The primary objective is to evaluate the peri-operative hemostatic efficacy of BAX 855 in male PTPs aged 18 - 75 years with severe hemophilia A (FVIII
ID
Source
Brief title
Condition
- Blood and lymphatic system disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Global Hemostatic Efficacy score, which is composed of 3 individual ratings:
1. Assessment of intra-operative hemostatic efficacy of BAX855 performed by the
operating surgeon
2. Assessment of postoperative hemostatic efficacy of BAX855 at postoperative
day 1 performed by the operating surgeon
3. Assessment of postoperative hemostatic efficacy of BAX855 at EOS visit
performed by the investigator, at discharge or Day 14 , whichever is
first.
Secondary outcome
EFFICACY:
* Intra- and post-operative blood loss at the end of surgery, at postoperative
Day 1 and until discharge or Day 14 (whichever is first), as applicable,
compared to the estimated volume of expected average and maximum blood loss in
a comparable healthy individual as predicted preoperatively by the
investigator/surgeon
* Volume of blood, red blood cells, platelets, and other blood products
transfused
* Occurrence of bleeding episodes and additional need for surgical intervention
* Daily and total weight-adjusted consumption of BAX 855 per subject
SAFETY:
* Incidence of inhibitory antibodies to FVIII
* Development of binding antibodies to FVIII, BAX 855, and PEG
* Development of binding antibodies to CHO proteins
* Occurrence of thrombotic events
* Incidence of severe allergic reactions (e.g. anaphylaxis)
* Other IP-related adverse events (AEs)
* Incidence of clinically significant changes in vital signs and routine
laboratory parameters (hematology, clinical chemistry )
PHARMACOKINETICS
* Presurgical PK (only in subjects undergoing major elective surgery who did
not undergo a PK assessment in previous BAX 855 study)
* Incremental recovery (IR), area under the plasma concentration /time curve
from time 0 to infinity (AUC0-*), area under the plasma concentration versus
time curve from 0 to 96 h (AUC0-96h) terminal half *life (T1/2), mean residence
team (MRT), clearance (CL), volume of
distribution at steady state (Vss) will be calculated.
* Incremental recovery (IR) following the initial bolus infusion prior to
surgery
Background summary
The absence of FVIII leads to 'spontaneous' bleeding episodes (occurring
primarily in joints, muscles, and less commonly, in soft tissues) and to
excessive bleeding following trauma or injury. Hemophilia A is currently
treated with FVIII replacement using either plasma-derived (pdFVIII) or rFVIII
concentrates.
The intended indication for BAX 855 is treatment and prevention of bleeding in
subjects with hemophilia A.
The investigational product (IP) in this study is BAX 855, a PEGylated
recombinant FVIII (rFVIII), intended for use as a long-acting FVIII replacement
therapy in prophylaxis and treatment of bleeding in patients with severe
hemophilia A.
Current management of severe hemophilia A includes on-demand treatment for
bleeding events and prophylaxis to prevent bleeds. Since the half-life of
current FVIII products is in the range of 12-14 h, current prophylaxis regimens
call for infusion of FVIII every other day, or every 2-3 days when based on
each patient*s individual PK profile. PEGylation of FVIII is designed to
prolong the half-life of FVIII, with the intent of reducing the frequency of
administration while maintaining similar therapeutic benefit as existing FVIII
products; improving patient convenience and compliance with therapy; and
thereby, improving overall health outcomes.
The study design is in compliance with EMA/CHMP/BPWP/144533/2009
recommendations for the study of FVIII in hemophilia A, and consists of 1
completed, 3 ongoing and 3 planned studies. A Phase 1 study (Baxter Clinical
Study 261101) has been completed, and the results showed that BAX 855 was safe
and well tolerated.
A Phase 3 pivotal study is ongoing since January 2013 (protocol 261201) and
investigates PK properties in 25 subjects of whom at least 6 subjects are
adolescents, as well as hemostatic efficacy, safety and immunogenicity in the
control and prophylaxis of bleeding episodes in a total of 143 previously
treated patients (PTPs) with severe hemophilia A * 12 years of age.
The Phase 3 continuation study 261302 will further evaluate safety,
immunogenicity, and hemostatic efficacy of BAX 855, and health-related quality
of life over a prolonged period of time.
Study objective
The primary objective is to evaluate the peri-operative hemostatic efficacy of
BAX 855 in male PTPs aged 18 - 75 years with severe hemophilia A (FVIII <1%)
undergoing major or minor, elective or minor emergency surgical, dental or
other invasive procedures as determined by the Global Hemostatic Efficacy
Assessment (GHEA) score.
