Hemophilia A
Conditions
Interventions
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, subjec
Sponsors
Baxter
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
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
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 outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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. | — |
Countries
Netherlands
Outcome results
None listed