An 18-month low-interventional prospective, multicentre study to assess joint outcomes in patients with haemophilia A or B on prophylaxis with efmoroctocog alfa or eftrenonacog alfa

The primary objective of this study is to evaluate the overall **joint status** as detected by ultrasound (US) in patients with **hemophilia A and B** who are treated with efmoroctocog alfa (rFVIIIFc) or eftrenonacog alfa (rFIXFc) prophylaxis over an 18-month period. This is clinically relevant as it aims to assess the effectiveness of these prophylactic treatments in maintaining joint health, which is a critical aspect of managing hemophilia and preventing long-term joint damage.

Secondary objectives include: - Evaluating the joint status using the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) system, focusing on hypertrophic synovium, cartilage, and bone damage. - Assessing the clinical joint status through the Hemophilia Joint Health Score (HJHS). - Evaluating the presence, resolution, recurrence, and new development of target joints. - Describing bleeding episodes. - Evaluating the quality of life in these patients. These secondary objectives provide a comprehensive understanding of the impact of prophylactic treatment on various aspects of patient health and disease progression.

The clinical trial involves a total of **three participants** diagnosed with **Hemophilia A and B**. The study population includes both male and female subjects, with an age range starting from 6 years and above. Participants were selected based on specific criteria, including a documented history of treatment for at least six months prior to the baseline visit and previous treatment with recombinant or plasma-derived FVIII or FIX concentrates. The trial focuses on individuals who have commenced prophylactic treatment with efmoroctocog alfa (rFVIIIFc) or eftrenonacog alfa (rFIXFc) either before or at the baseline visit. The study also considers lifestyle factors, as participants eligible for the florio HAEMO sub-study must have used the florio HAEMO app for at least three months. The trial includes a vulnerable population, ensuring informed consent is obtained from all participants or their legally authorized representatives, with assent from pediatric patients as per local regulations.

The clinical trial is designed as an 18-month low-interventional, prospective, multicentre study aimed at assessing joint outcomes in patients with **hemophilia A** or **hemophilia B** undergoing prophylaxis with **efmoroctocog alfa** or **eftrenonacog alfa**. The trial employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The primary objective is to evaluate the overall joint status as detected by ultrasound in the specified patient population over the study period. The trial is expected to conclude by November 15, 2025, with recruitment having commenced on March 15, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥ 6 years), diagnosis of hemophilia A or B, and prior treatment history. Following the baseline visit, participants will attend follow-up visits at 6, 12, and 18 months to monitor changes in joint health and other secondary endpoints. These endpoints include changes in the HEAD-US score for hypertrophic synovium, cartilage, and bone, as well as the total HJHS score, target joint locations, and various bleeding rates. Patient-reported outcomes, such as physical function and pain intensity, will also be assessed at baseline and 18 months.

The expected length of participant involvement is 18 months, with conditions for early termination including non-compliance with the study protocol or withdrawal of consent. The study aims to minimize additional risks or burdens to participants, adhering to the definition of a low-intervention clinical trial. The investigational medicinal products (IMPs) are authorized and used in accordance with their marketing authorizations, ensuring that the trial procedures align with standard clinical practice. The trial's design and procedures are structured to provide comprehensive data on the efficacy and safety of the prophylactic treatments in improving joint health outcomes for patients with hemophilia A and B.

The clinical trial involves the administration of **Efmoroctocog alfa**, a recombinant fusion protein consisting of human coagulation factor VIII attached to the Fc domain of human IgG1. This experimental medication is provided in various dosages, including 250 IU, 500 IU, 750 IU, 1000 IU, 1500 IU, 2000 IU, 3000 IU, and 4000 IU, all formulated as a **powder and solvent for solution for injection**. The pharmaceutical form is a solution for injection, and the route of administration is via injection. The maximum daily dose is 100 IU/kg, with a total maximum dose of 65 IU/kg. The treatment period extends up to 1200 days. The medication is not a pediatric formulation and is not designated as an orphan drug.

Another experimental medication used in the trial is **Eftrenonacog alfa**, a recombinant fusion protein consisting of human coagulation factor IX attached to the Fc domain of human IgG1. This medication is available in dosages of 250 IU, 500 IU, 1000 IU, 2000 IU, and 3000 IU, also provided as a powder and solvent for solution for injection. The pharmaceutical form is a solution for injection, administered via injection. The maximum daily dose is 100 IU/kg, with a total maximum dose of 100 IU/kg. The treatment period is up to 1200 days. This medication is designated as an orphan drug.

Both medications are manufactured by Swedish Orphan Biovitrum AB (Publ) and are authorized for use in the European Union. Participant compliance with the dosing schedule will be monitored throughout the study period. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial documentation.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in the total HEAD-US score up to month 18, which marks the end of the study. Secondary endpoints include changes from baseline in the HEAD-US score for hypertrophic synovium, cartilage, and bone at 6, 12, and 18 months. Additionally, the change from baseline in the total Hemophilia Joint Health Score (HJHS) at month 18 will be evaluated. Other secondary endpoints involve the number and location of target joints at baseline, 6, 12, and 18 months, as well as various bleeding rates such as total annualized bleeding rate (ABR), joint ABR, target joint ABR, and traumatic/spontaneous ABR.

Patient-reported outcomes will also be measured using the Patient-Reported Outcomes Measurement Information System (PROMIS) for physical function/activity scores and pain intensity and interference scores at baseline and 18 months. The International Physical Activity Questionnaire-Short Form (IPAQ-SF) scores will be collected at the same time points. The efficacy parameters will be collected and analyzed at specified intervals throughout the 18-month study period, ensuring a comprehensive evaluation of the treatment's impact on joint health and overall patient well-being in individuals with **hemophilia A** and **hemophilia B**. The use of validated scales and patient-reported outcomes will provide a robust framework for assessing the efficacy of the prophylactic treatments with efmoroctocog alfa and eftrenonacog alfa.