Secondary Objective(s)
* Efficacy
- To determine intra- and post-operative blood loss, volume of blood, red
blood cells, platelets, and other blood products transfused, the occurrence of
bleeding episodes and additional need for surgical intervention, and daily and
total weight-adjusted consumption of BAX 855 per subject
* Safety
- To determine the safety of BAX 855 in subjects undergoing surgery, as
assessed by occurrence of AEs and changes in vital signs and clinical
laboratory parameters
* Pharmacokinetics
- To determine PK parameters prior to major surgeries,
- To determine IR following the initial bolus infusion prior to surgery
Study design
This is a Phase 3 prospective, open-label, uncontrolled, multicenter study to
evaluate the efficacy and safety of BAX 855 in male PTPs 18 -75 years
of age, with severe hemophilia A (FVIII <1%). Subjects will have no history of
FVIII inhibitors and will be undergoing, major or minor elective, or minor
emergency surgical, dental or other invasive procedures.
Eligible subjects may be actively participating in or have completed
participation in another BAX 855 study or may be newly recruited; however
newly-recruited subjects will not be enrolled if they require minor emergency
and minor elective surgeries.
Elective surgical procedures will prospectively be defined as major or minor by
the investigator/surgeon and agreed with the medical director or designee,
based on the protocol guidance and definitions and in consideration of each
subject*s characteristics. Major emergency surgeries are not in the scope of
this study.
Subjects may undergo more than one surgery or 2 parallel surgeries, such as
bilateral knee replacement, however in these cases prior approval by the
sponsor is required.
The study will be conducted globally and will be divided into 5 periods:
Screening, Preoperative including PK assessment, Intraoperative, Postoperative,
and End of study.
Intervention
This is a phase 3 studie to the efficaty and safety of PEGylated recombinant
FVIII (BAX 855) adminsitered to Previously treated patients (PTPs) with severe
hemophilia A (FVIII <1%) undergoing elective surgical procedures
The (most) standard treatment for this population is ADVATE (rFVIII). the
investigational product BAX 855 has not yet been used during intervention.
Study burden and risks
Patient will be treated with investigational product during surgery, for which
he
- normally received his standard FVIII treatment. The patient can enter the
follow-up study afterwards (261302)
- or already participate in another BAX 855 study and therefore already receive
BAX 855 treatment.
Additional blood samples will be taken to follow the course of the treatment,
and see how the body responds to BAX 855.
Industriestrasse 67
Vienna A-1221
AT
Industriestrasse 67
Vienna A-1221
AT
Listed location countries
Age
Inclusion criteria
1. Subject requires an elective major surgical, dental or other invasive procedure (e.g. biopsy, endoscopy).
2. Subject and/or legal representative has/have provided signed informed consent.
3. Subject is 18 to 75 years of age at the time of enrollment.
4. Subject is male with severe hemophilia A (FVIII level <1%) as confirmed by the central lab at screening.
5. Subject was previously treated with FVIII concentrates with *150 documented exposure days (EDs).
6. Subject is currently receiving prophylaxis or on-demand therapy with FVIII concentrate.
7. Subject has a Karnofsky performance score of *60 at screening.
8. Subject is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count *200 cells/mm3, as confirmed by central laboratory at screening.
9. Subject is Hepatitis C virus negative (HCV-) by antibody or PCR testing, as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis as assessed by the investigator. If positive, antibody titer will be confirmed by PCR.
10. Subject is willing and able to comply with the requirements of the study protocol.
11. For subjects transitioning from parent BAX 855 studies, the subjects continue to meet the entry criteria
Exclusion criteria
1. Subject has detectable FVIII inhibitory antibodies (*0.4 BU using the Nijmegen modification of the Bethesda assay) at screening as determined by the central laboratory or at any timepoint prior to screening (*0.4 BU using the Nijmegen modification of the Bethesda assay or *0.6 BU using the Bethesda assay).
2. History of ongoing or recent thrombotic disease, fibrinolysis or disseminated intravascular coagulation (DIC).
3. Subject has a platelet count <100 x 109/L, as confirmed by central laboratory at screening.
4. Subject has severe renal impairment (serum creatinine > 2.0 mg/dL), as confirmed by central laboratory at screening.
5. Subject has severe chronic hepatic dysfunction (eg *5 X upper limit of normal alanine aminotransferase (ALT), as confirmed by central laboratory at screening, or a documented INR > 1.5).
6. Subject has a known hypersensitivity towards mouse or hamster proteins, polysorbate 80 or to PEG.
7. Subject is currently using or has recently (< 30 days) used pegylated drugs (other than BAX855) prior to study participation or is scheduled to use such drugs during trial participation.
8. Subject is currently participating in another clinical drug (other than BAX855) or device study or use of another investigational product or device within 30 days prior to study entry.
9. Subject has a diagnosis of an inherited or acquired hemostatic defect other than hemophilia A.
10. Subject is currently receiving, or scheduled to receive during the course of the study, an immunomodulating drug (e.g., systemic corticosteroid agent at a dose equivalent to hydrocortisone greater than 10 mg/day, or alpha interferon) other than anti-retroviral chemotherapy.
11. Subject has a clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect subject safety or compliance.
12. The subject has an incremental recovery < 1.5 IU/dL:IU/kg as determined in the parent study, if applicable
13. Subjects undergoing minor of major emergency surgery
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 | EUCTR2013-001359-11-NL |
| ClinicalTrials.gov | NCT#pending |
| CCMO | NL45421.018.14 |