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

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

The WIL-33 study aimed 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.

Study Overview

• Status: Completed
• Conditions: Von Willebrand Disease
• Intervention / Treatment: Drug: Wilate

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 3

Contacts and Locations

Study Locations

• Czechia
  • Ostrava, Czechia
    • University Hospital Ostrava Department for Pediatric Medicine
  • Prague, Czechia
    • University Hospital Motol, Department of Paediatric Haematology and Oncology
• Germany
  • Duisburg, Germany
    • Gerinnungszentrum Rhein-Ruhr Ambulanz und Fachlaboratorium für Gerinnungserkrankungen/Hämophilie
• Moldova
  • Chisinau, Moldova
    • IMSP Mother and Child Institute
• North Macedonia
  • Skopje, North Macedonia
    • PHI University Clinic for Child Diseases
• Russia
  • Moscow, Russia
    • FSBI National Research Medical Center of Pediatric Hematology, Oncology and Immunology
  • Moscow, Russia
    • Morozovskaya Children's Hospital
• Ukraine
  • Lviv, Ukraine
    • Danylo Halytsky Lviv National Medical University, Communal Institution of Lviv Regional Council "Western Ukrainian Specialized Children's Medical Centre"
• United States
  • Louisiana
    • New Orleans, Louisiana, United States, 70118
      • Tulane University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 5 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients aged <6 years at the time of screening
2. 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
3. Minimum BW 12.5 kg at the time of screening (for Moldova and Czech Republic, minimum BW 11.0 kg at the time of screening)
4. 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:

1. History or current suspicion of VWF or FVIII inhibitors
2. Injection of 1-deamino-8-D-arginine vasopressin (DDAVP) or VWF-containing product within 72 hours prior to inclusion
3. Medical history of a thromboembolic event
4. Platelet count <100,000/µL at screening (except for VWD type 2B)
5. Patients receiving, or scheduled to receive, immunosuppressant drugs (other than antiretroviral chemotherapy), such as prednisone (equivalent to >10 mg/day), or similar drugs
6. Treatment with any investigational medicinal product (IMP) in another interventional clinical study currently or within four weeks before enrolment
7. Other coagulation disorders or bleeding disorders
8. Known hypersensitivity to any of the components of the study drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Wilate treatment; PK: Single dose of 80 IU/kg body weight (BW). Prophylactic treatment: 30-50 IU/kg BW administered 2-3 times per week at recommended dose 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 Factor VIII coagulant activity (FVIII:C) trough levels of >30%. Major haemorrhage: loading dose 50-80 IU/kg BW then 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 then 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 then 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; 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 VWD and/or haemophilia A

