The Empower Study - Design of a Randomized Clinical Trial to Assess the Efficacy and Safety of a Plasma-Derived Von Willebrand Factor / Factor VIII Concentrate for Heavy Menstrual Bleeding in Women with Von Willebrand Disease

Background: Although von Willebrand disease (VWD) is inherited by men and women equally, women are more likely to experience bleeding symptoms due to the challenges of menstruation and childbirth. Heavy menstrual bleeding (HMB) is the most common symptom observed in women and girls with VWD, and increases risk of iron deficiency anemia, blood transfusion, hospitalization and decreased health-related quality of life. While replacement therapy with von Willebrand factor (VWF) is recommended for prophylaxis in patients with VWD with severe and frequent bleeding, recommendations on its use for prophylaxis of HMB are limited due the lack of clinical trial data.

Aims: The EMPOWER pilot trial will determine the feasibility of the trial design, as well as explore assay sensitivity to inform the determination of the primary outcome for the definitive randomized trial which will evaluate the effect of prophylaxis with plasma-derived VWF/FVIII (1:1; pdVWF:FVIII) concentrate compared with placebo on HMB in women with VWD.

Methods: EMPOWER is a pilot, randomized, placebo-controlled, crossover, double-blind (patient and outcome assessor blinded), 2-year trial in female outpatients with VWD and HMB. We will evaluate the effect of 2-3 doses of prophylaxis with 40-60 IU VWF:RCo/kg pdVWF/FVIII concentrate when provided on the 2 heaviest days within the first 4 days of menstruation compared with placebo (normal saline). For the first treatment period, participants will be randomized to receive either pdVWF/FVIII concentrate or placebo for 4 cycles, crossing over to the comparator treatment during the second treatment period (see Figure 1).

Non-pregnant female patients, ≥18 years of age with a diagnosis of inherited VWD (any type) with HMB defined as a modified pictorial blood assessment chart (mPBAC) score >100, on stable treatment for HMB and iron-deficiency anemia will be eligible. Patients with diagnosis of another bleeding disorder or the presence of >2 risk factors for venous thromboembolism will be excluded.

The pilot trial viability outcomes include blinding index scores and participant drop-out rates. Feasibility outcomes include data completeness and rate of enrolment. The proposed primary clinical efficacy outcome is the mPBAC score and the key secondary efficacy outcome is the need for rescue therapy (i.e. >2 days of oral tranexamic acid use, additional treatment with pdVWF:FVIII concentrate, additional hormonal therapy for HMB, urgent/emergent gynecological surgery for HMB, treatment with intravenous iron, red blood cell transfusion, or hospital admission for HMB). Other secondary outcomes include major bleeding, clinically relevant non-major bleeding, red blood cell transfusion, fatigue and quality of life scores. Given the uncertainty in this area of research and the relative comparable clinical importance of proposed clinical efficacy outcomes, we will evaluate assay sensitivity to determine the outcome that has the greatest chance of detecting a difference between treatment periods. Assay sensitivity is defined as the ability of a scale to distinguish an effective from a less effective intervention or placebo. Assay sensitivity along with the proportion of missing data per clinical efficacy outcome and sample size considerations will influence the choice of primary outcome for the definitive trial. Safety will be evaluated by monitoring for hypersensitivity reactions, thromboembolic events and VWF inhibitors. The pilot trial will recruit 20 participants from Hemophilia Treatment Centres in Canada over 2 years.

Results: The pilot trial is aiming to launch by the fall 2022. If the pilot trial is deemed feasible and viable, we will subsequently conduct a definitive international randomized controlled trial.

Conclusion: Data from the EMPOWER trial will fill an important knowledge gap to facilitate evidence-based management of HMB in women with VWD.

Sholzberg:Octapharma: Research Funding. James:Band Therapeutics: Consultancy; Bayer: Research Funding. Sun:Shire: Consultancy; Sanofi: Honoraria; Sobi: Honoraria. Jüni:Terumo: Other: unpaid member of steering group of trials; Ava: Honoraria, Other: travel; Abbott Vascular: Other: unpaid member of steering group of trials; Appili Therapeutics: Other: unpaid member of steering group of trials, Research Funding; Fresnesius: Consultancy, Honoraria, Other: travel; Amgen: Consultancy, Honoraria, Other: travel.

This study is investigating the use of a VWF/FVIII concentrate for the prevention of bleeds in patients with von Willebrand disease of any type.