A Phase 3 Open-label Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of CSL312 (Garadacimab) in the Prophylactic Treatment of Hereditary Angioedema in Pediatric Subjects 2 to 11 Years of Age

The primary objective of this Phase 3 open-label study is to evaluate the **safety** and **pharmacokinetics** of subcutaneous administration of CSL312 (garadacimab) in the prophylactic treatment of pediatric subjects aged 2 to 11 years with **Hereditary Angioedema (HAE)**. This is clinically relevant as it aims to establish the safety profile and appropriate dosing regimen of garadacimab, which is crucial for preventing HAE attacks in this vulnerable population.

Secondary objectives include evaluating the **efficacy**, **pharmacodynamics**, and **safety** of CSL312 in the prophylactic treatment of pediatric subjects with C1-INH HAE. These objectives are important for understanding the therapeutic potential and mechanism of action of garadacimab, as well as ensuring its long-term safety and effectiveness in managing HAE symptoms in children.

The clinical trial involves a total of **13 participants** diagnosed with **hereditary angioedema (HAE)**, specifically focusing on pediatric subjects aged 2 to 11 years. The study population includes both male and female participants, with a body weight at or above the 10th percentile based on age. Participants were selected based on a clinically confirmed diagnosis of C1-INH HAE and a history of experiencing at least two HAE attacks in the six months preceding the screening. The trial population is considered vulnerable due to the young age of the participants. No specific lifestyle considerations such as diet or physical activity are highlighted in the selection criteria. The trial aims to evaluate the safety and pharmacokinetics of subcutaneous administration of CSL312 for prophylactic treatment in this demographic.

The clinical trial is designed as a **Phase 3 open-label study** to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of **garadacimab** in the prophylactic treatment of pediatric subjects aged 2 to 11 years with **hereditary angioedema (HAE)**. The trial will involve the subcutaneous administration of garadacimab, a solution for injection, with a maximum daily dose of 100 mg and a total dose not exceeding 1200 mg over a treatment period of up to 12 months. The study aims to assess the number and percentage of subjects experiencing treatment-emergent adverse events (TEAEs), as well as the pharmacokinetic parameters such as maximum concentration (Cmax) and trough concentration (Ctrough) at steady-state.

Participants will be required to attend several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, body weight, and a clinically confirmed diagnosis of C1-INH HAE with a history of at least two HAE attacks in the six months prior to screening. Follow-up visits will be scheduled to monitor safety, efficacy, and pharmacokinetic parameters, with the primary endpoint being the number of subjects with TEAEs. Secondary endpoints include the time-normalized number of HAE attacks and the percentage reduction in attack frequency. The end-of-study visit will conclude the trial, assessing the overall safety and efficacy outcomes.

The expected duration of participant involvement is approximately 12 months, with conditions for early termination including the occurrence of serious adverse events (SAEs) or TEAEs leading to study discontinuation. The trial is anticipated to start recruitment on May 28, 2024, and is estimated to conclude by June 11, 2026. Participants will be closely monitored throughout the study to ensure their safety and the integrity of the trial data.

The clinical trial involves the administration of **garadacimab**, an experimental medication, in the form of a **solution for injection**. Garadacimab is a protein-based substance developed by CSL Behring LLC, designated with the sponsor product code CSL312. The medication is administered via **subcutaneous use**. The dosing regimen for garadacimab includes a maximum daily dose of 100 mg, with a total maximum dose of 1200 mg over the course of the treatment period. The maximum treatment period is specified as 12 weeks. The trial aims to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of garadacimab in the prophylactic treatment of **hereditary angioedema** in pediatric subjects aged 2 to 11 years.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for use in this study. The trial is designed to focus solely on the effects and safety profile of garadacimab. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen. The trial is conducted under the orphan drug designation EU/3/21/2532, indicating its potential benefit for a rare condition. The pharmaceutical form and administration route are chosen to optimize the delivery and efficacy of the treatment in the target pediatric population.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the evaluation of treatment-emergent adverse events (TEAEs), with specific metrics such as the number of subjects experiencing TEAEs, the percentage of subjects with TEAEs, the number of TEAEs, and TEAE rates per injection and per subject year. Additionally, pharmacokinetic parameters such as the maximum concentration (**Cmax**), trough concentration (**Ctrough**), and time to maximum concentration (**Tmax**) of CSL312 at steady-state will be measured.

Secondary endpoints focus on the frequency and severity of **Hereditary Angioedema (HAE)** attacks. These include the time-normalized number of HAE attacks per month and per year, the number of attacks treated with on-demand treatment, and the number of moderate and/or severe attacks. The study will also assess the percentage reduction in the time-normalized number of HAE attacks and the number of subjects achieving significant reductions in attack frequency, including those who become attack-free. Additional secondary endpoints involve the evaluation of serious adverse events (SAEs), related TEAEs, and the presence of Anti-CSL312 antibodies. The study will also monitor FXIIa-mediated kallikrein activity and laboratory findings reported as adverse events.