Evaluation of the Efficacy and Safety of Recombinant Von Willebrand Factor with or without Octocog Alfa in Pediatric Severe Hereditary Von Willebrand Disease

The primary objective of this clinical study is to evaluate the **hemostatic efficacy** and safety of **vonicog alfa**, with or without ADVATE, in the treatment and control of nonsurgical bleeding events in pediatric subjects diagnosed with severe, hereditary von Willebrand Disease (VWD). This is clinically relevant as it addresses the management of bleeding episodes in a vulnerable population, aiming to improve therapeutic outcomes and safety profiles for children with this condition.

Secondary objectives include:

• Evaluating the hemostatic efficacy of vonicog alfa after the last perioperative infusion in elective or emergency surgeries.
• Assessing the safety of vonicog alfa.
• Evaluating the pharmacokinetics (PK) of vonicog alfa.

The clinical trial involves a total of **23 participants** diagnosed with **hereditary severe von Willebrand Disease** in children. The study population comprises pediatric subjects under the age of 18, including both male and female participants. The selection criteria for the trial population include a confirmed diagnosis of severe von Willebrand Disease, with specific subtypes such as Type 1, Type 2A, Type 2B, Type 2N, Type 2M, or Type 3, as defined by von Willebrand factor activity levels. Participants were required to provide assent, and their legally authorized representatives provided informed consent. Female participants of childbearing potential were required to present a negative serum pregnancy test and agree to employ adequate birth control measures during the study. The trial also includes previously treated subjects who have experienced a minimum of one documented bleeding event requiring von Willebrand factor replacement therapy in the past year, as well as previously untreated subjects. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial aims to evaluate the hemostatic efficacy and safety of vonicog alfa, with or without ADVATE, in managing nonsurgical bleeding events in this vulnerable pediatric population.

The clinical trial is designed to evaluate the **hemostatic efficacy** and safety of **vonicog alfa**, with or without **ADVATE**, in pediatric subjects diagnosed with severe, hereditary von Willebrand Disease (VWD). This is a Phase 3, prospective, multicenter, uncontrolled, open-label study. The trial aims to assess the treatment and control of nonsurgical bleeding events, the efficacy and safety in elective and emergency surgeries, and the pharmacokinetics of vonicog alfa in children under 18 years of age. The trial is expected to last until September 19, 2025, with participant involvement potentially extending up to 18 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of severe VWD, and willingness to comply with study requirements. Follow-up visits will be scheduled to monitor the efficacy and safety of the treatment, including the number of treated nonsurgical bleeding episodes and the incidence of adverse events. The end-of-study visit will conclude the participant's involvement, assessing the overall treatment success and any long-term effects.

The trial employs a non-randomized, open-label design, meaning that both the investigators and participants are aware of the treatment being administered. Participants may be withdrawn from the study early if they experience severe adverse reactions, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The primary endpoint is the hemostatic efficacy, defined by the number of pediatric subjects with treatment success for vonicog alfa-treated nonsurgical bleeding episodes. Secondary endpoints include the number of infusions required, the incidence of adverse events, and the development of antibodies.

The clinical trial involves the administration of **ADVATE**, a recombinant antihemophilic factor (octocog alfa), which is provided in two dosages: 1000 IU and 500 IU. The pharmaceutical form is a **powder and solvent for solution for injection**, intended for intravenous use. The active substance, octocog alfa, is a protein derived from recombinant DNA technology. The administration involves reconstitution of the powder with the provided solvent, followed by intravenous injection. The dosing is measured in international units per kilogram (IU/kg) of body weight, with the maximum treatment period set at 18 months. The **BaxJect II** device, a needleless transfer device, is utilized for the preparation and administration of the solution, ensuring efficient mixing and transfer of the drug into a syringe.

Another experimental medication used in the trial is **VEYVONDI**, which contains the active substance vonicog alfa. This medication is available in two dosages: 650 IU and 1300 IU. Similar to ADVATE, VEYVONDI is provided as a **powder and solvent for solution for injection** and is administered intravenously. Vonicog alfa is also a protein produced through recombinant DNA technology. The dosing is expressed in IU/kg, with a maximum treatment duration of 18 months. The **Mix2Vial** device is employed for the reconstitution of VEYVONDI, facilitating the transfer of the diluent into the vacuum powder vials and subsequent aspiration into a syringe for administration.

Both ADVATE and VEYVONDI are used in the study to evaluate their efficacy and safety in the treatment and control of bleeding episodes in pediatric subjects diagnosed with severe von Willebrand Disease. The trial does not include any non-experimental treatments such as placebo or standard-of-care therapy. Participant compliance is monitored through regular assessments and documentation of dosing schedules and administration techniques.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on **hemostatic efficacy**, which is defined by the number of pediatric subjects achieving treatment success for vonicog alfa-treated nonsurgical bleeding episodes. Treatment success is quantified using a 4-point scale, with a mean efficacy rating score of less than 2.5 indicating success.

Secondary efficacy endpoints include the number of treated nonsurgical bleeding episodes rated as 'excellent' or 'good', the number of infusions, and the units of vonicog alfa and ADVATE used per bleeding episode. For surgical interventions, an overall assessment of hemostatic efficacy will be conducted 24 hours after the last perioperative infusion of vonicog alfa or on Day 14, whichever occurs first, using a 4-point scale evaluated by the Investigator.

Pharmacokinetic and pharmacodynamic parameters will also be analyzed, including the area under the plasma concentration/time curve from 0 to 96 hours post-infusion (AUC0-96h), maximal plasma concentration (Cmax), and other related metrics for VWF:RCo, VWF:Ag, and VWF:CB. These will be assessed using non-compartmental analysis methodology, with point estimates presented per age cohort.