Introduction:
Systemic inflammation, typically defined as high-sensitivity C-reactive protein (hsCRP) levels ≥2 mg/L, is an important target for cardiovascular (CV) risk reduction. Although colchicine is effective at preventing CV events in patients with atherosclerotic CV disease (ASCVD), more targeted therapies are required, particularly for people with chronic kidney disease (CKD) who are at very high CV risk and for whom colchicine is contraindicated. Ziltivekimab, a human monoclonal antibody that targets the interleukin 6 ligand, is being studied for the prevention of CV events, based on phase 2 data showing reductions in hsCRP levels of around 90% compared with placebo. We report the design of the ZEUS trial (NCT05021835) investigating the effects of subcutaneous ziltivekimab 15 mg monthly, compared with placebo, in participants with CKD, ASCVD, and elevated hsCRP levels.
Methods:
ZEUS is a randomized, double-blind, parallel-group CV outcomes trial. Participants with CKD, defined by an estimated glomerular filtration rate (eGFR) ≥15‒<60 mL/min/1.73 m^2 or a urine albumin:creatinine ratio ≥200 mg/g and eGFR ≥60 mL/min/1.73 m^2, established ASCVD, and hsCRP ≥2 mg/L, were randomized 1:1 to ziltivekimab 15 mg monthly or matching placebo. The composite primary outcome is time to first major adverse CV event (MACE; defined as nonfatal myocardial infarction, nonfatal stroke, or CV death); the main secondary outcome is a composite kidney outcome (eGFR decline ≥40%, eGFR <15 mL/min/1.73m^2, initiation of dialysis, or kidney transplant, death due to kidney or CV causes).
Results:
The ZEUS trial will recruit >6200 participants between 2021 and 2024 and follow them until approximately 1044 primary outcomes have accrued. This will provide 95% power to detect a 20% relative risk reduction in the primary outcome, with a one-sided alpha level of 2.5%. Interim analyses for efficacy have been prespecified.
Conclusions:
ZEUS will evaluate the effect of ziltivekimab on MACE and kidney outcomes in participants with CKD, ASCVD, and elevated hsCRP levels, as well as additional efficacy and safety endpoints, and is expected to be completed in 2026.
I have potential conflict of interest to disclose.
This abstract was funded by Novo Nordisk A/S. V. Perkovic is employed by University of New South Wales Sydney; and serves as a board director for St Vincent’s Health Australia, Kidney Health Australia, and several medical research institutes. He has received honoraria for steering committee roles, scientific presentations, and/or advisory board attendance from AbbVie, Amgen, AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, Chinook, Durect, Eli Lilly, Gilead, GSK, Janssen, Merck,Mitsubishi Tanabe Pharma Corporation, Mundipharma, Novartis, Novo Nordisk, Otsuka, Pfizer, PharmaLink, Reata, Relypsa, Roche, Sanofi, Servier, Travere, Tricida and UpToDate, and has shares in George Clinical.
I did not use generative AI and AI-assisted technologies in the writing process.