A phase 3b open-label, multicenter study evaluating physical activity and joint health in previously treated patients ≥12 years of age with severe haemophilia A treated with intravenous recombinant coagulation factor VIII Fc-von Willebrand Factor-XTEN fusion protein (rFVIIIFc-VWF-XTEN; efanesoctocog alfa) for 24 months

The primary objective of this study is to describe the change from baseline in **physical activity** over a 24-month prospective period in patients with severe **Haemophilia A** undergoing once-weekly prophylactic treatment with **efanesoctocog alfa**. This objective is clinically relevant as it aims to assess the impact of the treatment on the physical activity levels of patients, which is a critical aspect of managing Haemophilia A and improving patient outcomes.

Secondary objectives include: - To describe the relationship between physical activities and other variables such as bleeds, joint status, pain, injuries, and Quality of Life. - To describe changes from baseline in joint and musculoskeletal status. - To evaluate the efficacy of efanesoctocog alfa as a prophylactic treatment and its consumption for the prevention and treatment of bleeding episodes. - To describe changes from baseline in patient-reported outcome (PRO) measurements. - To assess the safety and tolerability of efanesoctocog alfa. - To describe healthcare resource use. These secondary objectives provide a comprehensive evaluation of the treatment's impact on various health parameters and resource utilization, which are essential for understanding the overall benefits and implications of the treatment in clinical practice.

The clinical trial involves a total of **9 participants** diagnosed with **Haemophilia A**, a severe bleeding disorder characterized by a deficiency in clotting factor VIII. The study population includes both male and female subjects, aged 12 years and older, who have been previously treated with recombinant or plasma-derived factor VIII for at least 150 exposure days. Participants are required to have been on prophylactic treatment for at least 12 months prior to enrollment and must have documented pre-study treatment data. The trial includes individuals who are able to self-administer the investigational drug, efanesoctocog alfa, intravenously at home. Participants are also required to use an activity tracker to monitor physical activity and heart rate throughout the study. The trial population was selected based on specific inclusion criteria, including a platelet count of at least 100,000 cells/µL and, for those who are HIV positive, a CD4 lymphocyte count greater than 200 cells/mm³ and a viral load of less than 400 copies/mL. The study aims to assess changes in physical activity over a 24-month period while on once-weekly prophylactic treatment.

The clinical trial is designed to evaluate the impact of **efanesoctocog alfa** on physical activity and joint health in patients aged 12 years and older with severe **haemophilia A**. This is a Phase IIIb, open-label, multicenter study with a duration of 24 months. The trial employs a prospective design, focusing on once-weekly prophylactic treatment with **efanesoctocog alfa**, administered via **intravenous injection**. The primary objective is to assess changes in physical activity from baseline over the study period, with secondary endpoints including joint and musculoskeletal status, efficacy of **efanesoctocog alfa**, patient-reported outcomes, and safety assessments.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of severe **haemophilia A**, and previous treatment history. Following the screening, participants will be enrolled and begin the treatment phase, which includes regular follow-up visits to monitor progress and collect data on physical activity, joint health, and any adverse events. The end-of-study visit will conclude the trial, with a comprehensive evaluation of the primary and secondary endpoints.

The expected length of participant involvement is 24 months, with conditions for early termination including the development of significant adverse events, non-compliance with the study protocol, or withdrawal of consent. Participants are required to be able and willing to administer the study drug at home and use an activity tracker provided by the sponsor. The trial aims to provide valuable insights into the long-term effects of **efanesoctocog alfa** on physical activity and joint health in this patient population.

The clinical trial involves the administration of **BIVV001 - efanesoctocog alfa**, an experimental medication designed for the treatment of severe **haemophilia A**. The active substance, **efanesoctocog alfa**, is a recombinant coagulation factor VIII Fc-von Willebrand Factor-XTEN fusion protein. This medication is provided in the form of a **powder for solution for injection**. The route of administration is via **intravenous injection**. The dosing regimen involves a maximum daily dose of 50 IU/kg, with a total maximum dose of 5200 IU/kg over a treatment period of up to 24 months. The medication is not formulated for pediatric use and is designated as an orphan drug under the designation number EU/3/19/2176.

Participants in the study will receive once-weekly prophylactic treatment with **efanesoctocog alfa**. The study aims to evaluate the change in physical activity and joint health over a 24-month period. Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for use in this study. The investigational product is manufactured by Swedish Orphan Biovitrum AB, and the administration will be facilitated using a device as detailed in the Q-IMPD DP Diluent documentation.

The efficacy of **efanesoctocog alfa** in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in the International Physical Activity Questionnaire (IPAQ) scoring at month 24. Secondary endpoints include various measures of physical activity, such as changes from baseline in IPAQ scoring at month 12, mean daily minutes of tracker-recorded physical activity, and mean daily number of tracker-recorded steps. Additionally, the trial will evaluate changes in patient-reported workouts, tracker-recorded workouts, and the achievement of World Health Organization-recommended levels of moderate to vigorous physical activity (MVPA).

Joint and musculoskeletal status will be assessed by changes from baseline in Hemophilia Joint Health Score (HJHS), HEAD-US, and MRI at both total/joint and item domain levels. The development, resolution, and recurrence of target joints will also be monitored. The efficacy of **efanesoctocog alfa** will be further evaluated by the number of bleeding episodes, annualized bleeding rate (ABR) by type and location, total annualized consumption of the drug, and the number of injections and dose required to treat a bleeding episode.

Patient-reported outcomes (PROs) will be measured using tools such as the PROMIS Pain Intensity and PROMIS-SF Pain Interference scales, as well as the EQ-5D-5L for quality of life assessment. The Treatment Preference Survey will be conducted at the end of the study. Safety assessments will include monitoring the occurrence of adverse events (AEs) and serious adverse events (SAEs), clinically significant changes from baseline in physical examinations, vital signs, and laboratory tests, as well as the development of inhibitors against factor VIII as determined by the Nijmegen modified Bethesda assay. The occurrence of thrombotic and embolic events will also be recorded. Healthcare resource utilization will be tracked by the number and duration of non-study medical care encounters, including outpatient, inpatient, and emergency room visits.