Primary ObjectiveThe primary objective is to compare the annualized rates of bleeding episodes (ABR)between subjects receiving a prophylactic regimen of BAX 855 with an on-demandtreatment regimen.Secondary ObjectivesThe key secondary objective is to…
ID
Source
Brief title
Condition
- Blood and lymphatic system disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome measure is the annualized bleed rate (ABR).
Secondary outcome
Efficacy
1. Rate of success of BAX 855 for treatment of bleeding episodes
2. Number of BAX 855 infusions needed for the treatment of bleeding episodes
3. Time intervals between bleeding episodes
4. Weight-adjusted consumption of BAX 855
Safety
1. Occurrence of AEs and SAEs
2. Changes in vital signs and clinical laboratory parameters (hematology,
clinical chemistry, and lipids)
3. Immunogenicity
- Inhibitory antibodies to FVIII
- Binding antibodies (IgG and IgM) to FVIII, BAX 855, and PEG
- Anti-CHO antibodies
Patient Reported Outcomes
Changes from baseline in the following PROs:
1. Bleed and pain severity as measured using the Haemo-SYM questionnaire
2. Physical HRQoL as assessed using the SF-36 questionnaire
Pharmacokinetics
BAX 855 PK parameters based on FVIII levels following an initial single dose of
BAX 855 and after *50 EDs to BAX 855 (PK subset in Arm A)
1. Primary PK parameters:
- Plasma half-life (T1/2)
- MRT
- Total body clearance (CL)
- Incremental recovery over time (IR)
2. Other PK parameters:
- Area under the concentration versus time curve from 0 to infinity (AUC0-*)
- Apparent volume of distribution at steady state (Vss)
- Maximum plasma concentration Cmax
- Time to maximum concentration in plasma (Tmax)
Exploratory Outcomes Measures
1. Changes in the following PROs:
- Health utility as assessed using the EQ-5D
- Patient satisfaction/preference with treatment as assessed using the
Satisfaction Question Set
- Patient activity level
2. Health resource use
Background summary
Hemophilia A is an X-linked recessive, congenital bleeding disorder caused by
deficient or defective coagulation FVIII. 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 study design is in compliance with
EMA/CHMP/BPWP/144533/2009 recommendations for the study of FVIII in 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.
Study objective
Primary Objective
The primary objective is to compare the annualized rates of bleeding episodes
(ABR)
between subjects receiving a prophylactic regimen of BAX 855 with an on-demand
treatment regimen.
Secondary Objectives
The key secondary objective is to estimate the rate of success of BAX 855 for
treatment
of bleeding episodes.
- To characterize the success of BAX 855 for treatment of bleeding episodes
through the number of BAX 855 infusions needed for the treatment of a bleeding
episode and through the length of intervals between bleeding episodes
- To compare the total weight-adjusted consumption of BAX 855 for each regimen
- To determine the immunogenicity of BAX 855
- To determine the safety of BAX 855
- To assess Health-Related Quality of Life (HRQoL) over time for subjects
receiving BAX 855
- To assess health utility, using the EQ-5D, patient satisfaction, patient
activity
levels and health resource use, over time for subjects receiving BAX 855
Study design
This study is a Phase 2/3, multicenter, open label, 2-arm study in a total of
approximately 132 adolescent (12 - <18 years) and adult (* 18 to 65 yrs) male
PTPs with severe hemophilia A to evaluate efficacy, safety, and PK of BAX 855
and HRQoL in subjects receiving BAX 855. Subjects will be enrolled into 1 of 2
arms: prophylaxis with BAX 855 at a dose of 45 IU/kg twice weekly (Arm A) or
ondemand therapy with BAX 855 at a dose of 10-60 IU/kg dose (Arm B). A group of
25 subjects will be included as a PK subgroup of Arm A.
For an elaborate overview, please see protocol section 8.
For the Netherlands only the Adults group is applicable.
Intervention
This is a non-randomized, open-label, treatment regimen comparison clinical
study.
Subjects will be assigned to prophylaxis (Arm A) or on-demand treatment (Arm
B), based upon the type of Factor VIII treatment they received prior to
enrollment. Subjects currently receiving prophylaxis will be assigned to the
prophylaxis arm (Arm A). Subjects who were previously receiving on-demand
therapy will be assigned to the ondemand arm (Arm B). Once the on-demand arm is
complete (17 subjects assigned), subjects who had been receiving on-demand
treatment prior to study enrollment will be assigned to prophylactic treatment
(Arm A).
