A Phase 3, single-arm, multicenter, multinational, open-label, one-way crossover study to investigate the efficacy and safety of fitusiran prophylaxis in male participants aged ≥ 12 years with severe hemophilia A or B with or without inhibitory antibodies to factor VIII or IX

The primary objective of this study is to **characterize** the frequency of treated bleeding episodes in male participants aged 12 years and older with severe **hemophilia** A or B, with or without inhibitory antibodies to factor VIII or IX, while receiving **fitusiran** prophylaxis. This objective is clinically relevant as it aims to assess the potential of fitusiran in reducing bleeding episodes, which is a critical concern in the management of hemophilia, thereby potentially improving patient outcomes and quality of life.

Secondary objectives include:

• Evaluating the efficacy of fitusiran prophylaxis treatment compared to prophylaxis standard of care (SOC).
• Evaluating the efficacy of fitusiran prophylaxis treatment compared to on-demand SOC.
• Characterizing the frequency of treated spontaneous and joint bleeding episodes, and health-related quality of life (HRQOL) in participants aged 17 years and older while receiving fitusiran prophylaxis relative to SOC.
• Characterizing the frequency of treated bleeding episodes during the 18-month efficacy period and 36-month treatment period in participants receiving fitusiran.
• Characterizing the annualized weight-adjusted consumption of clotting factor concentrates/bypassing agents (CFC/BPA).
• Characterizing the safety and tolerability of fitusiran.

The clinical trial involves a total of **58 male participants** diagnosed with severe congenital **hemophilia** A or B. The study population includes individuals across various age ranges, specifically categorized as children, adolescents, and adults. Participants were selected based on their diagnosis, with a requirement for those not currently on prophylaxis to have experienced a minimum of four bleeding episodes necessitating treatment within the last six months prior to screening. The trial does not include female subjects and focuses on a vulnerable population, emphasizing the need for participants to be willing and able to comply with study requirements. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **single-arm**, multicenter, multinational, open-label, one-way crossover study to evaluate the efficacy and safety of **fitusiran** prophylaxis in male participants aged 12 years and older with severe **hemophilia** A or B, with or without inhibitory antibodies to factor VIII or IX. The primary objective is to characterize the frequency of treated bleeding episodes while receiving fitusiran prophylaxis. The trial will span an estimated duration from July 2023 to March 2028, with participant involvement expected to last up to 36 months. The study will include a screening visit to confirm eligibility based on criteria such as a diagnosis of severe congenital hemophilia and a history of bleeding episodes. Participants will then enter the fitusiran primary efficacy period, during which the primary endpoint, the annualized bleeding rate (ABR), will be assessed. Secondary endpoints include comparisons of ABR during fitusiran prophylaxis and standard of care periods, as well as changes in quality of life scores and adverse event monitoring. Study visits will be scheduled periodically to monitor safety, efficacy, and adherence to the treatment regimen. The end-of-study visit will conclude the participant's involvement, with data collection on long-term outcomes. Conditions that may lead to early termination from the study include non-compliance with study requirements or the occurrence of significant adverse events. The trial is not categorized as low intervention and is conducted under the regulatory framework for clinical trials. Participants will receive fitusiran via subcutaneous injection, with a maximum treatment period of 36 months, while auxiliary treatments such as **antithrombin alfa** and **eptacog alfa (activated)** will be administered intravenously as needed. The study aims to provide comprehensive data on the long-term management of hemophilia with fitusiran prophylaxis.

The clinical trial involves the administration of several experimental medications, each with specific characteristics and administration protocols. **ANTITHROMBIN ALFA**, marketed as **ANTITHROMBIN III**, is administered as an **intravenous injection**. The pharmaceutical form is denoted as **PHF00230MIG**. The medication is not a pediatric formulation and is used as an auxiliary treatment in the trial. The maximum treatment period is 1 day, with no specified maximum daily or total dose amount.

**DAMOCTOCOG ALFA PEGOL**, known as **COAGULATION FACTOR VIII**, is also administered via **intravenous injection**. It is presented in the pharmaceutical form **PHF00231MIG**. This treatment is not intended for pediatric use and serves as an auxiliary treatment in the study. The maximum treatment period is 1 day, with no specified maximum daily or total dose amount.

**ALBUTREPENONACOG ALFA**, referred to as **COAGULATION FACTOR IX**, is delivered through **intravenous injection** in the form **PHF00231MIG**. It is not a pediatric formulation and is used as an auxiliary treatment. The maximum treatment period is 1 day, with no specified maximum daily or total dose amount.

**FACTOR VIII INHIBITOR BYPASSING FRACTION**, marketed as **FACTOR VIII INHIBITOR BYPASSING ACTIVITY**, is administered via **intravenous injection**. The pharmaceutical form is **PHF00231MIG**. This treatment is not for pediatric use and is used as an auxiliary treatment. The maximum treatment period is 1 day, with no specified maximum daily or total dose amount.

**FITUSIRAN**, with the product name **SAR439774**, is administered as a **subcutaneous injection**. The pharmaceutical form is a **solution for injection**. This medication is not a pediatric formulation and is the primary test treatment in the trial. The maximum daily dose is 80 mg, with a total maximum dose of 2740 mg over a treatment period of 36 months.

**EPTACOG ALFA (ACTIVATED)**, known as **EPTACOG ALFA (ACTIVATED)**, is administered via **intravenous injection**. The pharmaceutical form is **PHF00231MIG**. It is not a pediatric formulation and is used as an auxiliary treatment. The maximum treatment period is 1 day, with no specified maximum daily or total dose amount.

All medications, except for **FITUSIRAN**, are used as auxiliary treatments in the trial. The administration of these medications is monitored to ensure compliance with the dosing schedules and to evaluate their efficacy and safety in the context of the study's objectives.

The efficacy of the clinical trial will be assessed primarily through the measurement of the **Annualized Bleeding Rate (ABR)** during the fitusiran primary efficacy period. This primary endpoint will provide a quantitative evaluation of the frequency of bleeding episodes experienced by participants while receiving fitusiran prophylaxis. Secondary endpoints will further explore the efficacy by comparing the ABR during the fitusiran primary efficacy period with the ABR during the standard of care (SOC) period, both for prophylaxis and on-demand treatments. Additional secondary endpoints include the annualized spontaneous bleeding rate, annualized joint bleeding rate, and changes in the Haem-A-QOL physical health score and total score during both SOC and fitusiran prophylaxis periods. The trial will also assess the annualized bleeding rate over an 18-month and a 36-month fitusiran treatment period, as well as the annualized weight-adjusted consumption of clotting factor concentrates (CFC) or bypassing agents (BPA). The number of participants experiencing adverse events will also be recorded as part of the efficacy assessment.