The primary objective of this study is to prospectively evaluate the annualized bleeding rate (ABR) for spontaneous bleeding episodes while on prophylactic treatment with rVWF (vonicog alfa) and to compare it to the subject's historical ABR for…
ID
Source
Brief title
Condition
- Blood and lymphatic system disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding
episodes during prophylactic treatment with rVWF (vonicog alfa).
Secondary outcome
Additional efficacy of prophylactic treatment with rVWF (vonicog alfa).
ABR present reduction success for OD subjects defined as at least 25% reduction
of ABR for spontaneous (not related to trauma) bleeding episodes during rVWF
(vonicog alfa) prophylaxis relative to the subject's own historical ABR during
on-demand treatment.
ABR preservation success for pdVWF switch subjects defined as achieving an ABR
for spontaneous bleeding episodes during rVWF (vonicog alfa) prophylaxis that
is no greater than the subject's own historical ABR during prophylactic
treatment with pdVWF.
Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episoces
during the 12-month prophylactic treatment with rVWF (vonicog alfa).
Total number of infusions and the average number of infusions per week during
prophylactic treatment with rVWF (vonicog alfa).
Total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic
treatment.
Spontaneous ABR by location of bleeding (Gastrointestinal [GI], epistaxis,
joint bleeding, menorrhagia, oral and other mucosa, muscle and soft tissue,
etc.) while on prophylactic treatment with rVWF (vonicog alfa).
Safety
Adverse events (AEs): incidence, severity, causality
Thromboembolic events
Hypersensitivity reactions
Development of neutralizing antibodies to VWF and FVIII
Development of total binding antibodies to VWF and FVIII
Development of binding antibodies to Chinese hamster ovary (CHO) proteins,
mouse immunoglobulin G (IgG) and rFurin.
Clinically seignificant changes in vital signs and clinical laboratory
parameters relative to baseline.
Pharmacokinetics (PK) and Pharmacodynamics (PD)
PK parameters after a washout for on-demand subjects: incremental recovery
(IR), terminal half-time (T/2), mean residence time (MRT), area under the
concentration versus time curve from 0 to infitity (AUC0-infinity), area under
the concentration versus time curve from 0 to the last measurable concentration
(AUC0-tlast), maximum concentration (Cmax), minimum time to reach the maximum
concentration (Tmax), volume of distribution at steady state (Vss), and
clearance (CL) based on VWF:RCo, Von Willebrand Factor antigen (VWF:Ag), Von
Willebrand collagen binding activity (VWF:CB).
PD parameters after a washout for on-demand subjects: Cmax, Tmax, and
AUC0-tlast as measured in FVIII activity by the 1-stage clotting assay
(FVIII:C).
PK parameters at steady state for on-demand and switch subjects: areas under
the concentation versus time curve from 0 to end of the partial dosing interval
(AUC0-tau;ss), maximum concentration during the partial dosing interval
(Cmax;ss), minimum time to reacht the maximum concentration (Tmin;ss), ad
minimum concentration during the partial dosing interval (Cmin;ss) based on
VWF:RCo, VWF:Ag, and VWF:CB. PK parameters at steady state will be assessed
shortly after reachting stady state for switch subjects and at the end of the
study for on-demand as well as for switch subjects all based on the longer
interval of the irregular dosing intervals employed.
PD parameters at steady state for on-demand and switch subjects: AUC0-tau;ss,
Cmax;ss, Tmax;ss, and Cmin;ss as measured in FVIII activity by the 1-stage
clotting assay (FVIII:C). PD parameters at steady state will be assessed
shortly after reaching steady state for switch subjects and at the end of the
study for on-demand as well as for switch subjects all based on the longer
interval of the irregular dosing intervals employes.
Time course of FVIII clotting activity (FVIII:C) levels.
Background summary
Baxalta US Inc. (hereafter referred to as Baxalta or sponsor) has developed a
human
recombinant von Willebrand Factor (rVWF), which is co-expressed with recombinant
factor VIII (rFVIII) in a Chinese hamster ovary (CHO) cell line and separated
during the
subsequent downstream process. To address concerns regarding the risk of
transmission of blood-borne pathogens that may be introduced by human plasma,
no exogenously added raw materials of human or animal origin are employed in
the cell culture, purification, or formulation of the final container product.
The only proteins present in the final container product other than rVWF are
trace quantities of murine
immunoglobulin (IgG, from the immunoaffinity purification), host cell (i.e.,
CHO)
protein, rFurin (used to further process rVWF). rVWF is intended for the
treatment of
von Willebrand disease (VWD).
Study objective
The primary objective of this study is to prospectively evaluate the annualized
bleeding rate (ABR) for spontaneous bleeding episodes while on prophylactic
treatment with rVWF (vonicog alfa) and to compare it to the subject's
historical ABR for spontaneous bleeding episodes during ondemand treatment.
Efficacy of the treatment of perioperative bleeding management, if surgery is
required.
