1. To assess tolerability and safety of BAX 826 after a single infusion in previously PTPs with severe hemophilia A.2. To determine the pharmacokinetic (PK) parameters of BAX 826 compared to ADVATE.3. To evaluate the impact of anti- PSA antibodies…
ID
Source
Brief title
Condition
- Platelet disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Analysis
Adverse Events
Adverse events occurring up to 6 weeks±4 days (Visit 4) after infusion with BAX
826 and ADVATE
(the number of AEs [including the number of product related serious and
non-serious AEs] and the
number/proportion of subjects) will be summarized by treatment.
Safety and Tolerability
Vital signs and clinical laboratory assessments will be summarized
descriptively by treatment and cohort at
each scheduled assessment and for the corresponding change from baseline. Shift
tables will also be
presented for clinical laboratory assessments by treatment and cohort at each
scheduled assessment.
Immunogenicity
The number and proportion of subjects will be summarized by treatment for
developing the following:
inhibitory antibodies to FVIII (Nijmegen assay), binding antibodies to BAX 826
(IgG and IgM), total
binding antibodies to FVIII (IgG and IgM), anti-PSA antibodies (IgG and IgM),
anti-CHO antibodies and
anti-HAMA antibodies.
Secondary outcome
Pharmacokinetic
Pharmacokinetic parameters will be calculated using non-compartmental methods
and summarized
descriptively by treatment: AUC0-*, t1/2, *z, MRT, CL, IR, Vss, Cmax, tmax,
AUC0-last and truncated AUCs
([AUC0-72h] and [AUC0-168h] for BAX 826 only).
The ratios of t1/2, MRT and CL between the 2 treatment periods will be computed
for each subject and
summarized descriptively by cohort.
Log*transformed PK parameters AUC0-*, AUC0-72h, Cmax, t1/2, MRT and CL will be
analyzed by cohort for
treatment comparison using a linear mixed-effects model with treatment as a
fixed effect and subject as a
random effect.
Plots of individual and geometric mean and median PK parameters AUC0-*,
AUC0-last and Cmax versus dose
(both linear and log scale) will be presented, as appropriate. The dose
proportionality of the PK parameters
AUC0-*, AUC0-last and Cmax for BAX 826, over the administered dose range, will
be explored using the
power model.
Exploratory Analysis
Data from the thrombin generation assay will be evaluated to determine the
impact of BAX 826
administration on global hemostasis. The assessments will be summarized
descriptively by treatment at
each scheduled assessment.
The correlation between pre-infusion VWF antigen and BAX 826 t1/2 will be
assessed using appropriate
scatter plots and correlation coefficients. The ratio of pre-infusion VWF
antigen concentrations between the
2 treatment periods will be computed for each subject and descriptive
statistics will be prepared for the
ratios by cohort.
Interim Safety Reviews
There is no planned interim analysis other than a safety and PK data review by
the SRC.
Background summary
This study is a phase 1 prospective, open label, first-in-man, 2 period, fixed
sequence, dose-escalation study in PTPs (male subjects) with severe hemophilia
A (FVIII levels <1%) to evaluate the safety and PK parameters of a single dose
of BAX 826 compared to a single dose of ADVATE.
The target population is 30 evaluable adult male PTPs with severe hemophilia A
(FVIII <1%). To achieve this number of evaluable subjects, it is anticipated
that approximately 40 subjects will be enrolled. All eligible, enrolled
subjects will receive investigational product unless they discontinue from the
study prematurely. Evaluable subjects are subjects who have received at least 1
BAX 826 infusion and who are evaluable for PK for the BAX 826 infusion.
Subjects are to remain on their standard treatment (during the screening and
follow up period after the PK assessment) and should undergo a minimum 4-day
(96-hour) washout period prior to the first ADVATE infusion. Similarly,
subjects should revert back to their standard treatment if they have a bleeding
episode and then undergo a minimum 4-day (96-hour) washout period before
repeating the appropriate study regimen.
Study objective
1. To assess tolerability and safety of BAX 826 after a single infusion in
previously PTPs with severe
hemophilia A.
2. To determine the pharmacokinetic (PK) parameters of BAX 826 compared to
ADVATE.
3. To evaluate the impact of anti- PSA antibodies on PK parameters.
Study design
Phase 1. Open-label study.
Intervention
The study has 3 distinct cohorts, each of which will consist of 10 evaluable
subjects:
- Cohort 1: Eligible subjects will receive an infusion of 25 ±3 IU/kg ADVATE.
Following ADVATE infusion, subjects will undergo a minimum 4-day (96-hour)
washout period, which includes a 3-day PK evaluation. Following the washout
period, subjects will receive a single dose of BAX 826, equivalent to the
ADVATE dose they have received, followed by a 7-day PK evaluation.
