A Phase 2b/3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Combined Dose-Finding and Cardiovascular Outcome Study to Investigate the Efficacy and Safety of CSL300 (Clazakizumab) in Subjects with End Stage Kidney Disease Undergoing Dialysis

The primary objective of this study is to evaluate the **efficacy** of different intravenous doses of **Clazakizumab** (CSL300) in subjects with end-stage kidney disease (ESKD) undergoing maintenance dialysis, specifically focusing on the reduction of high-sensitivity C-reactive protein (hs-CRP) levels. This is clinically relevant as elevated hs-CRP is a marker of inflammation and is associated with increased cardiovascular risk in patients with ESKD. The study aims to determine the optimal dosing strategy for Clazakizumab to potentially mitigate cardiovascular complications in this patient population.

The clinical trial involves a total of **1143 participants** diagnosed with **atherosclerotic cardiovascular disease** in patients with **end-stage kidney disease (ESKD)**. The study population includes both male and female subjects who are at least 18 years of age. Participants are required to have been undergoing maintenance dialysis for a minimum of 12 weeks. The trial does not focus on a vulnerable population. The health status of participants is characterized by elevated serum high-sensitivity C-reactive protein (hs-CRP) levels, specifically (geq) 2.0 mg/L, and a diagnosis of either diabetes mellitus or atherosclerotic cardiovascular disease (ASCVD). The selection criteria ensure a representative sample of individuals with the specified medical conditions, without any specific lifestyle considerations such as diet or physical activity being highlighted. The trial aims to evaluate the efficacy of different intravenous doses of CSL300 in reducing hs-CRP levels in this population.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of CSL300 (**Clazakizumab**) in subjects with end-stage kidney disease (ESKD) undergoing dialysis. The trial is structured in two phases: Phase 2b, which is a dose-finding study, and Phase 3, which assesses cardiovascular outcomes. The primary objective is to evaluate the efficacy of different intravenous doses of CSL300 in reducing high-sensitivity C-reactive protein (hs-CRP) levels in this patient population. The trial is expected to run from January 2023 to April 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of ESKD, and serum hs-CRP levels. Following randomization, participants will receive either CSL300 or a placebo. The study includes regular follow-up visits to monitor safety, efficacy, and any adverse events. The end-of-study visit will conclude the participant's involvement, with a comprehensive assessment of outcomes and any long-term effects.

The expected duration of participant involvement is up to 60 weeks, depending on the phase of the trial they are enrolled in. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial aims to provide valuable insights into the potential benefits of CSL300 in managing systemic inflammation and cardiovascular risk in patients with ESKD.

The clinical trial involves the administration of **Clazakizumab**, a **solution for injection** developed by CSL Behring LLC. Clazakizumab is an investigational medication administered intravenously. The trial evaluates two dosing regimens: a maximum daily dose of 10 mg with a total dose of 60 mg over a treatment period of 34 weeks, and a maximum daily dose of 5 mg with a total dose of 330 mg over a treatment period of 60 weeks. Clazakizumab is a protein-based therapeutic agent, specifically categorized under "Protein - Other," and is identified by the sponsor product code CSL300.

In addition to Clazakizumab, the trial includes the use of a **placebo** designed to match the excipient content and concentration of the CSL300 product, minus the active ingredient. The placebo is administered in a manner consistent with the experimental treatment to maintain the double-blind nature of the study. The placebo serves as a comparator to assess the efficacy and safety of Clazakizumab in subjects with end-stage kidney disease undergoing dialysis.

Furthermore, a **saline solution** (0.9% w/v NaCl) is utilized within the trial. This solution is employed as a standard diluent or vehicle for the administration of the investigational product and placebo. The saline solution is not considered an active treatment but is essential for maintaining the integrity of the intravenous administration process.

The efficacy of CSL300 (Clazakizumab) in subjects with **End Stage Kidney Disease (ESKD)** undergoing dialysis will be assessed through a series of primary and secondary endpoints. The primary endpoints include the change from baseline on the log scale in high-sensitivity C-reactive protein (hs-CRP) during Phase 2b, and the time to first occurrence of cardiovascular (CV) death or myocardial infarction (MI) during Phase 3. Secondary endpoints for Phase 2b involve the percentage of subjects achieving hs-CRP levels below 2.0 mg/L, changes from baseline in various biomarkers such as serum amyloid A (SAA), secretory phospholipase A2 (sPLA2), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), and lipoprotein(a) (Lp(a)). Additional secondary endpoints include pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (Cmax), trough concentration (Ctrough), and time to maximum concentration (Tmax).

In Phase 3, secondary endpoints will focus on time to first occurrence of all-cause death or MI, CV death, MI, or ischemic stroke, and other cardiovascular events. The study will also evaluate the total number of CV hospitalizations, heart failure hospitalizations, and urgent visits. Efficacy assessments will be conducted using validated laboratory tests and patient-reported outcomes at specified timepoints throughout the trial. The trial is designed as a multicenter, randomized, double-blind, placebo-controlled study, with a dose-finding component in Phase 2b and a focus on CV outcomes and safety in Phase 3.