Study design
This is a phase 3, prospective, open-label, non-randomized, international
multicenter study evaluating efficacy, safety, including immunogenicity and
thrombogenicity, and HRQoL of prophylactic treatment regimen with rVWF for
subjects with severe VWD.
Intervention
Subjects transitioning from on-demand treatment will be infused twice weekly
with BAX 111 (rVWF) at doses of 50 ± 10 IU/kg rVWF:RCo. The dose may be
adjusted within this range based on the PK data, subject*s history of bleeding
episodes, and the results from clinical and laboratory assessments.
During treatment any bleeding episodes requiring substitution therapy with VWF
concentrate to control bleeding will be treated with rVWF with or without
ADVATE.
The dose will be according to the bleeding severity and it will be adjusted to
the clinical
response
Study burden and risks
The benefits mentioned in protocol section 6.6 outweigh the following potential
risks of rVWF:
• allergic-type hypersensitivity reactions as with any intravenous protein
product
• the occurrence of thromboembolic events
• the development of neutralizing antibodies to VWF
Refer to the IB for further details on benefits and risks of the IP.
Industriestrasse 67
Vienna A-1221
AT
Industriestrasse 67
Vienna A-1221
AT
Listed location countries
Age
Inclusion criteria
Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject has a documented diagnosis of severe VWD (baseline VWF:RCo <20 IU/dL) with a history of requiring substitution therapy with von Willebrand factor concentrate
to control bleeding:
a. Type 1 (VWF:RCo <20 IU/dL) or,
b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2M or,
c. Type 3 (VWF:Ag <=3 IU/dL).
2. Diagnosis is confirmed by genetic testing and multimer analysis, documented in patient history or at screening.
3. For on-demand patient groep, subject currently receiving on-demand treatment for whom prophylactic treatment is recommended by the investigator.
4. For pdVWF switch patient group, subject has been receiving prophylactic treatment of pdVWF products for no less than 12 months prior to screening.
5. For on-demand patient groep, subject has >=3 documented spontaneous bleeds (ont including menorrhagia) requiring VWF treatment during the past 12 months.
6. Availability of records to reliably evaluate type, frequency and treatment of bleeding episodes during at least 12 months preceeding enrollment.
Up to 24 months of retrospective data should be collected if available. Availability of dosing and factor consumption during 12 months (up to 24 months) of treatment prior to enrollment is required for pdVWF switch subjects and is desired (but not a requirement) for on-demand subjects.
7. Subject is >=18 years old at the time of screening and has a body mass index >=15 but <40 kg/m2.
8. If female of childbearing potential, subject presents with a negative blood/urine pregnancy test at screening and agrees to employ adequate birth control measures for the duration of the study.
9. Subject is willing and able to comply with the requirements of the protocol.
Exclusion criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1. The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another hereditary or acquired coagulation disorder other than VWD (e.g., qualitative and quantitative platelet disorders or elevated prothrombin time (PT)/international normalized ratio [INR] 1.4).
2. The subject is currently receiving prophylaxis treatment with more than 5 infusions per week.
3. The subject is currently receiving prophylaxis treatment with a weekly dose exceeding 240 IU/kg.
4. The subject has a history or presence of a VWF inhibitor at screening.
5. The subject has a history or presence of a FVIII inhibitor with a titer >=0.4 Bethesda units (BU) (by Nijmegen modified Bethesda assay) or >=0.6 BU (by Bethesda assay).
6. The subject has a known hypersensitivity to any of the components of the study drugs, such as to mouse or hamster proteins.
7. The subject has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8. The subject has a medical history of a thromboembolic event.
9. The subject is human immunodeficiency virus (HIV) positive with an absolute Helper T cell (CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease per investigator's medical assessment of the subject's current condition or medical history or as evidenced by any of the following:
serum alanine aminotransferase (ALT) 5 times the upper limit of normal; hypoalbuminemia; portal vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal varices).
11. The subject has been diagnosed with renal disease, with a serum creatinine (CR) level >=2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject has been treated with an immunomodulatory drug, excluding topical treatment (e.g., ointments, nasal sprays), within 30 days prior to signing the informed consent.
14. The subject is pregnant or lactating at the time of enrollment.
15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, dysplasia).
16. The subject has participated in another clinical study involving another investigational product (IP) 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.
17. The subject has a progressive fatal disease and/or life expectancy of less than 15 months.
18. The subject is scheduled for a surgical intervention.
19. The subject is identified by the investigator as being unable or unwilling to cooperate with study procedures.
20. The subject has 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.
21. The subject is in prison or compulsory detention by regulatory and/or juridical order
22. The subject is member of the study team or in a dependent relationship with one of the study team members which includes close relatives (i.e., children, partner/spouse,
siblings and parents) as well as employees.
Delay criteria
1. If the subject presents with an acute bleeding episodes or acute illness (e.g., influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) the screening visit will be postponed until the subject has recovered.
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 | EUCTR2016-001478-14-NL |
CCMO | NL59762.078.16 |