Evaluation of Treatment Strategies in Haemophilia A Patients with FVIII Inhibitors Using Simoctocog Alfa, Emicizumab, and Drug Combination

The primary objective of this study is to evaluate the outcomes of **immune tolerance induction (ITI)** in patients with **Haemophilia A** who have developed inhibitors against factor VIII. For Groups 1 and 2, the focus is on achieving specific ITI criteria: inhibitor titre less than 0.6 Bethesda units per milliliter for at least two consecutive measurements, factor VIII recovery of at least 66% of the predefined reference value of 1.5% international units per kilogram body weight, and a factor VIII half-life of at least 6 hours. For Group 3, the primary objective is to assess the annualised bleeding rate (ABR) in comparison to Groups 1 and 2. These objectives are clinically relevant as they aim to improve the management of bleeding episodes and enhance the quality of life for patients with Haemophilia A who have developed inhibitors.

Secondary objectives for participants in Groups 1 and 2 include:

• Time to achieve ITI outcome
• Use of emicizumab, activated prothrombin complex concentrate (aPCC), and recombinant activated factor VII (rFVIIa) during ITI
• Rate of factor VIII inhibitor relapses during a follow-up period in participants who have achieved complete ITI success

• Frequency and severity of all bleeding episodes, all treated bleeding episodes, all spontaneous bleeding episodes, all joint bleeding episodes, and target joint bleeding episodes over time (defined as three or more bleeds in the same joint within 24 weeks)
• Number of infusions required to control bleeding episodes
• Frequency and severity of bleeding during and after surgical procedures
• Proportion of participants experiencing adverse drug reactions
• Thrombotic events, including location, treatment, and outcome
• Treatment costs

The clinical trial involves a total of **101 participants** diagnosed with **Haemophilia A**. The study population is exclusively male, encompassing individuals of any age, including those who have previously attempted immune tolerance induction (ITI) without success. Participants are required to have a historical inhibitor titre of at least 0.6 Bethesda units per milliliter. The trial includes individuals undergoing ITI with specific treatments such as Nuwiq®, octanate®, or wilate®, and those receiving prophylactic therapy with emicizumab, aPCC, or rFVIIa. The selection process ensures that participants or their legal guardians are capable of providing informed consent. The trial does not include female subjects, and it involves a vulnerable population due to the nature of the condition and treatment requirements. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of various treatment regimens for **Hemophilia A** in patients with a history of inhibitors. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The trial is expected to span approximately nine years, with an estimated end date in May 2029. Participants will be involved in the study for a maximum treatment period of 60 days, with the possibility of early termination if specific criteria are not met or adverse events occur.

Study visits are structured to include an initial screening visit, multiple follow-up visits, and a final end-of-study visit. The inclusion visit will assess eligibility based on criteria such as age, gender, and historical inhibitor titre. Follow-up visits will monitor the participants' response to treatment, including the measurement of inhibitor titres, **Factor VIII** recovery, and half-life. The end-of-study visit will evaluate the overall treatment outcomes and any adverse events experienced during the trial.

Participants are expected to adhere to the study protocol, which includes the administration of investigational products such as Nuwiq, Octanate, Wilate, and Hemlibra, either intravenously or subcutaneously, depending on the specific treatment group. The primary endpoints focus on the achievement of immune tolerance induction (ITI) criteria and the annualized bleeding rate (ABR) comparison across different groups. Secondary endpoints include the time to achieve ITI, the use of additional therapies, and the rate of inhibitor relapses.

Conditions that may lead to early termination from the study include failure to achieve the ITI criteria, significant adverse drug reactions, or the participant's decision to withdraw consent. The trial aims to provide comprehensive data on the effectiveness and safety of the treatment regimens, contributing to the optimization of therapeutic strategies for patients with **Hemophilia A** and inhibitors.

The clinical trial involves several experimental medications, each with specific administration protocols. **Nuwiq**, containing the active substance **simoctocog alfa**, is available in various dosages including 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU, 2500 IU, 3000 IU, and 4000 IU. It is formulated as a powder and solvent for solution for injection, intended for **intravenous** administration. The maximum daily dose is 200 IU/kg, and the treatment period is up to 60 days.

**Hemlibra**, with the active substance **emicizumab**, is provided as a solution for injection in concentrations of 30 mg/mL and 150 mg/mL. It is administered via **subcutaneous use**. The dosing schedule is based on milligrams per kilogram, with a treatment period extending up to 60 days.

**CEVENFACTA**, containing **eptacog beta (activated)**, is available in dosages of 1 mg (45 KIU), 2 mg (90 KIU), and 5 mg (225 KIU). It is formulated as a powder and solvent for solution for injection, administered **intravenously**. The dosing is measured in micrograms per kilogram, with a treatment duration of up to 60 days.

**FEIBA**, which includes the **factor VIII inhibitor bypassing fraction**, is available in dosages of 500 E, 1000 E, and 2500 E. It is provided as a powder and solvent for solution for infusion, administered **intravenously**. The dosing is in units per gram, with a treatment period of up to 60 days.

**NovoSeven**, containing **eptacog alfa (activated)**, is available in dosages of 1 mg (50 KIU), 2 mg (100 KIU), 5 mg (250 KIU), and 8 mg (400 KIU). It is formulated as a powder and solvent for solution for injection, administered **intravenously**. The dosing is in micrograms per kilogram, with a treatment period of up to 60 days.

**OCTANATE**, with the active substance **human coagulation factor VIII**, is available in dosages of 250, 500, and 1000 units. It is provided as a powder and solvent for solution for injection, administered **intravenously**. The dosing is in international units per kilogram, with a treatment period of up to 60 days.

**Wilate**, containing both **human coagulation factor VIII** and **human von Willebrand factor**, is available in dosages of 500 I.E. VWF/500 I.E. FVIII and 1000 I.E. VWF/1000 I.E. FVIII. It is formulated as a powder and solvent for solution for injection, administered **intravenously**. The dosing is in international units per kilogram, with a treatment period of up to 60 days.

Participant compliance is monitored through regular assessments of dosing schedules and administration routes. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The focus is on evaluating the efficacy and safety of the experimental medications in achieving the trial's primary objectives.

The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. For Groups 1 and 2, the primary endpoint is the evaluation of Immune Tolerance Induction (ITI) outcomes, determined by achieving the following criteria: an **inhibitor titre** of less than 0.6 Bethesda units (BU)/mL for at least two consecutive measurements, **Factor VIII (FVIII) recovery** of at least 66% of the predefined reference value of 1.5% international units (IU)/kg body weight, and an **FVIII half-life** of at least 6 hours. For Group 3, the primary endpoint is the evaluation of the annualised bleeding rate (ABR) compared with the ABR in Groups 1 and 2.

Secondary endpoints for participants in Groups 1 and 2 include the time to achieve ITI outcome, the use of emicizumab, activated prothrombin complex concentrate (aPCC), or recombinant activated factor VII (rFVIIa) during ITI, and the rate of FVIII inhibitor relapses during a follow-up period in participants who have achieved complete ITI success. For all groups, secondary endpoints include the frequency and severity of all bleeding episodes, the number of infusions required to control bleeding episodes, the frequency and severity of bleeding during and after surgical procedures, the proportion of participants experiencing adverse drug reactions (ADRs), thrombotic events, and treatment costs.