The 2 treatment arms are as follows:
* Arm A: Prophylaxis with BAX 855 administered twice weekly (ie, every 3-4
days) at a dose of 45 ± 5 IU/kg for *50 EDs (N=115 subjects assigned)
* Arm B: On-demand therapy with BAX 855 at a dose of 10-60 ± 5 IU/kg for an
approximate duration of 6 months (N=17 subjects assigned)
Study burden and risks
Preclinical study results suggest that BAX 855 has a comparable safety profile
to ADVATE. A safety profile similar to ADVATE is expected for BAX 855 when
infused in humans. The most commonly reported adverse drug reactions described
for ADVATE in post-marketing clinical studies include: FVIII inhibitors,
pyrexia, and headache. Allergic-type hypersensitivity reactions, including
anaphylaxis, have been reported with ADVATE and have been manifested by
dizziness, paresthesia, rash, flushing, face swelling, urticaria, and pruritus.
Additional safety experience for ADVATE is provided in the ADVATE IB.
Since BAX 855 is a PEGylated form of ADVATE, it is possible that additional
toxicity related to PEG may be observed. BAX 855 may react with preexisting
anti-PEG antibodies, resulting in a clinical hypersensitivity reaction. There
is also the potential risk of inducing anti-PEG or anti-BAX 855 antibodies
following BAX 855 administration. The PEG component of BAX 855 may become
dissociated from the FVIII molecule when incorporated into tissues. This
accumulation can lead to formation of macrophage foam cells, which function to
actively remove the PEG molecules. In reclinical studies, the presence of these
*foamy macrophages* has not been associated with any adverse effects. To date,
BAX 855 has been administered as a single dose of 30 IU/kg to 9 subjects and a
single dose of 60 IU/kg to 10 subjects with severe hemophilia A in a Phase 1
study (Baxter clinical study 261101).
Based on data from this study, there currently are no anticipated risks of BAX
855, beyond those associated with ADVATE, when administered in human subjects.
Additional details related to risks and benefits can be found in the BAX 855 IB.
Based on the comparability of BAX 855 to ADVATE, the preclinical safety profile
of BAX 855, and the data from the Phase 1 study, Baxter believes that the risk
benefit profile for BAX 855 is acceptable.
Based on the data from Phase 1, BAX 855 appears to be safe and well tolerated
after single doseadministration. The mean T1/2 was 1.4 and 1.5-fold higher for
BAX 855 compared to ADVATE in Cohorts 1 and 2, demonstrating prolonged
circulation of BAX 855 compared to ADVATE. Dosing must be administered twice
weekly, at 3 and 4 day intervals.
Industriestrasse 67
Vienna A-1221
AT
Industriestrasse 67
Vienna A-1221
AT
Listed location countries
Age
Inclusion criteria
- Subject and/or legal representative has/have voluntarily provided signed informed consent
- Subject is 12 to 65 years old at the time of screening
- Subject is male with severe hemophilia A (FVIII clotting activity < 1%) as confirmed by central laboratory at screening after the appropriate washout period or a documented FVIII clotting activity <1%
- Subject has been previously treated with plasma-derived FVIII concentrates or recombinant FVIII for *150 documented exposure days (EDs)
- Subject is currently receiving prophylaxis or on-demand therapy with FVIII
- Subject has a Karnofsky performance score of * 60 at screening (Table 6)
- 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
- Subject is hepatitis C virus negative (HCV-) by antibody or PCR testing (if positive, antibody titer will be confirmed by PCR), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis
- Subject is willing and able to comply with the requirements of the protocol
Exclusion criteria
- Subject has detectable FVIII inhibitory antibodies (* 0.4 BU using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening
- Subject has history of FVIII inhibitory antibodies (* 0.4 BU using the Nijmegen modification of the Bethesda assay or * 0.6 BU using the Bethesda assay) at any time prior to screening
- Subject has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand*s disease).
- Subject has known hypersensitivity towards mouse or hamster proteins, PEG, or Tween 80
- Subject has severe chronic hepatic dysfunction [eg, *5 times upper limit of normal alanine aminotransferase (ALT), as confirmed by central laboratory at screening, or a documented INR > 1.5]
- Subject has severe renal impairment (serum creatinine > 2.0 mg/dL), as confirmed by central laboratory at screening
- Subject has current or recent (< 30 days) use of other PEGylated drugs prior to study participation or is scheduled to use such drugs during study participation
- Subject has participated in another clinical study involving an 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
- Subject has a medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect subject safety or compliance
- 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
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-003599-38-NL |
| ClinicalTrials.gov | NCT01736475 |
| CCMO | NL42730.018.13 |