Prevention of Bleeding in Patients With Moderate and Severe Hemophilia A Playing Sports: A Comparison Between Factor VIII and Emicizumab Prophylaxis

Hemophilia A (HA) is a genetic bleeding disorder resulting from a deficiency or absence of factor VIII (FVIII), which is necessary in the clotting process. This disorder occurs mostly in males and in severe cases causes frequent bleeding episodes in joints and muscles which can lead to progressive damage that affects mobility and quality of life. Prophylactic FVIII administered intravenously every other day has been the standard of care treatment for HA for the past few decades.

Sports and physical activity are generally encouraged in patients with hemophilia on appropriate prophylactic treatment to increase strength, prevent or decrease obesity, accrue and maintain bone density and encourage normal socialization. To ensure safety with participation in sports in persons with hemophilia A (PWHA), timing of FVIII administration is often adjusted to maximize FVIII at the time of sports. The exact factor level that is needed to safely participate in sports and minimize bleeding risk is not yet known. Based on clinical practice, infusion of FVIII to near the lower limit of normal right before participation in sports generally works to prevent bleeding.

The study is looking at how well the newly approved medication Emicizumab works compared to Factor VIII to prevent bleeding in patients with Hemophilia A who play sports. The study will enroll children and adolescents who are already on Emicizumab or Factor VIII who are currently playing sports.

Hemophilia A (HA) is a genetic bleeding disorder resulting from a deficiency or absence of factor VIII (FVIII) which is necessary in the clotting process. This disorder occurs mostly in males and in severe cases causes frequent bleeding episodes in joints and muscles which can lead to progressive damage that affects mobility and quality of life. Intravenous prophylactic (preventative) treatment is the standard of care used in minimizing bleeding events and complications. Since the 1990s recombinant FVIII (rFVIII) concentrates have been standard of care treatment options for patients with hemophilia A. Prophylactic treatment is burdensome because it requires self-administered intravenous infusions several (3-4) times a week and prophylactic FVIII does not completely prevent bleeding.

Sports and physical activity are generally encouraged in patients with hemophilia on appropriate prophylactic treatment to increase strength, prevent or decrease obesity, accrue and maintain bone density and encourage normal socialization. To ensure safety with participation in sports in persons with hemophilia A (PWHA), timing of FVIII administration is frequently adjusted to maximize FVIII at the time of sports. The exact factor level that is needed to safely participate in sports and minimize bleeding risk is not yet known. Based on clinical practice, infusion of FVIII to near the lower limit of normal right before participation in sports generally works to prevent bleeding.

Emicizumab is an engineered antibody that mimics what activated factor VIII does in the blood to help it clot. Emicizumab is an antibody and is present in the blood for a long time and approximately 50% of an injected dose is still circulating in the blood 4 weeks later; this permits less frequent dosing (Anywhere from once a week to once every 4 weeks). Emicizumab can be injected under the skin (subcutaneous) instead of having to be injected into a vein (intravenous). Emicizumab's convenience compared to FVIII, reduced bleeding rate, and in many cases decreased annual cost, have led to its adoption by many patients with HA. Emicizumab does not completely normalize hemostasis (the physiological process that stops bleeding) and although the exact comparison of hemostatic correction on maintenance doses of Emicizumab to that with FVIII replacement cannot be determined with existing assays, it has been clinically demonstrated that Emicizumab changes the bleeding characteristics of a patient with severe hemophilia A to a milder profile. While this may provide sufficient protection to prevent spontaneous bleeding into the joints, it remains unknown if this is sufficient to prevent activity/sports related joint bleeds (especially activities with moderate to high risk of bleeding).

A disadvantage of Emicizumab prophylaxis is that the steady state produced with Emicizumab prophylaxis does not allow dosing at the time of sports participation. One major question is whether the "steady state" levels of hemostasis achieved with Emicizumab are enough to prevent joint damage with sports participation, and whether there is a threshold of participant age or size or activity intensity above which Emicizumab is not generally adequate.

Emicizumab use permits maintenance of "steady state" hemostasis in the range of mild hemophilia without frequent infusions. Studying patients taking Emicizumab while engaging in sports permits us to study the effects of participation in physical activity with steady state hemostasis levels in the range of mild hemophilia compared to peak hemostatic levels from factor infusions given immediately before engaging in activity/sports. This is a crucial factor in the decision-making process for physicians making treatment recommendations to optimize preventive therapy for physically active people with hemophilia A.

The purpose of this investigator-initiated study is to better understand the safety of sports in people with Hemophilia A, the breakthrough bleed rates, and the types of bleeds related to sports activities in patients on Emicizumab vs traditional FVIII prophylaxis. This information will help in the decision-making process for physicians making treatment recommendations for physically active people with hemophilia A.

Eligibility Criteria:
Inclusion Criteria:

1. Participant (if 18 years of age or older) or parent/LAR is willing and able to provide written informed consent; minor participant is willing and able to provide assent, if applicable based on site and local regulations
2. Male participants with moderate to severe Hemophilia A ( FVIII activity \</= 5%) between 6 to 19 years of age without inhibitors are eligible for participation in this study
3. Participants must be on Emicizumab or standard FVIII prophylaxis per institutional/primary hematologist recommendations
4. Participants must be engaging in sports activities with moderate to high risk of bleeding as defined by the NHF- Playing it Safe guidelines (numerical rating \>/= 2).
5. Participants must be compliant with completing all standard of care bleed and treatment logs
6. Participant must be willing to keep daily activity logs for the duration of the study.

Exclusion Criteria:

1. Participant/parent/LAR unwilling to provide informed consent/assent
2. Unwilling to log or document bleeds and treatment information as per study guidelines
3. Participants with any other bleeding disorders will be excluded
4. Participants on concomittent FVIII replacement and emicizumab for sports participation