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Annualised Bleeding Rate (TABR) During Prophylactic Treatment With Wilate.	TABR is defined as the total number of bleeding episodes (BEs) including spontaneous, traumatic, and other bleeds, occurring during the period from the first prophylactic dose of wilate to the study completion visit, divided by the duration (in years) between these two time points. Bleeding episodes that occurred during surgery periods were excluded from the calculation of TABR. Total BEs refers to all bleeding episodes that occurred during the study period, regardless of whether they were treated with wilate or not. Treated BEs are a subset of total BEs comprising of bleeding episodes that were treated with wilate.	During 12 months of prophylactic treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve (AUC) of Wilate for VWF:Ac (VWF:RCo) Over Time	Mean AUC of VWF:Ac after PK injection of wilate as measured by chromogenic assay.	At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate
Area Under the Curve (AUC) of Wilate for FVIII (OS) Over Time	Mean AUC of FVIII after PK injection of wilate as measured by chromogenic assay.	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) Over Time	Mean AUC of VWF:Ac after PK injection of wilate, normalised for the actual administered dose (IU/kg), over time. AUC norm was measured and reported as [h*kg/IU]/(dL/IU) which could also be reported as h*kg/dL.	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 FVIII:C (OS) Over Time	Mean AUC of FVIII after PK injection of wilate, normalised for the actual administered dose (IU/kg), over time. AUC norm was measured and reported as [h*kg/IU]/(dL/IU) which could also be reported as h*kg/dL.	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) Over Time	Mean clearance (CL) of VWF:Ac, measured by ristocetin cofactor assay [VWF:RCo]) after PK injection of wilate, calculated as the ratio of dose administered to the area under the plasma concentration-time curve (AUC), over time. Clearance was defined as the rate of drug elimination divided by plasma concentration, giving a volume of plasma from which drug is completely removed per unit of 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 FVIII:C (OS) Over Time	Mean clearance (CL) of FVIII:C, measured by one-stage assay [OS]) after PK injection of wilate, calculated as the ratio of dose administered to the area under the plasma concentration-time curve (AUC), 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) Over Time	Mean maximum plasma concentration (Cmax) of VWF:Ac, measured by ristocetin cofactor assay [VWF:RCo]) after PK injection of wilate, as determined from the observed peak value in the plasma concentration-time profile.	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 FVIII:C (OS) Over Time	Mean maximum plasma concentration (Cmax) of FVIII:C, measured by one-stage assay [OS]) after PK injection of wilate, as determined from the observed peak value in the plasma concentration-time profile.	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) Over Time	Mean residence time (MRT) of VWF:Ac, measured by ristocetin cofactor assay [VWF:RCo]) after PK injection of wilate, calculated as the average time a VWF:Ac molecule remains in the body, derived from the ratio of area under the first moment curve (AUMC) to AUC.	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 FVIII:C (OS) Over Time	Mean residence time (MRT) of FVIII:C, measured by one-stage assay [OS]) after PK injection of wilate, calculated as the average time a FVIII:C molecule remains in the body, derived from the ratio of area under the first moment curve (AUMC) to AUC.	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) Over Time	Mean in vivo half-life (T1/2) VWF:Ac, measured by ristocetin cofactor assay [VWF:RCo]) after PK injection of wilate, calculated as the time required for the plasma concentration to decrease by half during the terminal elimination phase.	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 FVIII:C (OS) Over Time	Mean in vivo half-life (T1/2) of FVIII:C, measured by one-stage assay [OS]) after PK injection of wilate, calculated as the time required for the plasma concentration to decrease by half during the terminal elimination phase.	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) Over Time	Mean time to reach maximum plasma concentration (Tmax) of VWF:Ac, measured by ristocetin cofactor assay [VWF:RCo]) after PK injection of wilate, defined as the time from dosing to the observed peak plasma concentration.	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 FVIII:C (OS) Over Time	Mean time to reach maximum plasma concentration (Tmax) of FVIII:C, measured by one-stage assay [OS]) after PK injection of wilate, defined as the time from dosing to the observed peak plasma concentration.	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) Over Time	Mean volume of distribution at steady state (Vd) of VWF:Ac, measured by ristocetin cofactor assay [VWF:RCo]) after PK injection of wilate, calculated as clearance (CL) multiplied by mean residence time (MRT).	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 FVIII:C (OS) Over Time	Mean volume of distribution at steady state (Vd) of FVIII:C, measured by one-stage assay [OS]) after PK injection of wilate, calculated as clearance (CL) multiplied by mean residence time (MRT).	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) Over Time	Mean incremental in vivo recovery (IVR) of VWF:Ac, measured by ristocetin cofactor assay [VWF:RCo]) after PK injection of wilate, calculated as the increase in plasma VWF:Ac concentration per IU/kg of wilate administered.	Measures were taken at the following timepoints: baseline and 1, 2, 3, 6, 9, and 12 months of treatment with IVR values reported at baseline and 12 months.
Incremental In-vivo Recovery (IVR) of Wilate for FVIII:C (OS) Over Time	Mean incremental in vivo recovery (IVR) of FVIII:C, measured by one-stage assay [OS]) after PK injection of wilate, calculated as the increase in plasma FVIII:C concentration per IU/kg of wilate administered.	Measures were taken at the following timepoints: baseline and 1, 2, 3, 6, 9, and 12 months of treatment with IVR values reported at baseline and 12 months.