- Cohort 2: After the data from Cohort 1 have been reviewed and subject to
approval by the internal Baxalta Safety Review Committee (SRC), Cohort 2 will
receive an infusion of 50 ±5 IU/kg ADVATE. Following the ADVATE infusion,
subjects will undergo a minimum 4-day (96-hour) washout period, which includes
a 3-day PK evaluation. Following the washout period, subjects will receive a
single dose of BAX 826, equivalent to the ADVATE dose they have received,
followed by a 7-day PK evaluation.
- Cohort 3: After the data from Cohort 2 have been reviewed and subject to
approval by the SRC, Cohort 3 will receive an infusion of 75 ±5 IU/kg ADVATE.
Following the ADVATE infusion, subjects will undergo a minimum 4-day (96-hour)
washout period, which includes a 3-day PK evaluation. Following the washout
period, subjects will receive a single dose of BAX 826, equivalent to the
ADVATE dose they have received, followed by a 7-day PK evaluation.
In Cohort 1, the first human dose of BAX 826 (25 IU/kg) will be administered to
the first 3 subjects with a minimum 24-hour staggered interval. The safety of
these 3 subjects will be assessed over a minimum of 24 hours' of in-hospital
observation. Further subjects in Cohort 1 will only be infused with BAX 826
once it has been confirmed by the SRC that there were no acute post-infusion
reactions or safety issues for the first 3 subjects. Subjects should remain at
the study site for 12 hours post-infusion, where after they can leave and come
back for the following day for the 24-hour PK sampling. Subjects could be
screened for the next cohort before the final SRC approval, but the dosing for
the next cohort should not start until the SRC has provided approval.
Study burden and risks
An immunological risk assessment revealed that the risk of hemophilia A patients
without a history of neutralizing antibodies against FVIII (the patient
population of the
phase 1 study) to develop or boost anti-2,8 PSA antibodies after a single dose
of
BAX 826 is considered to be low. Moreover, abundant and striking data from in
vivo
animal models and clinical trials suggest that anti-2,8 PSA antibodies are
non-pathogenic.
Results of the nonclinical safety studies indicated that there are high safety
margins compared to an expected maximum clinical dose of 75 IU/kg (8 or 10
times in
monkeys and rats, respectively) and the degree of safety is considered
sufficient to
support entry into clinical development in humans.
Factor VIII prophylaxis has been shown to reduce hemarthroses and other bleeding
episodes in patients with severe hemophilia A
See section 6.5 of the protocol.
Industriestrasse 67
Vienna A-1221
AT
Industriestrasse 67
Vienna A-1221
AT
Listed location countries
Age
Inclusion criteria
1. Previously treated male subjects aged 18 to 65 years (inclusive) at the time of screening.
2. Prior diagnosis of severe hemophilia A (FVIII level <1%) or as confirmed by the central laboratory at screening.
3. Previously treated with FVIII concentrates for *150 documented EDs.
4. Karnofsky performance score of *60
5. Human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and cluster of differentiation 4 (CD4+) count *200 cells/mm3, as confirmed by the central laboratory at screening
6. Hepatitis C virus negative (HCV-) by antibody or polymerase chain reaction (PCR) testing as confirmed by the central laboratory at screening; or HCV+ with chronic stable hepatitis as assessed by the investigator
7. Able to understand and have provided written informed consent including signature on an informed consent form (ICF) approved by an ethics committee (EC)
8. Have provided written authorization for use and disclosure of protected health information
9. Agree to abide by the study schedule and to return for the required assessments
10. Willing and able to comply with the requirements of the protocol
Exclusion criteria
1. Detectable FVIII inhibitor at screening, with a titer *0.6 BU (Nijmegen modification of the Bethesda assay) as determined at the central laboratory
2. Documented history of FVIII inhibitors with a titer *0.4 BU (using the Nijmegen modification of the Bethesda assay or *0.6 with Bethesda assay) at any time prior to screening
3. Known clinical hypersensitivity towards mouse or hamster proteins or to PSA
4. Scheduled elective surgery during study participation
5. Severe chronic hepatic dysfunction (defined as *5 x upper limit of normal [ULN] alanine aminotransferase [ALT] or an international normalized ratio [INR] >1.5).
6. Severe renal impairment (serum creatinine >2.0 mg/dL)
7. Currently receiving, or has recently received (less than 3 months prior to study participation), or is scheduled to receive during the course of the study, other PSA-ylated drugs
8. Have received another investigational drug within 30 days prior to study entry and/or is scheduled to receive additional investigational drug during the course of the study in the context of another investigational drug study
9. Diagnosis of an inherited or acquired hemostatic defect other than hemophilia A
10. Currently receiving, or scheduled to receive during the course of the study, an immune-modulating drug (eg, systemic corticosteroid agent at a dose equivalent to hydrocortisone greater than 10 mg/day, or alpha interferon) other than anti-retroviral chemotherapy
11. Has a clinically significant medical, psychiatric or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect the safety or compliance of the subject during the study
12. 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 | EUCTR2015-004079-60-NL |
| CCMO | NL55816.078.15 |