To evaluate the perioperative hemostatic efficacy of BAX 802 in male subjects with CHA with inhibitors to human factor VIII (hFVIII) undergoing major or minor elective surgical, dental, or other invasive procedures as determined by the Global…
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Source
Brief title
Condition
- Platelet disorders
- Blood and lymphatic system disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome measure is the proportion of all surgical, dental, or other
invasive procedures with a "good"or "excellent"response as measured by GHEA
score, which is composed of 3 individual ratings:
- GHEA1: Assessment of intraoperative (Day 0) hemostatic efficacy of BAX 802
performed by the operating surgeon at the end of surgery.
- GHEA2: Assessment of postoperative hemostatic efficacy of BAX 802 at
postoperative Day 1 (approximately 24 hours (+ / - 6 hours) post-surgery
performed by the operating surgeon. Note: If a patient is discharged <24 hours
following surgery, then the GHEA2 hemostatic efficacy assessment will require a
return visit the following day.
-GHEA3: Assessment of overall perioperative hemostatic efficacy of BAX 802 at
the GHEA3 Visit (discharge or within 24 to 72 hours after the last
perioperative treatment dose of BAX 802 (whichever is earlier), performed by
the investigator, and where possible, also by the operating surgeon. Assessment
by both is strongly recommended. In cases where there are differing
assessments, the Investigator's assessment will be used.
The scores of each of the 3 individual ratings (GHEA1, GHEA2, GHEA3) described
above, will be added together to form a GHEA
score.
Secondary outcome
Efficacy
1. Intra -and post-operative blood loss compared to the estimated volume of
expected average blood loss and expected maximum
blood loss in a comparable healthy individual with similar demographic
characteristics as predicted preoperatively by the investigator/surgeon at
the following time points:
* Intraoperative, from start until the end of surgery
* Postoperative Day 1, from end of surgery to approximately 24 hours (+ /- 6
hours) after surgery
* Overall perioperative at discharge or 24 to 72 hours after the last
perioperative treatment dose of BAX802 (whichever is earlier)
2. Proportion of major surgeries with good or excellent hemostatic score
3. Daily and total weight-adjusted administration of BAX 802 per subject
4. Amount of blood products (e.g whole blood, red blood cells, platelets, and
plasma transfused
Safety
1. Development of, and changes to, the titer of inhibitory and binding
antibodies (IgG and IgM) to PFVIII
2. Development of, and changes to, the titer of inhibitory and binding
antibodies (IgG and IgM) to to hFVIII
3. Development of binding antibodies to BHK proteins
4. Occurrence of thrombo-embolic events
5. Incidence of severe allergic reactions (eg, anaphylaxis)
6. Incidence of other IP-related AEs
7. Incidence of clinically significant changes in vital signs and routine
laboratory parameters (hematology, clinical chemistry)
Background summary
The investigational product (IP), BAX 802, is a recombinant form of porcine
factor VIII (rpFVIII) from which the B domain has been deleted. Deletion of the
B domain does not affect the safety or efficacy of this recombinant form of
human factor VIII (rhFVIII) in the treatment of hemophilia A. BAX 802 (rpFVIII)
is being developed for the perioperative management of hemostasis in subjects
with congenital hemophilia A (CHA) with inhibitors to human factor VIII
(hFVIII) undergoing surgical or other invasive procedures. This rpFVIII was
approved by the United States Food and Drug Administration (FDA) in 2014 for
the treatment of bleeding episodes in adults with acquired hemophilia A (AHA;
non hemophilia subjects developing spontaneous autoantibody inhibitors to
hFVIII) under the trade name OBIZUR®.
Study objective
To evaluate the perioperative hemostatic efficacy of BAX 802 in male subjects
with CHA with inhibitors to human factor VIII (hFVIII) undergoing major or
minor elective surgical, dental, or other invasive procedures as determined by
the Global Hemostatic Efficacy Assessment (GHEA) score.
Study design
This study is a Phase 3, uncontrolled, open-label, single-group, multicenter
study to determine the safety and efficacy of BAX 802 in at least 10 surgeries
in 10 evaluable male subjects with CHA with inhibitors to hFVIII who are
undergoing major or minor elective surgical, dental, or other invasive
procedures (at least 5 major surgeries in 5 evaluable subjects).
