ARTEMIS: RAvulizumab to PRotect PaTients with Chronic Kidney DisEase (CKD) froM Cardiac Surgery Associated Acute Kidney Injury (CSA-AKI) and Subsequent Major Adverse Kidney Events (MAKE): A Phase 3, Randomized, Double-blind, Placebo-controlled, Multicenter Study

The primary objective of this study is to assess the efficacy of **ravulizumab** in reducing the risk of Major Adverse Kidney Events (MAKE90) following cardiopulmonary bypass (CPB). This is clinically relevant as it aims to prevent cardiac surgery-associated acute kidney injury (CSA-AKI), a significant complication that can lead to increased morbidity and mortality in patients with chronic kidney disease (CKD).

Secondary objectives include:

• Assessing the efficacy of ravulizumab in reducing the risk of acute kidney injury (AKI) based on serum creatinine (sCr) following CPB.
• Evaluating the efficacy of ravulizumab in reducing the risk of MAKE based on serum cystatin C (sCysC), MAKE based on sCr, AKI based on sCr, and related outcomes following CPB.
• Assessing the effect of ravulizumab on health resource utilization in participants with CKD undergoing non-emergent CPB.
• Evaluating the effect of ravulizumab on quality of life in participants with CKD undergoing non-emergent CPB.
• Evaluating the pharmacokinetics (PK) and pharmacodynamics (PD) of ravulizumab in participants with CKD undergoing non-emergent CPB.
• Evaluating the safety of ravulizumab IV in participants with CKD undergoing non-emergent CPB.
• Evaluating the immunogenicity of ravulizumab IV in participants with CKD undergoing non-emergent CPB.

The clinical trial involves a total of **480 participants** who are being studied for the **prevention of cardiac surgery associated acute kidney injury**. The study population includes both male and female subjects, aged between 18 and 90 years, with a body weight of at least 30 kg. Participants are selected based on their planned non-emergent cardiac surgery requiring cardiopulmonary bypass (CPB) for procedures such as multi-vessel coronary artery bypass grafting (CABG), valve replacement or repair, and ascending aorta surgery when combined with aortic valve replacement or repair. The trial includes individuals with known or apparent chronic kidney disease (CKD) and an estimated glomerular filtration rate (eGFR) between 20 to less than 60 mL/min/1.73 m², as calculated using the CKD-EPI equation. Participants are also at risk for postsurgical kidney events, as indicated by a minimum STS Calculator Renal Failure Risk Score of 2.8% or higher. The trial population is capable of providing informed consent and includes vulnerable populations. Lifestyle considerations such as diet, physical activity, or habits are not specified by the sponsor.

The clinical trial is a **randomized, double-blind, placebo-controlled** study designed to evaluate the efficacy of **ravulizumab** in reducing the risk of major adverse kidney events (MAKE90) following cardiopulmonary bypass (CPB) in patients with chronic kidney disease (CKD) undergoing cardiac surgery. The trial is set to run from May 31, 2023, to February 17, 2027, with an estimated duration of approximately four years. Participants will be randomly assigned to receive either ravulizumab or a placebo, administered via **intravenous infusion**. The primary endpoint is the occurrence of MAKE90, defined as a decrease in estimated glomerular filtration rate (eGFR) of ≥25% at Day 90 post-CPB, initiation of kidney replacement therapy (KRT), or death from any cause through Day 90 post-CPB.

The study will include several key visits: an initial screening visit to assess eligibility based on criteria such as age, body weight, and CKD status, followed by randomization. Participants will undergo regular follow-up visits to monitor for acute kidney injury (AKI) and other secondary endpoints, including the occurrence of severe AKI, length of post-operative intensive care unit (ICU) stay, and all-cause mortality. These visits will occur at Days 3, 7, 15, 30, 60, and 90 post-CPB. The end-of-study visit will occur at Day 90, where final assessments will be conducted to evaluate the primary and secondary endpoints.

Participant involvement is expected to last approximately 90 days from the time of randomization. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or adverse events that, in the opinion of the investigator, warrant discontinuation of the study drug. The trial aims to provide valuable insights into the potential protective effects of ravulizumab against cardiac surgery-associated acute kidney injury and subsequent major adverse kidney events in a high-risk population.

The clinical trial involves the administration of **ravulizumab**, marketed under the name Ultomiris, which is a **concentrate for solution for infusion**. This experimental medication is a humanized monoclonal antibody targeting the C5 component of the complement system. The pharmaceutical form is a solution for infusion, with each vial containing 300 mg of ravulizumab in 30 mL. The medication is administered via **intravenous infusion**. The dosing regimen is based on the participant's body weight, with a maximum daily dose of 90 mg/kg and a total maximum dose of 3600 mg. The treatment period is limited to a maximum of one day. Compliance with the dosing schedule is monitored through regular assessments and documentation of infusion administration.

The study also includes a **placebo** control, referred to as the Anti C5 Complement mAb Placebo. This placebo is designed to match the experimental treatment in appearance and administration route, ensuring the study remains double-blind. The placebo does not contain any active substance and is used to assess the efficacy of ravulizumab by providing a baseline for comparison. Participants receiving the placebo will follow the same infusion schedule as those receiving the active treatment, with compliance similarly monitored to ensure adherence to the study protocol.

The efficacy of **ravulizumab** in the clinical trial will be assessed by evaluating its ability to reduce the risk of Major Adverse Kidney Events (MAKE90) following cardiopulmonary bypass (CPB). The primary endpoint for efficacy is defined as meeting at least one of the following criteria by Day 90 post-CPB: a decrease from baseline in estimated Glomerular Filtration Rate (eGFR) of ≥ 25% using the CKD-EPI formula with serum cystatin C (sCysC), initiation of Kidney Replacement Therapy (KRT), or death from any cause.

Secondary endpoints include the occurrence of Cardiac Surgery Associated Acute Kidney Injury (CSA-AKI) without recovery at Day 90 post-CPB, occurrence of severe CSA-AKI (KDIGO Stage 2 or 3) from randomization to Day 7 post-CPB, and occurrence of severe AKI (KDIGO Stage 2 or 3) from randomization to Day 30 post-CPB. Additional secondary endpoints involve the length of post-operative ICU stay, all-cause mortality, and the occurrence of KRT or death from randomization to Day 90 post-CPB. Efficacy will also be assessed through changes in patient-reported outcomes such as KDQOL-36™, EQ-5D-5L, and FACIT-Fatigue at Days 30, 60, and 90 post-CPB.

Measurements will be collected at various timepoints, including Days 3, 7, 15, 30, 60, and 90 post-CPB, to monitor the progression and recovery of AKI. Serum concentrations of ravulizumab and changes in serum free C5 concentrations will also be evaluated. The analysis will include the assessment of Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs), as well as changes in laboratory parameters at scheduled visits. The trial is designed to provide comprehensive data on the efficacy of ravulizumab in this new indication.