Efficacy of Wilate Measured by the Proportion of BEs Successfully Treated With Wilate	Proportion of BEs successfully treated with wilate, as assessed using a predefined 4-point ordinal haemostatic efficacy scale. Each BE was rated at the end of treatment as "excellent", "good", "moderate", or "none" based on the time to bleeding cessation and the dose required. A BE is considered successfully treated if the efficacy rating is "excellent" (bleeding stopped within 3 days for minor bleeds, within 7 days for major bleeds, or within 10 days for gastrointestinal bleeds) or "good" (bleeding stopped, but time and/or dose slightly exceeded expectations). The outcome is reported as the percentage of BEs with a rating of "excellent" or "good" out of all treated BEs	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	Overall efficacy of wilate in perioperative prophylaxis against excessive bleeding, as assessed at the end of the postoperative period by the responsible treating investigator using a predefined 4-point ordinal haemostatic efficacy scale. The assessment is based on the presence or absence of postoperative bleeding or oozing, the need for additional dosing, and the ability to control bleeding with wilate. Excellent: No postoperative bleeding or oozing not due to surgical complications; all postoperative bleeding due to complications controlled with wilate as anticipated for the procedure. Good: No postoperative bleeding or oozing not due to surgical complications; control of postoperative bleeding due to complications required increased dosing or additional injections of wilate not originally anticipated. Moderate: Some postoperative bleeding or oozing not due to surgical complications; control required increased dosing or additional injections of wilate not originally anticipated	Up to 12 months of treatment
Consumption of Wilate for Prophylactic Treatment	Mean dose of wilate administered for routine prophylactic treatment, reported as (a) mean dose per injection (IU/kg) and (b) mean dose per week (IU/kg). Dose per injection is calculated as the total amount of wilate (IU) administered per injection divided by the patient's body weight (kg). Dose per week was calculated as the total amount of wilate (IU) administered for prophylaxis in a week, divided by the patient's body weight (kg). Both measures were averaged across all prophylactic infusions during the study period	Up to 12 months of treatment
Consumption of Wilate for the Treatment of BEs (On-demand Treatment)	Mean dose of wilate administered for the on-demand treatment of BEs, reported as (a) mean dose per BE (IU/kg) and (b) mean dose per injection (IU/kg). Dose per BE is calculated as the total amount of wilate (IU) administered per BE treatment divided by the patient's body weight (kg). Dose per injection is calculated as the total amount of wilate (IU) administered for BE treatment in a week, divided by the patient's body weight (kg). Both measures are averaged across all treated BEs during the study period	Up to 12 months of treatment
Consumption of Wilate During Surgical Prophylaxis	Mean dose of wilate administered for surgical prophylaxis, reported as dose per exposure day (ED) in IU/kg. Dose per exposure day is calculated as the total amount of wilate (IU) administered for surgical prophylaxis on each day, divided by the patient's body weight (kg). The measure is averaged across all exposure days during the perioperative period	Up to 12 months of treatment
Number of Participants With Detectable Inhibitory Antibodies Against VWF and/or FVIII	Number of patients with detectable inhibitory antibodies to von Willebrand factor (VWF) and factor VIII (FVIII) during the study testing. Inhibitor testing is performed at baseline, every 3 months, and at any time if inhibitor development is suspected.	Up to 12 months of treatment
Number of Participants With Detectable Thromboembolic Events	Incidence of thromboembolic events, defined as the proportion of patients who experience one or more thromboembolic events (such as deep vein thrombosis, pulmonary embolism, or other clinically relevant thromboses) during the study period. Thromboembolic events are monitored and recorded as adverse events throughout the study, and are confirmed by clinical assessment and/or diagnostic imaging as appropriate. The outcome is reported as the number and percentage of patients with at least one thromboembolic event during the study	Up to 12 months of treatment
Change in Haemophilia Joint Health Score	Change from baseline in the Haemophilia Joint Health Score (HJHS) total score, assessed at baseline and at the end of the study (12 months). The HJHS is a validated clinical tool used to evaluate joint health in patients with bleeding disorders, measured over a scale of 0-124, with higher scores indicating worse joint health. This score is comprised of the assessments of 6 joints according to 8 criteria (each joint is scored from 0 to 20, giving a possible assessment range for all joints of 0 to 120) plus the Global Gait Score (measured from 0 to 4). The outcome is reported as the mean change in total HJHS score from baseline to study completion for each participant. An increase (positive value) indicates an increase in HJHS over the course of the study and worsening of joint health. A decrease (negative value) reflects a reduction in HJHS over the study duration and improvements in joint health. Assessments are performed by trained investigators using the standard HJHS protocol.	At baseline and at 12 months of treatment

Collaborators and Investigators

• Sponsor: Octapharma

Study record dates

Study Major Dates

• Study Start (Actual): September 22, 2021
• Primary Completion (Actual): December 16, 2024
• Study Completion (Actual): December 16, 2024

Study Registration Dates

• First Submitted: June 18, 2021
• First Submitted That Met QC Criteria: July 7, 2021
• First Posted (Actual): July 8, 2021

Study Record Updates

• Last Update Posted (Actual): February 20, 2026
• Last Update Submitted That Met QC Criteria: February 2, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Blood Coagulation Disorders; Hemorrhagic Disorders; Blood Platelet Disorders; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; von Willebrand Diseases; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Blood Proteins; Blood Coagulation Factors; von Willebrand Factor
• Other Study ID Numbers: WIL-33

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No