Phase 4 Study on Synovial Hypertrophy Progression in Haemophilia A Patients Undergoing Efanesoctocog Alfa Prophylaxis Using Ultrasound and MRI

The primary objective of this study is to assess the improvement of existing **synovial hypertrophy** in joints of patients with **haemophilia A** receiving **efanesoctocog alfa** prophylaxis. This is clinically relevant as synovial hypertrophy can lead to joint damage and reduced mobility, impacting the quality of life in patients with haemophilia A. Evaluating the improvement in synovial hypertrophy can provide insights into the effectiveness of efanesoctocog alfa in managing joint health in these patients.

Secondary objectives include: - Assessing the incidence of synovial hypertrophy in joints of patients receiving efanesoctocog alfa prophylaxis. - Evaluating the joint health status during 12 months of prophylaxis with efanesoctocog alfa. - Assessing health-related outcomes of patients during 12 months of prophylaxis with efanesoctocog alfa. - Evaluating the preference for efanesoctocog alfa treatment. - Assessing the efficacy of efanesoctocog alfa prophylaxis during 12 months. - Evaluating the safety of efanesoctocog alfa.

The clinical trial involves participants diagnosed with **Haemophilia A**, specifically targeting individuals with moderate to severe conditions, defined as having ≤5% of normal FVIII clotting activity. The study population includes both male and female subjects aged 12 years and older. Participants must have been on prophylactic treatment with any marketed FVIII product or emicizumab for at least 12 months prior to the baseline visit. The trial does not focus on a vulnerable population. Participants are required to have at least one eligible index joint, such as an ankle, elbow, or knee, and must have documented pre-study treatment data on haemophilia prescriptions and treated bleeding episodes for the 12 months preceding the baseline visit. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that participants are capable of providing informed consent, or have consent provided by a parent or legally designated representative if under 18 years of age. Female participants must not be pregnant at enrollment and must have a negative highly sensitive serum pregnancy test at the screening visit. The trial does not impose specific lifestyle considerations such as diet or physical activity. Participants or their legally designated representatives must be willing and able to complete training in the use of the study patient diary and maintain it throughout the study.

The clinical trial is designed as a **phase IV**, open-label, interventional study aimed at investigating the course of synovial hypertrophy in patients with **haemophilia A** receiving prophylaxis with **efanesoctocog alfa**. The trial will span a duration of 12 months, with the estimated recruitment start date set for November 11, 2024, and an anticipated end date of June 7, 2027. Participants will be administered **efanesoctocog alfa** via intravenous injection, with a maximum daily dose of 50 IU/kg and a total dose not exceeding 2600 IU/kg over the treatment period. The study will include several key visits: an initial screening visit to confirm eligibility, followed by regular follow-up visits at months 6 and 12, and a final end-of-study visit. The primary endpoint is the assessment of joints with synovial hypertrophy at baseline and the change in the synovial hypertrophy domain score at month 12. Secondary endpoints include changes in joint scores, patient-reported outcomes, and the occurrence of treatment-emergent adverse events. Participants are expected to be involved in the study for the full 12-month duration unless conditions such as serious adverse events or non-compliance with the study protocol necessitate early termination. The trial will adhere to rigorous scientific standards to ensure the reliability and validity of the findings, contributing valuable insights into the management of **haemophilia A** with **efanesoctocog alfa** prophylaxis.

The clinical trial involves the administration of **efanesoctocog alfa**, a recombinant human coagulation factor VIII Fc - von Willebrand factor - XTEN fusion protein, also known by its synonyms rFVIIIFc-VWF-XTEN, BIVV001, and BIVV-001. This experimental medication is provided in the form of a powder and solvent for solution for injection, marketed under the name ALTUVOCT. The pharmaceutical form is a solution for injection, and it is administered via **intravenous injection**. The trial includes multiple dosage strengths of ALTUVOCT, specifically 250 IU, 500 IU, 2,000 IU, 3,000 IU, and 4,000 IU. The maximum daily dose is 50 IU/kg, with a total maximum dose of 2,600 IU/kg over a treatment period of up to 52 weeks.

There are no non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, specified in this study. The focus is solely on the administration of efanesoctocog alfa. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to assess the improvement of existing synovial hypertrophy in joints of patients with **hemophilia A** receiving efanesoctocog alfa prophylaxis. The study is conducted under the authorization of the European Union, with the marketing authorization number EU/1/24/1824, and is designated as an orphan drug under the number EU/3/19/2176.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints focused on the improvement of **synovial hypertrophy** in patients with **hemophilia A** receiving efanesoctocog alfa prophylaxis. The primary endpoint involves evaluating joints with synovial hypertrophy at baseline, as indicated by a HEAD-US synovial hypertrophy domain score of 1 or 2, and observing at least a 1-point decrease in this score at Month 12. Secondary endpoints include assessing joints with no synovial hypertrophy at baseline and any increase in the HEAD-US synovial hypertrophy domain score at Month 6 or Month 12. Additionally, the distribution of joint HEAD-US synovial hypertrophy domain scores at baseline and at Months 6 and 12 will be analyzed.

Further secondary endpoints involve changes from baseline in total and domain scores of HEAD-US, International Prophylaxis Study Group (IPSG) MRI, and Hemophilia Joint Health Score (HJHS) per patient and per joint at specified timepoints. Patient-reported outcomes (PROs) will be evaluated using tools such as the 5-level EuroQol-5 dimensions (EQ-5D-5L) and the Patient-Reported Outcomes Measurement Information System (PROMIS) for pain intensity, pain interference, and physical function. The study will also assess patient-reported treatment preferences at Month 12, changes in annualized bleeding rates, and the occurrence of treatment-emergent adverse events. Data collection will occur at baseline, Month 6, and Month 12, with analysis focusing on the changes from baseline to these timepoints.