Primary objective: The primary objective of the study is to evaluate the hemostatic efficacy and safety of rVWF, with or without ADVATE, in the treatment and control of nonsurgical bleeding events in pediatric subjects (
ID
Source
Brief title
Condition
- Haematological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome measure is hemostatic efficacy, defined as the number of
pediatric subjects with treatment success for rVWF-treated
nonsurgical bleeding episodes (using a 4-point scale). Bleeding episode
treatment success is defined as a mean efficacy rating score of <2.5.
Timepoint of evaluation:
Timepoint of assessment is within 24 hrs after onset of each bleeding episode
an infusion of study drug, recording is made after resolution of each bleeding
episode.
Secondary outcome
Efficacy
1. Number of treated nonsurgical bleeding episodes with an efficacy rating of
'excellent' or 'good'.
2. Number of infusions, rVWF units, and ADVATE units (if needed), per bleeding
episode.
3. For elective surgery: an overall assessment of hemostatic efficacy 24 hours
after the last perioperative infusion of rVWF, assessed by the Investigator
(hematologist) on a 4-point scale.
Safety
1. Incidence and severity of adverse events (AEs) by system organ class
(SOC) and preferred term.
2. Incidence of thrombotic events.
3. Incidence of severe hypersensitivity reactions.
4. Development of neutralizing antibodies to VWF and FVIII.
5. Development of total binding antibodies to VWF.
6. Development of antibodies to CHO proteins, murine IgG, and rFurin.
Pharmacokinetics
1.Area under the plasma concentration/time curve from 0 to 96 hours
post-infusion (AUC0-96h), area under the plasma concentration/time curve from
time 0 to infinity (AUC0-*), mean residence time (MRT), clearance (CL),
incremental recovery (IR), in-vivo recovery (IVR), elimination phase half-life
(T1/2), and volume of distribution at steady state (Vss) for VWF:RCo.
2. Area under the plasma concentration/time curve from 0 to 96 hours
post-infusion (AUC0-96h) for VWF:Ag and VWF:CB. Point estimates per age cohort
will be presented.
3. Area under the plasma concentration/time curve from 0 to 96 hours
post-infusion (AUC0-96h) for FVIII activity. Point estimates per age cohort
will be presented.
Timepoint of evaluation:
Hemostatic Efficacy Assessments for surgeries are performed immediately after
surgery by operating surgeon and then 24 hours after last perioperative rVWF
infusion, Day 7 and Day 14 by the investigator. (See section 11 of protocol for
reference)
Background summary
Von Willebrand factor (VWF) is a large multimeric glycoprotein (with multimers
ranging in molecular weight from 500 to >20000 KDa) that is normally found in
plasma, alpha-granules of platelets, and intracellular organelles known as
Weibel-Palade bodies.
VWF is the carrier molecule for factor VIII (FVIII), an essential cofactor of
secondary hemostasis that leads to fibrin clot formation, and facilitates
platelet adhesion to subendothelium at sites of vascular injury.
Human VWF produced by recombinant technology provides a new perspective in
treatment of von Willebrand disease (VWD). Limitations associated with
plasma-derived VWF (pdVWF) concentrates can be overcome by recombinant VWF
(rVWF). Baxalta has developed an rVWF, which is synthesized by a genetically
engineered Chinese hamster ovary (CHO) cell line that expresses the VWF gene.
Recombinant VWF has undergone extensive in vitro and in vivo non-clinical
investigation supporting its safe evaluation in humans. The clinical
development program consists of 4 completed trials (3 in VWD and 1 in
hemophilia) and 1 ongoing trial.
Recombinant VWF was granted licensure in the United States in December 2015
under the brand name VONVENDI for on-demand treatment and control of bleeding
episodes in adults diagnosed with VWD, although it is not yet available on the
market.
Study objective
Primary objective:
The primary objective of the study is to evaluate the hemostatic efficacy and
safety of rVWF, with or without ADVATE, in the treatment and control of
nonsurgical bleeding events in pediatric subjects (<18 years of age) diagnosed
with severe, hereditary VWD.
Secondary objectives:
Efficacy:
The secondary efficacy objective will be an overall assessment of hemostatic
efficacy after the last perioperative rVWF infusion in pediatric subjects
undergoing elective or emergency surgery
Safety:
The overall AE profile of rVWF will be assessed by frequency, severity, and
seriousness. Additionally, there will be focused review of thrombotic events
and severe hypersensitivity events.
