Evaluation of Long-term Safety and Efficacy of Garadacimab (CSL312) in Prophylactic Management of Hereditary Angioedema

The primary objective of this study is to evaluate the long-term **safety** of subcutaneous administration of CSL312 (garadacimab) in the prophylactic treatment of subjects with C1-INH **hereditary angioedema**. This is clinically relevant as ensuring the safety of long-term prophylactic treatments is crucial for managing chronic conditions like hereditary angioedema, where patients require ongoing therapy to prevent acute attacks.

The secondary objectives of this study are to evaluate the long-term efficacy, safety, and patient-reported assessment of response to therapy. These objectives aim to provide a comprehensive understanding of the treatment's impact over an extended period, including its effectiveness in preventing attacks, its safety profile, and the patient's perspective on the treatment's benefits and tolerability.

The clinical trial involves a total of **109 participants** diagnosed with **hereditary angioedema** (HAE), specifically those with C1-INH deficiency. The study population includes both **males and females** aged 12 years and older. Participants were selected based on their clinical history, having experienced at least three HAE attacks in the three months prior to screening and an average of one attack per month during a run-in period. The trial includes individuals who are considered part of a vulnerable population. The selection criteria ensure that participants have a clinically confirmed diagnosis of C1-INH HAE. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data. The study aims to evaluate the long-term safety of subcutaneous administration of CSL312 for prophylactic treatment in this population.

The clinical trial is designed to evaluate the long-term safety and efficacy of **garadacimab** in the prophylactic treatment of **hereditary angioedema** (HAE). This study is an open-label, phase III trial, focusing on the subcutaneous administration of the investigational product. The primary objective is to assess the long-term safety of CSL312, with secondary endpoints including the time-normalized number of HAE attacks and the percentage reduction in attack frequency. The trial is expected to conclude by November 2025, with recruitment having commenced in March 2021.

Participants eligible for the study include males and females aged 12 years and older, diagnosed with clinically confirmed C1-INH HAE, and who have experienced at least three HAE attacks in the three months prior to screening. The study involves a run-in period for CSL312-naïve subjects, requiring at least one month of participation and an average of one HAE attack per month during this period. The trial will monitor treatment-emergent adverse events (TEAEs) as primary endpoints, with secondary endpoints assessing the reduction in HAE attacks and the incidence of adverse events of special interest (AESIs) and serious adverse events (SAEs).

The trial involves a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the inclusion criteria. Follow-up visits will be scheduled to monitor the safety and efficacy of the treatment, with assessments of TEAEs and HAE attack frequency. The end-of-study visit will conclude the participant's involvement, summarizing the overall treatment outcomes and any adverse events experienced. The expected length of participant involvement is aligned with the trial's duration, with conditions for early termination including the occurrence of significant adverse events or withdrawal of consent by the participant.

The clinical trial involves the administration of **garadacimab**, an experimental medication, in the form of a **solution for injection**. Garadacimab is a protein-based therapeutic agent developed by CSL Behring LLC, specifically designed for the prophylactic treatment of **hereditary angioedema** (HAE). The medication is administered subcutaneously, with a maximum daily dose of 6.66 mg and a total maximum dose of 6000 mg over a treatment period of 30 days. The study aims to evaluate the long-term safety and efficacy of garadacimab in subjects with C1-INH HAE.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are utilized in this study. The trial is open-label, meaning that both the researchers and participants are aware of the treatment being administered. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen. The study does not include a pediatric formulation of the medication, and garadacimab has been designated as an orphan drug, indicating its use in treating a rare condition.

The efficacy of garadacimab in the prophylactic treatment of **Hereditary Angioedema (HAE)** will be assessed through several secondary endpoints. These include the time-normalized number of HAE attacks per month and year throughout the study, and the percentage reduction in the number of subjects experiencing at least a 50%, 70%, 90%, or 100% reduction in HAE attacks compared to the Run-in Period. Additionally, the time-normalized number of HAE attacks requiring on-demand treatment, as well as moderate and/or severe HAE attacks, will be evaluated.

Further efficacy assessments will involve the number and percentage of subjects rating their response to therapy as good or excellent. The study will also monitor the number and percentage of subjects experiencing treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs), serious adverse events (SAEs), and the development of anti-CSL312 antibodies. These parameters will be collected and analyzed to determine the efficacy of garadacimab in reducing the frequency and severity of HAE attacks in subjects undergoing treatment.