Pharmacokinetic-Guided Dosing of Emicizumab in Patients with Congenital Hemophilia A: A Non-Inferiority Study

The primary objective of this study is to determine whether individualized **pharmacokinetic** (PK)-guided dosing of **emicizumab** is non-inferior to conventional dosing in the prevention of treated bleeds, spontaneous joint or muscle bleeds, and overall bleeding in patients with **congenital haemophilia A**. This is clinically relevant as it may optimize treatment efficacy and safety, potentially improving patient outcomes by tailoring therapy to individual needs.

Secondary objectives include:

• Proportion of patients without treated bleeds 12 months before and after intervention.
• Proportion of patients without spontaneous joint or muscle bleeds 6 and 12 months before and after intervention.
• Annualized bleeding rate (ABR) of treated bleeds, including joint bleeds and sports-induced bleeds, 6 and 12 months before and after intervention.
• Comparison of cost-effectiveness between conventional dosing and individualized PK-guided dosing of emicizumab.
• Assessment of the performance of the population PK model.
• Investigation of joint health stability when switching to lower-dosed emicizumab treatment.
• Evaluation of whether Health Related Quality of Life (HR-QoL) and sports participation are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab.
• Investigation of whether thrombin generation parameters can be used as a pharmacodynamic (PD) biomarker for emicizumab treatment efficacy.
• Assessment and monitoring of pain during emicizumab administration.
• Assessment of the cumulative number of coagulation factors (subcutaneous and/or intravenous) per year.

The clinical trial involves **male** participants diagnosed with **congenital haemophilia A**. The study population includes individuals aged over 1 year, with specific age categories represented. Participants are required to have been receiving conventional dosing of emicizumab for at least 12 months prior to inclusion and must demonstrate good bleeding control, characterized by no spontaneous joint or muscle bleeds and a maximum of two treated traumatic bleeds in the previous six months. The trial does not include a vulnerable population, and the sponsor has not provided the total number of participants. Participants are expected to adhere to the medication regimen and provide bleeding assessment information. The selection criteria ensure that participants have a confirmed diagnosis and are willing to provide informed consent, either personally or through a legal guardian.

The clinical trial is designed to evaluate the efficacy of **emicizumab** in patients with **congenital haemophilia A** through a randomized, double-blind, controlled methodology. The trial aims to compare individualized pharmacokinetic (PK)-guided dosing of emicizumab with conventional dosing to assess its non-inferiority in preventing treated bleeds, spontaneous joint or muscle bleeds, and overall bleeding. The study is expected to commence recruitment on June 25, 2024, and conclude by April 1, 2026, with a total duration of approximately 22 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of congenital haemophilia A, age over one year, and a history of receiving conventional emicizumab dosing for at least 12 months. The trial will include multiple follow-up visits to monitor the participants' response to treatment and adherence to the medication regimen. The end-of-study visit will assess the primary endpoint, which is the proportion of patients without treated bleeds during the 6-month PK-Guided Dosing Phase compared to the Bleeding Assessment Phase.

The expected length of participant involvement is approximately 12 months, with conditions for early termination including non-compliance with the study protocol or withdrawal of consent. Secondary endpoints will evaluate the proportion of patients with spontaneous joint or muscle bleeds, annualized bleeding rates, cost-effectiveness, and health-related quality of life, among others. The trial will utilize **Hemlibra** in various formulations, administered via subcutaneous injection, with dosing tailored to individual plasma concentrations to ensure optimal therapeutic outcomes.

The clinical trial involves the administration of **Hemlibra**, a pharmaceutical product containing the active substance **emicizumab**. Hemlibra is available in two concentrations: 30 mg/mL and 150 mg/mL, both formulated as a **solution for injection**. The active substance, emicizumab, is a humanized monoclonal antibody of protein origin. The medication is administered via **subcutaneous injection**. The maximum daily dose for the 30 mg/mL solution is 12 mg, while for the 150 mg/mL solution, it varies between 60 mg and 300 mg, depending on the specific formulation used. The treatment period for each formulation is limited to a maximum of one week.

In this study, the Hemlibra 30 mg/mL solution for injection is utilized in two different formulations, with maximum daily doses of 12 mg and 30 mg, respectively. The 150 mg/mL solution for injection is available in three formulations, with maximum daily doses of 60 mg, 105 mg, and 150 mg. Additionally, there is a 150 mg/mL suspension for injection with a maximum daily dose of 300 mg. All formulations are administered subcutaneously, and the dosing schedule is guided by pharmacokinetic parameters to ensure optimal therapeutic outcomes.

Participant compliance with the dosing regimen is monitored throughout the trial to ensure adherence to the prescribed treatment protocol. The trial aims to evaluate the non-inferiority of individualized pharmacokinetic-guided dosing compared to conventional dosing in preventing treated bleeds, spontaneous joint or muscle bleeds, and overall bleeding in patients with congenital hemophilia A. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study.

The clinical trial aims to assess the efficacy of **emicizumab** in patients with congenital hemophilia A through a pharmacokinetic-guided dosing approach. The primary endpoint for evaluating efficacy is the proportion of patients without treated bleeds during a 6-month Bleeding Assessment Phase compared to a 6-month PK-Guided Dosing Phase. Secondary endpoints include the proportion of patients without treated bleeds over a 12-month period, the proportion of patients with spontaneous joint or muscle bleeds, and the annualized bleeding rate (ABR) of treated bleeds, including joint and sports-induced bleeds. Additional secondary endpoints involve cost-effectiveness analysis, predictive performance of the MAP Bayesian procedure for dose adaptation, joint status assessment, health-related quality of life, pain assessment during administration, cumulative number of injections, sports participation, and plasma coagulation potential measured by thrombin generation tests.

Efficacy parameters will be collected and analyzed using various tools and methods. The Haemophilia Joint Health Score (HJHS) and ultrasound, if available, will be used to measure joint status, while biomarkers of bone and cartilage turnover will also be evaluated. Health-related quality of life will be assessed using the EQ5D(Y) and PROMIS instruments, focusing on physical function, mobility, and pain interference. Pain during administration will be measured using a Visual Analogue Scale (VAS). The Modifiable Activities Questionnaire (MAQ) will assess sports participation, and thrombin generation tests will evaluate plasma coagulation potential. Emicizumab plasma levels will be determined in the laboratory using a specifically developed LCMS/MS method. The trial is expected to conclude by April 2026, with recruitment starting in June 2024.