic
rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
• The subject has a medical history of a thromboembolic event.
• The subject is HIV positive with an absolute CD4 count <200/mm3.
• The subject has been diagnosed with cardiovascular disease (New York Heart Association [NYHA] classes 1-4).
• The subject has an acute illness (eg, influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) at screening.
• The subject has been diagnosed with significant liver disease as evidenced by 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).
• The subject has been diagnosed with renal disease, with a serum creatinine level >=2 mg/dL.
• In the judgment of the investigator, the subject has another clinically significant concomitant disease (eg, uncontrolled hypertension) that may pose additional risks for the subject.
• The subject has been treated with an immunomodulatory drug, excluding topical treatment (eg, ointments, nasal sprays), within 30 days prior to signing the informed consent.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-024108-84-NL |
| ClinicalTrials.gov | NCT01410227 |
| CCMO | NL37484.078.11 |