A phase III study comparing secondary long-term prophylaxis versus on-demand treatment with vWF/FVIII concentrates in severe inherited von Willebrand disease

Blood Transfus. 2019 Sep;17(5):391-398. doi: 10.2450/2019.0183-18. Epub 2019 Feb 4.


Background: There is a lack of prospective clinical trials specifically designed to evaluate the benefits of prophylaxis with vWF/FVIII concentrates in patients with inherited von Willebrand disease (vWD). The aim of the study was to compare efficacy of secondary long-term prophylaxis (PRO) with vWF/FVIII in the prevention of bleeding episodes in severe vWD patients to standard of care (on-demand treatment; ODT).

Materials and methods: In this 12-month, phase III, open-label study (PRO.WILL), vWD patients (aged ≥6 years) were randomised to PRO (n=9; 5 completed) or ODT (n=10; 7 completed) treatment with Fanhdi®/Alphanate® (Grifols) according to current licensing status for use in vWD. We assessed the proportion of patients who did not present any spontaneous bleeding episode, adverse events (AEs) or thrombotic events.

Results: All patients on ODT had vWD type 2 or 3 vs 70% of patients on PRO. All ODT patients experienced bleeds vs 60% on PRO. PRO patients showed fewer bleeds (n=32 vs n=172 [112 in the same patient, mostly mucosal]; p<0.0001) and lower risk of bleeding (relative attributable risk estimate: -0.667; 95% CI: -2.374, -0.107; p<0.001). Most frequent bleeds in ODT and PRO groups were, respectively, epistaxis (n=52 vs n=15) and gastrointestinal (n=13 [9 in the same patient] vs n=1). While most bleeds lasted one day under ODT (31/32), only epistaxis did so in PRO group (14/15). No AEs due to study medication were observed.

Discussion: Despite the small sample size and the heterogeneity of the study population, patients on vWF/FVIII prophylaxis showed a reduction in bleeding risk and rate compared to on-demand treatment.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Drug Combinations
  • Factor VIII / administration & dosage
  • Factor VIII / adverse effects
  • Factor VIII / therapeutic use*
  • Female
  • Hemorrhage / drug therapy
  • Hemorrhage / etiology
  • Hemorrhage / prevention & control*
  • Humans
  • Male
  • Middle Aged
  • Treatment Outcome
  • Young Adult
  • von Willebrand Diseases / complications
  • von Willebrand Diseases / drug therapy*
  • von Willebrand Diseases / prevention & control
  • von Willebrand Factor / administration & dosage
  • von Willebrand Factor / adverse effects
  • von Willebrand Factor / therapeutic use*


  • Drug Combinations
  • factor VIII, von Willebrand factor drug combination
  • von Willebrand Factor
  • Factor VIII