Clinical Study to Investigate the Efficacy and Safety of Wilate During Prophylaxis in Previously Treated Patients With VWD

Study Overview
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Brief Summary
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This is a prospective, non-controlled, international, multi-center phase 3 study investigating the efficacy and safety of Wilate in previously treated adult patients with VWD, to obtain additional data on the safety and efficacy of Wilate in previously treated patients with VWD undergoing regular prophylaxis.

Official Title
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Clinical Study to Investigate the Efficacy and Safety of Wilate During Prophylaxis in Previously Treated Patients With Von Willebrand Disease (VWD)

Conditions
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Von Willebrand Diseases

Intervention / Treatment
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* Drug: Wilate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who meet all of the following criteria are eligible for the study: Aged ≥6 years at the time of screening VWD type 1 (baseline von Willebrand factor activity [VWF:Ristocetin Co-factor (RCo)] <30 IU/dL, 2A, 2B, 2M, or 3 according to medical history requiring substitution therapy with a VWF-containing product to control bleeding Currently receiving on-demand treatment with a VWF-containing product with at least 1, and an average of ≥2, documented spontaneous BEs per month in the last 6 months, with at least 2 of these BEs requiring treatment with a VWF-containing product Availability of records to reliably evaluate type, frequency, and treatment of BEs for at least 6 months of on-demand treatment before screening Female patients of child-bearing potential must have a negative urine pregnancy test at screening and agree to use adequate birth control measures; in case hormonal contra-ception is used, the medication class should remain unchanged for the duration of the study All patients to provide voluntarily given, fully informed written and signed consent obtained before any study-related procedures are conducted Exclusion Criteria: Patients who meet any of the following criteria are not eligible for the study: Having received on-demand or prophylactic treatment with a VWF-containing product but having no records available to reliably evaluate the type, frequency, and treatment of BEs over a period of at least 6 months of on-demand treatment History, or current suspicion, of VWF or FVIII inhibitors Medical history of a thromboembolic event within 1 year before enrolment Severe liver or kidney diseases (alanine aminotransferase [ALAT] and aspartate trans-aminase [ASAT] levels >5 times of upper limit of normal, creatinine >120 µmol/L) Platelet count <100,000/µL at screening (except for VWD type 2B) Body weight <20 kg at screening Patients receiving, or scheduled to receive, immunosuppressant drugs (other than an-tiretroviral chemotherapy), such as prednisone (equivalent to >10 mg/day), or similar drugs Pregnant or breast-feeding at the time of enrolment Cervical or uterine conditions causing abnormal uterine bleeding (including infection, dysplasia) Treatment with any IMP in another interventional clinical study currently or within 4 weeks before enrolment Other coagulation disorders or bleeding disorders due to anatomical reasons Known hypersensitivity to any of the components of the study drug

Ages Eligible for Study
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Minimum Age: 6 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: All patients<br>Patients with type 3, type 2 (except 2N), or severe type 1 VWD aged ≥6 years at screening receiving Wilate for prophylactic treatment. | Drug: Wilate<br>* Produced from the plasma of human donors, Wilate is presented as a powder or solvent for intravenous injection containing normally 500 IU or 1000 IU human VWF and human FVIII per vial. The ratio between VWF ristocetin co-factor activity (VWF:RCo) and FVIII:C is 1:1. The product contains approximately 100 IU/ml human VWF when reconstituted with 5ml/10mL water for injection with 0.1% polysorbate 80. The specific activity of Wilate is ≥67 IU VWF:RCo/mg protein. The injection or infusion rate should not exceed 2-3mL per minute.<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 TABR was calculated as the total number of spontaneous bleeds, traumatic bleeds, and other bleeds (except menstrual bleeds) occurring in the time period between first dose of the investigational medicinal product (IMP) and the Study Completion Visit, divided by the duration (in years) between first dose of IMP and the Study Completion Visit. | 12 months | 
| Comparison of Total Annualized Bleeding Rates (TABR) During Prophylaxis Treatment in Study WIL-31 to On-demand Treatment in the Same Patient Population in the Preceding Study WIL-29 | Estimated TABR number calculated using a negative binomial counting regression model. Comparison between this number calculated for studies WIL-29 (NCT04053699) and WIL-31. For the comparison of results from WIL-31 to WIL-29 an estimated total annualized bleeding rate was calculated for each cohort, and compared with a negative binomial counting model. As these were estimated rates, there is only one value for each cohort with no measure of spread | 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spontaneous Annualized Bleeding Rate (SABR) | Spontaneous annualized bleeding rate (SABR) calculated in analogy with TABR | 12 months | 
| Comparison of Spontaneous Annualized Bleeding Rates (SABR) During Prophylaxis Treatment in Study WIL-31 to On-demand Treatment in the Same Patient Population in the Preceding Study WIL-29. | Estimated SABR number calculated using a negative binomial counting regression model. Comparison between this number calculated for studies WIL-29 (NCT04053699) and WIL-31. For the comparison of results from WIL-31 to WIL-29 an estimated total annualized bleeding rate was calculated for each cohort, and compared with a negative binomial counting model. As these were estimated rates, there is only one value for each cohort with no measure of spread | 12 Months | 
| Wilate Consumption for Prophylaxis (mFAS Population) | Data on the consumption of Wilate (VWF/FVIII IU/kg per month and per week per patient) for prophylactic treatment | 12 months | 
| Incremental In Vivo Recovery (IVR) of Von Willebrand Factor Activity (VWF:RCo) | Incremental VWF:RCo IVR of Wilate over time (at baseline and at 1, 2, 3, 6, 9, and 12 months of treatment) | From baseline and 12-month visit | 
| Incremental In Vivo Recovery (IVR) of FVIII | FVIII:C of Wilate in pediatric patients (at baseline PK visit) measured by chromogenic assay | Baseline and 12-month visit | 
| Efficacy of Wilate in the Treatment of Breakthrough Bleeding Events (BEs) | Treatment efficacy will be assessed at the end of a BE by the patient using predefined criteria of 'Excellent', 'Good', 'Moderate' or 'None'. All effectiveness ratings assessed as either excellent or good will be considered successfully treated. | 12 months | 
| Wilate Exposure for Prophylaxis (mFAS Population) | Data on the exposure days of Wilate prophylactic treatment | 12 months |