Prevention of Bleeding in Patients with Moderate and Severe Hemophilia A Playing Sports: A Comparison between Factor VIII and Emicizumab Prophylaxis (STEP: SporTs Emicizumab Prophylaxis)

Introduction: The risk of bleeding and hemarthrosis is a major concern in persons with Hemophilia A (PWHA), making sports participation unsafe without adequate prophylaxis. Physical activity and exercise on the other hand, have been shown to increase muscle strength and thereby joint stability, prevent or decrease obesity, accrue and maintain bone density and encourage normal socialization. The National Hemophilia Foundation has categorized sports according to bleeding risk to help PWHA choose activities safely and Factor VIII (FVIII) administration is often timed to maximize FVIII levels at the time of sports. While the exact factor level that is needed to safely participate in sports and minimize bleeding risk is yet unknown, it is evident that infusion of FVIII prior to sports is generally adequate to prevent bleeding. The emergence of new non-replacement therapies, like Emicizumab, has revolutionized hemophilia care but has brought about new challenges. With Emicizumab, a steady state level is achieved but this does not lend itself to augmentation at the time of intensive participation. The STEP study aims to determine the safety and the efficacy of Emicizumab prophylaxis versus FVIII replacement for preventing sports related bleeds in patients with moderate to severe hemophilia A playing moderate to high intensity sports. It is anticipated that the thrombin generation capacity with Emicizumab prophylaxis will be sufficient to prevent breakthrough bleeding related to sports participation.

Objective: To describe the design and objectives of an observational study aiming to confirm the efficacy and safety of Emicizumab in PWHA (moderate and severe) engaging in moderate to high intensity sports activities.

Study Design and Methods: This is a multicenter, prospective observational study comparing children and adolescents (6-19 years of age) with moderate to severe hemophilia A without inhibitors, on standard of care treatment of factor VIII prophylaxis or Emicizumab.

Primary Objective: To investigate the effectiveness of Emicizumab prophylaxis to prevent bleeding related to participation in moderate to high intensity sports in patients with moderate to severe Hemophilia A without inhibitors.

Secondary Objectives: Investigate progression of joint disease, measure markers of bone and joint health and compare treatment burden on patients and caregivers

Duration of Study: 156 weeks or 3 years.

Inclusion/Exclusion: Patients must be on prophylaxis for sports, either with FVIII replacement or Emicizumab and be willing to log activities, bleeds and treatment, along with consent to wear an activity monitor during sports activities. Patients receiving concomitant FVIII and Emicizumab or those with more than one bleeding disorder are excluded.

No objective data are available to determine the safety of sports participation with less than complete correction of hemostasis. This study is a pilot study to determine the safety of sports participation in PWHA on Emicizumab versus FVIII prophylaxis. Sixty participants will be enrolled in each group (Fig 1). The information from this study will guide power calculation for larger prospective trials of the safety of Emicizumab in high level sports activity. Final comparisons in hemophilia participants will be based on matching by age groups as well as Hemophilia Joint Health Score(HJHS) and type of prophylactic regimen. While subgroup descriptions may be explored, any inference of the data will be based on a joint model where all the data is included. More specifically, a full model with covariates for sports types, FVIII intensity/Emicizumab dose or frequency and age groups will be employed and least squares means and associated 95% confidence intervals will be extracted from this model to compare bleed rates (or other endpoints) between Emicizumab and FVIII prophylaxis groups.

The Primary endpoint of this study is the number of bleeds without trauma, during participation in sports. Secondary Endpoints include the measurement of change in HJHS scores, bone mineral density, biomarkers of bone and joint health, number of doses of factor needed to treat breakthrough bleeding episodes and will also evaluate the MRI changes in relevant joints in a subset of patients.

Summary: This ongoing study is designed to address the unmet need on the safety and efficacy of new treatments in Hemophilia, for the prevention of bleeding with sports activities.

Chitlur:BPL Inc: Honoraria; Emerging Therapeutics Inc: Honoraria; Genentech Pharmaceuticals: Honoraria, Research Funding; Sanofi/Genzyme Corp: Honoraria; Agios Pharmaceuticals: Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria.