A Phase 3, Prospective, Open-Label, Uncontrolled, Multicenter Study on Efficacy and Safety of Prophylaxis with Recombinant Von Willebrand Factor in Children Diagnosed with Severe Von Willebrand Disease
Authors: Marquez-Gomez Cecilia , Waliullah Maria , Wang Yi , Mokdad Ali G , Zhang Jingmei 
Published: December 2024

Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder and can cause recurrent bleeding (Connell et al, Blood Adv, 2021). Current data support the safety and efficacy of recombinant von Willebrand factor (rVWF) for on-demand (OD), perioperative, and prophylactic treatment in adults with VWD (Gill et al, Blood, 2015; Peyvandi et al, J Thromb Haemost, 2019; Leebeek et al, Blood, 2022). Current treatment guidelines conditionally recommend long-term prophylaxis in patients with VWD with a history of severe and frequent bleeds (Connell et al, Blood Adv, 2021). Expert consensus is that young age is a key factor in initiating long-term prophylaxis; however, further studies are needed to develop evidence-based guidelines for children with VWD (Schinco et al, Blood Transfus, 2018).
Objective: This study will investigate the efficacy, safety, pharmacokinetics (PK)/pharmacodynamics (PD), and healthcare resource utilization (HCRU) of rVWF prophylaxis in children from 0 to &lt;18 years of age with severe VWD.
Study Design and Methods: This study (NCT05582993) is a phase 3, prospective, open-label, uncontrolled, multicenter study to assess the efficacy and safety of prophylaxis with rVWF in children diagnosed with severe VWD.
Up to 24 pediatric participants diagnosed with severe VWD will be enrolled from three age ranges (≥12 to &lt;18 years, ≥6 to &lt;12 years, and &lt;6 years). Participants must have received prior treatment with a VWF-containing product for at least 12 months (6 months in participants aged &lt;2 years), including OD treatment with a VWF product or plasma-derived (pd) VWF prophylaxis. Key exclusion criteria include diagnosis with pseudo-VWD or another coagulation disorder other than VWD and history or presence of a VWF or factor VIII inhibitor. Sample size was determined by referencing the European Medicines Agency guideline “Clinical Investigation of Human pdVWF Products” with practical considerations for a clinical trial in a rare disease population.
Participants will initially receive twice-weekly rVWF at a dose range of 40-60 IU/kg, as measured by the ristocetin cofactor assay. Dose adjustments may be made based on individual drug-exposure response, as assessed by the investigator and in consultation with the sponsor. The study treatment duration will be 12 months with visits at prophylaxis initiation and at 1, 2, 3, 6, 9, and 12 months.
The primary objective is to prospectively evaluate the efficacy of rVWF prophylaxis in children. Intra-patient comparisons (on-study vs historical) of annualized bleeding rate (ABR) will be assessed for all bleeding episodes, classified by the investigator as spontaneous or traumatic, occurring during rVWF prophylaxis. Secondary efficacy endpoints include categorized ABR (0, &gt;0-2, &gt;2-5, &gt;5), ABR percentage reduction (prior OD) or ABR preservation (prior pdVWF prophylaxis), ABR for spontaneous bleeding event by location, ABR by cause and treatment given, rVWF factor consumption, and efficacy of breakthrough bleed treatment. Safety will be assessed by adverse events (AEs) and serious AEs, thromboembolic events, hypersensitivity reactions, infusion-related reactions, immunogenicity, and abnormal changes in vital signs and clinical laboratory parameters. PK/PD of rVWF in children will be assessed. Additionally, HCRU, missed school days, and efficacy of surgery management (if necessary) will also be explored. Descriptive statistics will be used to summarize the data, and no formal statistical hypothesis testing is planned for the analysis.
Conclusions: Overall, this study aims to evaluate the efficacy and safety of prophylactic treatment with rVWF in children with VWD, which has the potential to improve the management of this bleeding disorder and quality of life.