Evaluation of Emicizumab Prophylaxis on Joint Health and Physical Activity in Patients Aged ≥13 to <70 with Severe or Moderate Hemophilia A Without FVIII Inhibitors

The primary objective of this study is to evaluate the impact of **emicizumab** treatment on joint health and health-related quality of life (HRQoL) outcomes, as well as the physical activity of participants with severe or moderate **hemophilia A**. This is clinically relevant as it aims to assess the effectiveness of emicizumab in improving the overall health and daily functioning of individuals affected by this bleeding disorder, potentially leading to enhanced management strategies and improved patient outcomes.

Secondary objectives include:

• To evaluate the safety of emicizumab, which is crucial for understanding the risk profile and ensuring the well-being of patients undergoing treatment.
• To evaluate the immune response to emicizumab, which is important for determining the potential for immunogenicity and its implications on treatment efficacy and safety.

The clinical trial involves a total of **91 participants** diagnosed with **Severe or Moderate Hemophilia A**. The study population includes both male and female subjects, encompassing a broad age range from children to adults. Participants were selected based on specific inclusion criteria, such as a confirmed diagnosis of severe congenital hemophilia A with an intrinsic FVIII level of less than 1%, or moderate congenital hemophilia A with an intrinsic FVIII level of 5% or less if previously prescribed prophylaxis. Additionally, participants must have a negative test for FVIII inhibitor during the screening period and no history of FVIII inhibitory antibodies in the last five years. The trial also considers lifestyle factors, requiring participants to have been on standard FVIII prophylaxis for at least the last 24 weeks. Adequate hematologic, hepatic, and renal function is necessary for participation. The study includes a vulnerable population, and women of childbearing potential must agree to remain abstinent or use contraception during the treatment period and for at least 24 weeks after the final dose of emicizumab.

The clinical trial is designed to evaluate the impact of **emicizumab** treatment on joint health, health-related quality of life (HRQoL), and physical activity in participants with severe or moderate **hemophilia A** without FVIII inhibitors. This is a multicenter, open-label Phase IV study. Participants aged 13 to 70 years will be enrolled, with the trial expected to conclude by December 2026. The study will involve a series of visits, starting with a screening visit to confirm eligibility based on specific inclusion criteria, such as a diagnosis of severe or moderate hemophilia A and a negative test for FVIII inhibitors. Participants must have been on standard FVIII prophylaxis for at least 24 weeks prior to enrollment.

The trial will proceed with regular follow-up visits to monitor joint status, physical activity, and HRQoL. These assessments will be conducted using tools such as the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) scores, Hemophilia Joint Health Score (HJHS v2.1), and the Comprehensive Assessment Tool of Challenges in Hemophilia (CATCH) Questionnaire. Physical activity will be tracked using a wearable activity tracker, and changes will be measured through the International Physical Activity Questionnaire Short Format (IPAQ-SF). The primary endpoints include joint status over time, number of problem joints, and HRQoL, while secondary endpoints focus on the incidence and severity of adverse events, including thromboembolic events and hypersensitivity reactions.

The expected duration of participant involvement is up to 36 months, with conditions for early termination including the development of anti-FVIII inhibitors or significant adverse events. The study will conclude with an end-of-study visit to evaluate the overall outcomes and gather final data. Participants will be monitored for the development of anti-drug antibodies against emicizumab and any changes in their preference for emicizumab compared to previous FVIII regimens. The trial aims to provide comprehensive data on the long-term effects of emicizumab prophylaxis in this patient population.

The clinical trial involves the administration of **Hemlibra** (emicizumab), a **solution for injection** specifically formulated for subcutaneous administration. Hemlibra is provided as a 150 mg/mL solution and is utilized in this study to evaluate its impact on joint health and health-related quality of life outcomes in participants with severe or moderate **hemophilia A** without FVIII inhibitors. The pharmaceutical form of Hemlibra is a solution for injection, and it is administered via subcutaneous injection. The dosing regimen involves a maximum daily dose of 6 mg/kg, with a total maximum dose of 468 mg/kg over the course of the treatment period. The treatment duration is set for a maximum of 36 months. The product has been relabeled and repackaged specifically for clinical trial use, ensuring compliance with study protocols.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the administration of Hemlibra to assess its efficacy and safety in the specified patient population. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial is designed to provide comprehensive data on the effects of emicizumab prophylaxis in improving joint outcomes and overall health in individuals with hemophilia A.

Efficacy in this clinical trial will be assessed through a series of primary endpoints focused on joint health, health-related quality of life (HRQoL), and physical activity in participants with severe or moderate **hemophilia A** without FVIII inhibitors on emicizumab prophylaxis. The primary endpoints include joint status over time, evaluated using the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) scores, with a specific focus on synovitis scores in participants with synovitis. Clinical joint status will be assessed using the Hemophilia Joint Health Score (HJHS v2.1), excluding gait assessment. Joint status at screening and month 36 will be evaluated based on the International Prophylaxis Study Group (IPSG) score with MRI. The number and proportion of problem joints, defined by chronic joint pain and/or limited range of movement, will be monitored over time. The number of target joint bleeds will also be tracked, with target joints defined as those with three or more bleeds in the same joint during the last 24 weeks.

HRQoL will be assessed using the Comprehensive Assessment Tool of Challenges in Hemophilia (CATCH) Questionnaire, focusing on domains such as risk perception of recreational activities, restrictions in recreational activities, preoccupation with disease, treatment burden impact on HRQoL, and pain severity. Changes in physical activity levels will be measured using a wearable activity tracker (Fitbit), with metrics including daily step count, active minutes, metabolic equivalents of tasks (METs), and moderate to vigorous physical activity (MVPA). The International Physical Activity Questionnaire Short Format (IPAQ-SF) will be used to measure changes in the time and intensity level of physical activity. Additionally, the number of all bleeds, treated and untreated, will be assessed using the Bleed and Medication Questionnaire (BMQ). Participant preference for emicizumab compared to previous FVIII regimens will be evaluated using the Emicizumab Preference Survey (EmiPref) at month 6.