Clinical Study to Investigate the PK, Efficacy, and Safety of Wilate in Patients With Severe Hemophilia A

Study Overview
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Brief Summary
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The purpose of this study is to obtain additional data on the safety and efficacy of Wilate in PTPs with hemophilia A with at least 150 previous exposure days (EDs) to a FVIII concentrate who undergo prophylactic treatment with Wilate for 6 months and at least 50 EDs, thus supplementing the existing database to obtain approval of Wilate for the indication hemophilia A in the USA.

Official Title
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Clinical Study to Investigate the Pharmacokinetics, Efficacy, Safety, and Immunogenicity of Wilate in Previously Treated Patients With Severe Hemophilia 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 hemophilia A (<1% FVIII:C) according to medical history Male patients aged ≥12 years Previous treatment with a FVIII concentrate for at least 150 exposure days (EDs) Immunocompetence (CD4+ count >200/µL) Good documentation of the historical bleeding rate (at least for the 6 months preceding study start) Voluntarily given, fully informed written and signed consent obtained by the patient (or parent/legal guardian in case of adolescents) before any study-related procedures are conducted Whenever possible, the interval between the Screening Visit and the PK or Non-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., exclusion criterion no. 4). Exclusion Criteria: Any coagulation disorders other than hemophilia A History of FVIII inhibitor activity (≥0.6 BU) or detectable FVIII inhibitory anti-bodies (≥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 anti-retroviral chemotherapy) such as alpha-interferon, prednisone (equivalent to >10 mg/day), or similar drugs Treatment with any investigational medicinal product in another interventional clinical study currently or within 4 weeks before enrollment

Ages Eligible for Study
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Minimum Age: 12 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 | Drug: Wilate<br> <br> * Other names: von Willebrand factor / Factor VIII (plasma derived);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Annualized Bleeding Rate (TABR) | The total number of bleeding events (BEs) was documented by patients in a patient diary (together with the investigator in case of on-site treatments), which was reviewed at each follow-up visit by site personnel. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spontaneous Annualized Bleeding Rate (SABR) | The number of spontaneous bleeding events (BEs) was documented by patients in a patient diary (together with the investigator in case of on-site treatments), which was reviewed at each follow-up visit by site personnel. | 6 months | 
| Efficacy of Wilate in the Treatment of Breakthrough BEs | The proportion of BEs successfully treated with Wilate were documented by the patient (together with the investigator in case of on-site treatments) in the patient diary for all BEs according to a 4-point hemostatic efficacy scale including the four items: 'excellent,' 'good,' moderate,' and 'none', where '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) and 'none' was defined as No improvement within 12 hours, or worsening of symptoms, requiring more than two injections for complete resolution (worst outcome). All efficacy ratings assessed as either 'excellent' or 'good' were considered 'successfully treated.' | 6 months | 
| Wilate Consumption Data (Average Total Normdose of FVIII IU/kg Per Month of Study) for Prophylaxis | The average consumption of Wilate per month of study (IU/kg) for all patients receiving prophylaxis. | 6 months | 
| Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Norm) of FVIII:C | PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The value of the AUCnorm of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study. | Initial PK visit (Day -1) and PK study completion visit (6 months); data collected 1 h prior to injection and 15 min, 1 h, 3 h, 6 h, 9 h, 24 h, 30 h and 48 h after the end of injection | 
| Pharmacokinetic (PK) Assessment (in Vivo Half-Life (t1/2)) of FVIII:C | PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The in vivo half-life of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study. | Initial PK assessment (Day -1) and PK study completion visit (6 months); data collected 1 h prior to infusion and 15 min, 1 h, 3 h, 6 h, 9 h, 24 h, 30 h and 48 h after the end of injection | 
| Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration [Cmax]) of FVIII:C | PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The maximum plasma concentration of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study. | Initial PK assessment (Day -1) and 6 months | 
| Incremental in Vivo Recovery (IVR) of Wilate Over Time | The rise in FVIII activity in IU/dl per unit dose administered in IU/kg was determined from all patients at baseline, 3 and 6 months, using the OS assay. | Baseline, 3 and 6 months | 
| 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 an association between ABO blood type and the FVIII:C half-life of Wilate. This was analyzed by calculating the mean square in a one-stage assay. | 6 months | 
| Association Between VWF:Ag Concentration and the FVIII:C Half-life of Wilate | ANOVA was used in an exploratory sense to assess an association between VWF:Ag with the FVIII:C half-life of Wilate. This was analyzed by calculating the mean square in a one-stage assay. | 6 months | 
| Safety and Tolerability of Wilate by Monitoring Adverse Events (AEs) Throughout the Study | At each (scheduled or unscheduled) study visit, AEs were documented by the investigator throughout the study. | 6 months | 
| Immunogenicity of Wilate by Testing for FVIII Inhibitors | FVIII inhibitor activity was determined at each study visit before the injection of Wilate using the modified Bethesda assay (Nijmegen modification). | 6 months | 
| Virus Safety Measured by the Number of 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. All patients negative at screening were tested again at the study completion visit. The number with Parvovirus B19 seroconversions between BL and end of study was recorded. | 6 months |