Pharmacokinetics:
The PK profile of rVWF will be assessed.
Exploratory Objectives:
1. Health-related Quality of Life (HRQoL) variables
2. Health resource use
Study design
This is a Phase 3, prospective, open-label, uncontrolled, multicenter study to
evaluate the efficacy, safety, tolerability, and PK of rVWF, with or without
ADVATE, for the treatment and control of nonsurgical bleeding episodes and
bleeding associated with elective and emergency surgery in pediatric subjects
with severe VWD.
Intervention
Infusion with study drug, if in the elective or emergency surgery groups:
surgery
Study burden and risks
The benefit for the individual subject is anticipated to outweigh the potential
risks of rVWF during this Phase 3 clinical study. The subject may benefit from
a product 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 with unpredictable
efficacy outcomes.
By using a recombinant product, the risk of contamination with blood-borne
viruses or variant Creutzfeldt-Jakob Disease associated with the use of
products of human or animal origin has been virtually eliminated. As with any
IV protein product, allergic-type hypersensitivity reactions may occur, as well
as neutralizing antibodies to VWF.
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. Diagnosis of severe VWD (defined as VWF:RCo <20%):
a. Type 1 (VWF:RCo <20 IU/dL); or
b. 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
c. Type 3 (VWF:Ag *3 IU/dL).
2. Age 0 to <18 years at the time of screening
3. The subject has provided assent (if appropriate) and legally
authorized representative(s) has
provided informed consent
4. If female of childbearing potential, subject presents with a negative
serum pregnancy test
5. If applicable, subject agrees to employ adequate birth control
measures for the duration of the study
6. Subject 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 prescreening evaluation held between the Investigator and the
Sponsor, to ensure no eminent risk is present that could challenge the
subject's compliance with the study requirements.
Additional inclusion criteria for previously treated subjects and subjects
undergoing surgery are as follows:
1. Unable to tolerate or are inadequately responsive to deamino-delta-Darginine
vasopressin
2. The subject has had a minimum of 1 documented bleed requiring VWF
coagulation factor
replacement therapy (ie, treatment with a VWF product) during the previous 12
months prior to enrollment
and overall historically
3 or more exposure days (EDs) to plasma-derived VWF.
Additional inclusion criterion for previously untreated subjects are as
follows:
1. The subject has not received prior VWF coagulation factor
replacement therapy
Exclusion criteria
Subjects who meet ANY of the following criteria are not eligible for this
study:
1. Diagnosis of pseudo-VWD or another hereditary or acquired
coagulation disorder (eg, qualitative
and quantitative platelet disorders or elevated prothrombin
time/international normalized ratio
>1.4)
2. History or presence of a VWF inhibitor at Screening
3. History or presence of a FVIII inhibitor with a titer *0.4 Bethesda
units (BU) (by Nijmegen assay)
or *0.6 BU (by Bethesda assay)
4. Documented history of a VWF:RCo half-life <6 hours
5. Known hypersensitivity to any of the components of the study drug,
such as mouse or hamster
proteins
6. Medical history of immunological disorders, excluding seasonal
allergic rhinitis/ conjunctivitis/
asthma, food allergies, or animal allergies
7. Medical history of a thromboembolic event
8. Human immunodeficiency virus positive, with an absolute CD4 count
*200/mm3
9. In the judgment of the Investigator, the subject has another clinically
significant concomitant
disease (eg, uncontrolled hypertension, cancer) that may pose additional
risks for the subject
10. Diagnosis of significant liver disease, as evidenced by, but not
limited to, any of the following:
serum alanine aminotransferase 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
11. Diagnosis of renal disease, with a serum creatinine level *2.5 mg/dL
12. Immunomodulatory drug treatment other than anti-retroviral
chemotherapy (eg, *-interferon, or
corticosteroid agents at a dose equivalent to hydrocortisone greater than
10 mg/day (excluding
topical treatment [eg, ointments, nasal sprays]), within 30 days prior to
signing the informed
consent (or assent, if appropriate)
13. If female, subject is pregnant or lactating at the time informed
consent (or assent, if appropriate) is
obtained
14. Subject has participated in another clinical study involving an 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
15. Subject's legal representative is a family member or employee of the
Investigator
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 | EUCTR2016-001477-33-NL |
| ClinicalTrials.gov | NCT02932618 |
| CCMO | NL62983.078.17 |