#3259 ARTEMIS: A PHASE 3 STUDY OF RAVULIZUMAB TO PROTECT PATIENTS WITH CKD UNDERGOING CARDIAC SURGERY FROM AKI AND SUBSEQUENT MAJOR ADVERSE KIDNEY EVENTS
Authors: Winterberg Pamela , Solinsky Christine , LI Gerry , Smith William 
Published: June 2023

Background and Aims

In patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), pre-existing chronic kidney disease (CKD) confers a substantial risk for poor outcomes, including the development of cardiac surgery-associated acute kidney injury (CSA-AKI). CSA-AKI occurs in ≥50% of patients with CKD undergoing cardiac surgery with CPB vs ∼20–25% of patients without CKD1,2. The risk of subsequent Major Adverse Kidney Events (MAKE; a composite of sustained kidney dysfunction, initiation of dialysis, and death) is also elevated in patients with CKD. Causes of CSA-AKI are multifactorial and complex, and may include inflammation, oxidative stress, renal congestion, and ischaemic injury (such as ischaemic-reperfusion injury [IRI]). IRI is a common cause of AKI and typically results from early hypoperfusion while on bypass, followed by kidney injury upon reperfusion. There are currently no approved therapies that reduce the risk of AKI and associated poor outcomes after cardiac surgery with CPB3. Preclinical and clinical studies suggest that damage and inflammation caused by IRI and CPB is amplified by complement activation3; early treatment with C5 inhibitors, especially before onset of ischaemia, may lower the risk of damage.

Method

ARTEMIS is a Phase 3, randomised, double-blind, placebo-controlled, multicentre study of ravulizumab in adults with CKD and stable cardiac disease undergoing non-emergent sternotomy with CPB, to reduce the risk of post-operative AKI and subsequent MAKE 90 days post-surgery. Key inclusion and exclusion criteria can be found in Figure 1 and a study schematic in Figure 2. Briefly, the study consists of an up to 28-day screening period, randomisation and dosing 1–7 days prior to surgery with CPB (Day 1), a 90-day primary evaluation period post-CPB, and a survival follow-up at day 365 post-CPB. Approximately 736 participants will be randomised 1:1 to receive a single weight-based dose of ravulizumab or placebo; randomisation will be based on baseline CKD stage (3A, 3B, 4) and surgery type (mitral valve replacement or combined procedures vs other single procedures). The primary objective of this study is to assess the efficacy of ravulizumab in reducing the risk of MAKE90, defined as meeting ≥1 of the following by day 90 post-CPB: ≥25% sustained decrease from baseline in estimated glomerular filtration rate (calculated using the Chronic Kidney Disease Epidemiology Collaboration equation, based on serum Cystatin C); initiation of renal replacement therapy; death from any cause. The safety of ravulizumab in participants with CKD undergoing non-emergent CPB will also be evaluated. Other secondary objectives include assessment of ravulizumab efficacy for reducing AKI (based on serum creatinine) and MAKE risk at earlier timepoints following CPB, alongside any effects it may have on healthcare resource utilisation and health-related quality of life – as well as treatment immunogenicity – in participants with CKD undergoing non-emergent CPB.

Results

The final analysis will be conducted when all participants have completed the primary evaluation period.

Conclusion

The aim of this study is to assess whether terminal complement inhibition with ravulizumab is safe and effective in reducing kidney injury and improving outcomes in patients with CKD undergoing cardiac surgery with CPB.