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

Study Overview
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Brief Summary
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A prospective, non-controlled, international, multi-centre phase 3 study to investigate the pharmacokinetics, efficacy, safety, and immunogenicity of Wilate in previously treated children with severe haemophilia A

Official Title
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Clinical Study to Investigate the Pharmacokinetics, Efficacy, Safety, and Immunogenicity of Wilate in Previously Treated Paediatric Patients With Severe Haemophilia A

Conditions
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Severe Hemophilia A

Intervention / Treatment
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* Drug: Wilate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Severe haemophilia A (<1% FVIII:C) according to medical history Male patients aged 1 to <12 years Previous treatment with a FVIII concentrate for at least 50 exposure days (EDs) Immunocompetence (CD4+ count >200/μL) Voluntarily given, fully informed written and signed consent obtained by the patient's parent(s) or legal guardian and, depending on the children's developmental stage and intellectual capacity, informed assent by the patients before any study-related procedures are performed The interval between the Screening Visit and the PK Visit should not exceed 30 days. If the 30-day interval is exceeded, determination of the CD4+ count is to be repeated and must be >200/μL for patients to be enrolled (i.e., inclusion criterion no. 4). Exclusion Criteria: Any coagulation disorders other than haemophilia A History of FVIII inhibitor activity (≥0.6 BU) or detectable FVIII inhibitory antibodies (≥0.6 BU using the Nijmegen modification of the Bethesda assay) at screening, as determined by the central laboratory Severe liver or kidney diseases (alanine aminotransferase [ALAT] and aspartate transaminase [ASAT] levels >5 times of upper limit of normal, creatinine >120 μmol/L) Patients receiving or scheduled to receive immunomodulating drugs (other than antiretroviral chemotherapy), such as alpha-interferon, prednisone (equivalent to >10 mg/day), or similar drugs

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 11 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All patients<br>All patients will receive Wilate for prophylactic treatment. Patients will also receive Wilate for treatment of breakthrough bleeding events as required | Drug: Wilate<br>* von Willebrand factor / Factor VIII (plasma derived)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) Assessment (Area Under the Curve (AUC)) of FVIII:C | 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). | 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate | 
| Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Normalised (AUCNorm)) of FVIII:C for Wilate | 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. | 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate | 
| Pharmacokinetic (PK) Assessment (Half-life (h)) of FVIII:C | 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. | 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate | 
| Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration) for FVIII:C | 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) | 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate | 
| Pharmacokinetic (PK) Assessment (Time to Reach Maximum Plasma Concentration (Tmax)) of FVIII:C | 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). | 48 h following a single dose of Wilate | 
| Pharmacokinetic (PK) Assessment (Mean Residence Time (MRT)) of FVIII:C | 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. | 48 h following a single dose of Wilate | 
| Pharmacokinetic (PK) Assessment (Volume of Distribution (Vd)) of FVIII:C | 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). | 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate | 
| Pharmacokinetic (PK) Assessment (Clearance) of FVIII:C | 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). | 0h, 0.25h, 1h, 6h, 24h and 48 h following a single dose of Wilate | 
| Incremental In Vivo Recovery (IVR) of FVIII:C | 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) | 48 h following a single dose of Wilate | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Annualized Bleeding Rate (TABR) | 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. | 6 months | 
| Spontaneous Annualized Bleeding Rate (SABR) | 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. | 6 months | 
| Efficacy of Wilate in the Treatment of Breakthrough Bleeding Events (BEs) | 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. | 6 months | 
| Wilate Consumption Data: Average Dose of Wilate Per Week of Study | The average consumption of Wilate per week of the study (IU/kg) for all patients receiving prophylaxis | 6 months | 
| Incremental in Vivo Recovery (IVR) of Wilate Over Time | 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. | Baseline, and 3 and 6 months of treatment | 
| Association Between ABO Blood Type and the FVIII:C Half-life of Wilate (OS Assay) | 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. | 6 months | 
| Association Between VWF:Ag Concentration and the FVIII:C Half-life of Wilate | 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. | 6 months | 
| Safety and Tolerability of Wilate by Monitoring The Number of Adverse Events (AEs) Throughout the Study | 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. | 6 months | 
| Immunogenicity of Wilate: Number of Participants With FVIII Inhibitor Activity at 6 Months | 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. | 6 months | 
| Virus Safety Measured by the Number With Parvovirus B19 Seroconversions Between Baseline (BL) and End of Study | 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 | 6 months |