Efficacy, PK, Immunogenicity and Safety of Wilate in Severe Von Willebrand Disease VWD) Patients <6 Years of Age

Study Overview
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Brief Summary
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The WIL-33 study aims to determine the efficacy, pharmacokinetics, immunogenicity and safety of wilate as routine prophylaxis in up to 12 paediatric patients (eight evaluable) with severe von Willebrand Disease VWD (defined as screening von Willebrand factor ristocetin cofactor activity [VWF:RCo] <20%) under the age of 6 years, over a period of 12 months.

Official Title
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Clinical Study to Investigate the Efficacy, Pharmacokinetics, Immunogenicity and Safety of Wilate in Severe Von Willebrand Disease Patients Under the Age of 6 Years

Conditions
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Von Willebrand Disease

Intervention / Treatment
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* Drug: wilate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged <6 years at the time of screening Type 3 (at least four patients), severe type 2 (except 2N) or severe type 1 VWD (any of which with VWF:RCo <20%) according to medical history, requiring substitution therapy with a VWF-containing product Minimum body weight 12.5 kg at the time of screening Voluntarily given, fully informed written and signed consent obtained before any study-related procedures are conducted (obtained from the patient's parent(s)/ legal guardian(s)) Exclusion Criteria: History or current suspicion of VWF or FVIII inhibitors Injection of DDAVP or VWF-containing product within 72 hours prior to inclusion Medical history of a thromboembolic event Platelet count <100,000/µL at screening (except for VWD type 2B) Patients receiving, or scheduled to receive, immunosuppressant drugs (other than antiretroviral chemotherapy), such as prednisone (equivalent to >10 mg/day), or similar drugs Treatment with any investigational medicinal product (IMP) in another interventional clinical study currently or within four weeks before enrolment Other coagulation disorders or bleeding disorders Known hypersensitivity to any of the components of the study drug

Ages Eligible for Study
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Maximum Age: 5 Years

Sexes Eligible for Study
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All

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: wilate treatment<br>PK: Single dose of 80 IU/kg body weight (BW). Prophylactic treatment: 30-50 IU/kg BW administered 2-3 times per week at the recommended dose of over 12 months. Minor haemorrhage: loading dose 30-50 IU/kg BW followed by a maintenance dose of 30-40 IU/kg BW every 12-24 hours to achieve von Willebrand factor activity (VWF:Ac) and FVIII:C trough levels of >30%. Major haemorrhage: loading dose 50-80 IU/kg BW followed by a maintenance dose of 30-50 IU/kg BW every 12-24 hours to achieve VWF:Ac and FVIII:C trough levels of >50%. Minor surgery: loading dose of 40-60 IU/kg BW followed by a maintenance dose of 20-30 IU/kg BW every 12- 24 hours for up to 3 days, to achieve VWF:Ac peak levels of 50% after loading dose and trough levels >30% during maintenance. Major surgery: loading dose of 60-80 IU/kg BW followed by a maintenance dose of 30-40 IU/kg BW every 12-24 hours for up to 6 days or longer, to achieve VWF:Ac peak levels of 100% after loading dose and trough levels >50% during maintenance | Drug: wilate<br>* wilate is a plasma-derived, stable, highly purified, double virus inactivated concentrate of freeze-dried active VWF and factor VIII (FVIII) prepared from cryoprecipitate and intended for the treatment of patients with von Willebrand disease (VWD) and/or haemophilia A<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total annualised bleeding rate (tABR) during prophylactic treatment with wilate. |  | Up to 12 months of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC) of wilate for VWF:Ac (VWF:RCo) and FVIII:C (OS) over time |  | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | 
| AUC normalised for the administered dose (AUCnorm) of wilate for VWF:Ac (VWF:RCo) and FVIII:C (OS) over time |  | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | 
| In vivo half-life (T1/2) of wilate for VWF:Ac (VWF:RCo) and FVIII:C (OS) over time |  | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | 
| Maximum plasma concentration (Cmax) of wilate for VWF:Ac (VWF:RCo) and FVIII:C (OS) over time |  | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | 
| Time to reach maximum plasma concentration (Tmax) of wilate for VWF:Ac (VWF:RCo) and FVIII:C (OS) over time |  | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | 
| Mean residence time (MRT) of wilate for VWF:Ac (VWF:RCo) and FVIII:C (OS) over time |  | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | 
| Volume of distribution (Vd) of wilate for VWF:Ac (VWF:RCo) and FVIII:C (OS) over time |  | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | 
| Clearance (CL) of wilate for VWF:Ac (VWF:RCo) and FVIII:C (OS) over time |  | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | 
| Incremental in-vivo recovery (IVR) of wilate for VWF:Ac (VWF:RCo) and FVIII:C (OS) over time |  | At baseline and at 1, 2, 3, 6, 9, and 12 months of treatment | 
| Efficacy of wilate in the prevention and treatment of spontaneous and traumatic breakthrough BEs based on their rate and the proportion of spontaneous and traumatic BEs successfully treated with wilate | Assessed by the use of a 4-point ordinal haemostatic efficacy scale (excellent - good - moderate - none) | Up to 12 months of treatment | 
| The overall efficacy of wilate in perioperative prophylaxis against excessive bleeding as assessed at the end of the postoperative period by the responsible treating investigator | Assessed by the use of a 4-point ordinal haemostatic efficacy scale (excellent - good - moderate - none) | Up to 12 months of treatment | 
| wilate consumption data for prophylactic treatment, for on-demand treatment and during surgical prophylaxis |  | Up to 12 months of treatment | 
| Incidence of VWF and FVIII inhibitors |  | Up to 12 months of treatment | 
| Incidence of thromboembolic events |  | Up to 12 months of treatment | 
| Joint Health Status determination by the use of the Hemophilia Joint Health Score, given the patient's age and constitutional development allow this assessment |  | At baseline and at 12 months of treatment | 
| Safety and tolerability of wilate assessed by monitoring adverse events (AEs) throughout the study |  | Up to 12 months of treatment |