Clinical study to investigate the pharmacokinetics, efficacy, safety and immunogenicity of human-cl rhFVIII in previously treated patients with severe haemophilia A

To compare the area under curve (AUC) of human-cl rhFVIII and Kogenate®/Helexate® for FVIII:C using both the chromogenic (CHR) and the one-stage (OS) assays and the actual potency of human-cl rhFVIII and Kogenate®/Helexate®.

1. Pharmacokinetic (PK) parameters:
1.1. In vivo half-life (T1/2), Cmax, Tmax, MRT, Vd, and CL, calculated for FVIII:C using both the CHR and the OS assays and the actual potency of human-cl rhFVIII and Kogenate®/Helexate®
1.2. In-vivo recovery calculated from the FVIII levels before and peak level obtained in the 0.25, 0.5, 0.75, or 1 hour post-infusion samples
2. Efficacy in prophylactic treatment:
2.1. Overall efficacy assessment after a total of 50 EDs and at the end of the study
2.2. The frequency of bleeds under prophylactic treatment
2.3. Study drug consumption data (FVIII IU/kg per month, per year) per subject and in total
2.4. Efficacy assessment of each IMP injection and an overall efficacy assessment at the end of each BE
2.5. Surgical prophylaxis: the overall efficacy assessment after the end of the surgical prophylactic treatment phase by the surgeon and haematologist
2.6. Average and maximum expected estimated blood loss compared to the actual estimated blood loss
3. Safety: clinical tolerability assessed by:
3.1. Monitoring vital signs: blood pressure, heart rate, respiratory rate and body temperature will be assessed at pre-defined time-points
3.2. Laboratory parameters: the following routine safety laboratory parameters will be tested at pre-defined time-points:
3.2.1. Haematological parameters: red blood cell count, white blood cell count, haemoglobin, haematocrit, and platelet count
3.2.2. Clinical chemistry: total bilirubin, alanine aminotransferase, aspartate transaminase, blood urea nitrogen, serum creatinine, lactate dehydrogenase (LDH)
3.2.3. Serum electrolytes: sodium, potassium, bicarbonate, calcium
3.2.4. Urine analysis: urine dipstick chemical analysis (leucocyturia, haematuria, proteinuria, glucose, ketones, bilirubin, nitrites – if positive including microscopic examination)
3.3. Monitoring adverse events (AEs): at each study visit, all adverse events are documented by the Investigator.
3.4. Inhibitors against FVIII and anti-rhFVIII antibodies determined at pre-determined time points and in cases where an inhibitor development is suspected
3.5. Immunogenicity: inhibitor activity will be determined by the modified Bethesda assay (Nijmegen modification) at study entry, then immediately before the first human-cl rhFVIII administration, after 1 ED, after 10 to 15 EDs and the 3-months and 6-months visit. At the same time-point the anti-rhFVIII antibodies will be measured.