Pharmacokinetics, Efficacy, Safety, and Immunogenicity of Wilate in Previously Treated Paediatric Patients With Severe Haemophilia A

The incremental IVR was determined from all patients at baseline was determined using the one-stage (OS) assay (standardised to 50 IU/kg). The units of measure to calculate IVR is kilograms (kg) / deciliter (dL)

Time frame: 48 h following a single dose of Wilate

Population: This analysis was performed for the full-analysis (FAS) population which included all patients who has at least one injection of Wilate (n=10). The FAS population comprised 5 patients aged 1-\<6 years and 5 patients aged 6-\<12 years.

PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The mean area under the curve normalised for the administered dose (AUCnorm) was calculated for Wilate. The units of measure used were AUC divided by dose.

Time frame: 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate

Population: The analysis was performed in the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-\<6 years and 5 patients aged 6-\<12 years.

PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate AUC is hours (h) x international units (IU)/decilitre (dL).

Time frame: 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate

Population: The analysis was performed in the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-\<6 years and 5 patients aged 6-\<12 years.

PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate clearance are decilitre (dL)/ hours (h)/ kilograms (kg).

Time frame: 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate

Population: The analysis was performed in the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-\<6 years and 5 patients aged 6-\<12 years.

PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate half-life is hours.

Time frame: 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate

Population: The analysis was performed in the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-\<6 years and 5 patients aged 6-\<12 years.

PK assessments of FVIII:C were determined using the one-stage (OS) assays. The maximum plasma concentration of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study. Units of measure for maximum plasma concentration are international units (IU)/ decilitre (dL)

Time frame: 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate

Population: The analysis was performed in the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-\<6 years and 5 patients aged 6-\<12 years.

PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate MRT is hours.

Time frame: 48 h following a single dose of Wilate

Population: The analysis was performed in the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-\<6 years and 5 patients aged 6-\<12 years.

PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate Tmax is hours (h).

Time frame: 48 h following a single dose of Wilate

Population: The analysis was performed in the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-\<6 years and 5 patients aged 6-\<12 years.

PK assessments of the factor VIII coagulant activity (FVIII:C) for Wilate were determined using the one-stage (OS) assay. The units of measure to calculate Vd is decilitre (dL)/ kilograms (kg).

Time frame: 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate

Population: The analysis was performed in the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-\<6 years and 5 patients aged 6-\<12 years.

Analysis of variance (ANOVA) was used in an exploratory sense to assess a possible association between the ABO blood type and the FVIII:C half-life of Wilate. This was analysed by calculating the mean square in a one-stage (OS) assay.

Time frame: 6 months

Population: The analysis was performed for the PK population which included all patients who underwent PK assessment during the study (total: n=10). The PK population comprised 5 patients aged 1-\<6 years and 5 aged 6-\<12 years.

Analysis of variance (ANOVA) was used in an exploratory sense to assess a possible association between VWF:Ag with the FVIII:C half-life of Wilate. This was analysed by calculating the mean square in a one-stage (OS) assay.

Time frame: 6 months

Population: The analysis was performed for the PK population which included all patients who underwent PK assessment during the study (total: n=10).

The proportion of BEs successfully treated with Wilate was assessed by the patient (together with the investigator in case of on-site treatment) in a patient diary. The treatment efficacy for all BEs was assessed using a pre-defined four-point scale: 'excellent', 'good', 'moderate', 'none'. 'Excellent' was defined as Abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection (best outcome); 'good 'was defined as definite pain relief and/or improvement in signs of bleeding within approximately 8-12 hours after an injection, requiring up to 2 injections for complete resolution. All efficacy ratings assessed as either 'excellent' or 'good' were considered 'successfully treated'. 'Moderate' was defined as probable or slight beneficial effect within approximately 12 hours after the first injection and 'none' defined as no improvement within 12 hours, or worsening of symptoms.

Time frame: 6 months

Population: Analysis was performed in the per-protocol (PP) population. Of the patients in the PP population, only 8 patients had evaluable bleeding events. Five of these patients were aged 1-\<6 years, and 3 aged 6-\<12 years.

FVIII inhibitor activity was determined at each study visit: screening, PK, Day 14 visit, Day 30 visit, 3 Months visit and 6 Months visit before injection.

Time frame: 6 months

Population: The analysis was performed in the overall safety (SAF) population included all patients who received at least one injection of Wilate during the study (n=10). Of these, 5 patients 1-\<6 years were analyzed, and 5 patients aged 6-\<12 years were analyzed.

The rise in FVIII:C activity in IU/dl per unit dose administered in IU/kg was determined for all patients at baseline, 3 and 6 months, using the one-stage (OS) assay.

Time frame: Baseline, and 3 and 6 months of treatment

Population: The analysis was performed in the full analysis (FAS) population (total: n=10). The FAS comprised 5 patients were aged 1-\<6 years and 5 were aged 6-\<12 years.

At each visit (whether scheduled or unscheduled) , AEs will be documented by the investigator throughout the study. In addition, the investigator will check the patient diaries for any documented event.

Time frame: 6 months

Population: The safety (SAF) population included all patients who received at least one injection of Wilate during the study (n=10).

The SABR was calculated in analogy to the TABR. The total number of spontaneous bleeding events (BEs) in the time period between the first dose of IMP and the study completion visit, divided by the duration (in years) between the first dose of IMP and the study completion visit. Surgery periods, and BEs occurring within these periods, will be excluded from the calculation of the SABR.

Time frame: 6 months

Population: This analysis was performed for the full-analysis (FAS) population which included all patients who has at least one injection of Wilate (n=10). The FAS population comprised 5 patients aged 1-\<6 years and 5 patients aged 6-\<12 years.

The total number of bleeding events (BEs) in the time period between the first dose of IMP and the study completion visit, divided by the duration (in years) between the first dose of IMP and the study completion visit. Surgery periods, and BEs occurring within these periods, will be excluded from the calculation of TABR.

Time frame: 6 months

Population: This analysis was performed for the full-analysis (FAS) population which included all patients who has at least one injection of Wilate (n=10). The FAS population comprised 5 patients aged 1-\<6 years and 5 patients aged 6-\<12 years.

Virus safety was evaluated by taking a plasma sample for parvovirus B19 antibody testing before the first injection of Wilate at the PK visit. All patients negative at screening were tested again at the Study Completion visit. The number of Parvovirus B19 seroconversions between BL and end of study was recorded

Time frame: 6 months

Population: Analysis was performed in all patients who underwent full analysis (FAS population) (n=10).

The average consumption of Wilate per week of the study (IU/kg) for all patients receiving prophylaxis

Time frame: 6 months

Population: The analysis was performed in the full analysis (FAS) population (total: n=10). The FAS comprised 5 patients were aged 1-\<6 years and 5 were aged 6-\<12 years.