Intervention
BAX 802 will be administered as an intravenous infusion per the dosing schema
for major and minor surgeries. Based on the category (minor or major) and type
of surgery, the investigator must outline the expected FVIII maintenance plan
with target peak and trough levels covering the
surgical, dental or invasive procedure until expected wound healing.
Loading Dose of BAX 802:
* Major Surgery: 80 U/kg + body weight (kg) x 40(1-[Hct%/100]) x anti-pFVIII
inhibitor titer (BU), administered approximately 1 to 2 hours prior to the
surgery
* Minor Surgery: 50 U/kg + body weight (kg) x 40(1-[Hct%/100]) x anti-pFVIII
inhibitor titer (BU), administered approximately 1 to 2 hours prior to the
surgery
Subsequent doses, dosing frequency, and duration of treatment will be based on
the clinical judgment and measured FVIII levels achieved, and will require
empirically based adjustments until hemostasis is achieved based on the
following calculation:
Required dose (U) = [body weight (kg) x desired FVIII rise (U/dL or % of
normal)]/1.2 (U/kg per U/dL).
Study burden and risks
OBIZUR® was approved based on the safety and efficacy data from 28 subjects
with AHA treated with B-domain deleted rpFVIII glycoprotein in the Phase 2/3
open-label clinical study OBI-1-301. The safety, hemostatic activity, and PK
profile of B-domain deleted rpFVIII glycoprotein was also supported by results
of an open-label Phase 2 study in patients with CHA with inhibitors (CSR
OBI-1-201), and a randomized Phase 1 study comparing B-domain deleted rpFVIII
glycoprotein with a plasma-derived pFVIII (CSR OBI-1-101).
Overall, efficacy and safety clinical data for OBIZUR supported a favorable
benefit/risk determination for the proposed indication of treatment of bleeding
episodes in adults with AHA. These data support the investigation of efficacy
and safety of BAX 802 in subjects with CHA with inhibitors undergoing surgical
or other invasive procedures.
Industriestrasse 67
Vienna 1221
AT
Industriestrasse 67
Vienna 1221
AT
Listed location countries
Age
Inclusion criteria
1. Subject requires a major or minor elective surgical, dental or other invasive procedure.
2. Subject is male * 12 to * 75 years old at the time of screening
3. Subject has provided signed informed consent (and assent for adolescent subjects, as applicable) in accordance with local regulatory requirements
4. Subject has severe (FVIII level < 1%) or moderately severe (FVIII level * 2%)
CHA with inhibitors to hfVIII of * 0.6 BU, as tested at screening at the central
laboratory
5. Subject is not currently receiving or has received (< 30 days) ITI therapy
6. Subject has a Karnofsky performance score of * 60 at screening
7. Subject is human immunodeficiency virus negative (HIV-); or HIV+ with stable
disease and CD4+ count * 200 cells/mm3 at screening
8. Subject is hepatitis C virus negative (HCV-) by antibody or polymerase chain
reaction (PCR) testing; or HCV+ with chronic stable hepatitis disease. Positive serologies will be confirmed by PCR testing.
9. Subject is willing and able to comply with the requirements of the protocol.
Exclusion criteria
1. The subject requires emergency surgery
2. Severe chronic liver dysfunction or disease (eg, * 5 X upper limit of normal (ULN) alaine aminotransferase (ALT), as confirmed by central laboratory at screening or a documented prothrombin time/international normalized ration (PT/INR) >1.5)
3. Clinically symptomatic renal disease (serum creatinine > 2.0 mg/dl), as confirmed by central laboratory at screening
4. Anti-porcine inhibitor > 10 BU prior to surgery
5. Platelet count < 100,000/*L at screening
6. Subject has another active coagulation disorder other than hemophilia A, as per
the medical history
7. Planned use of *-interferon with or without ribavarin for HCV infected patients or
planned use of a protease inhibitor for HIV infected patients. Patients currently
taking any of these medications for * 30 days are eligible
8. Known hypersensitivity to rpFVIII, or hamster or murine proteins
9. Subject has an ongoing or recent (within 3 months of screening) thrombo-embolic disease, fibrinolysis, or disseminated intravascular coagulation (DIC)
10. Subject has been exposed to an IP 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
11. Subject is unable to tolerate quantity of blood to be drawn for protocol procedures
12. Subject is a family member or employee of the investigator.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-005521-39-NL |
| CCMO | NL56865.041.16 |