Evaluation of Ziltivekimab Versus Placebo on Cardiovascular Outcomes in Patients with Atherosclerotic Cardiovascular Disease, Chronic Kidney Disease, and Systemic Inflammation

The primary objective is to evaluate the superiority of once‑monthly subcutaneous ziltivekimab versus placebo, added to standard of care, in reducing the incidence of major adverse cardiovascular events (MACE) in participants with established atherosclerotic cardiovascular disease, chronic kidney disease, and systemic inflammation.

Secondary objectives include:

• Demonstrating superiority of ziltivekimab versus placebo in reducing the risk of an expanded MACE composite.
• Assessing the effect on the incidence of heart failure.
• Evaluating reduction in all‑cause mortality.
• Investigating delay of chronic kidney disease progression.
• Comparing the impact on systemic inflammation levels.
• Measuring improvement in patient‑reported outcomes (PRO).
• Confirming that the treatment does not increase the occurrence of severe infections.
• Assessing improvement in anemia markers.

The trial enrolled 3865 participants of both sexes, encompassing adult age categories corresponding to codes 3 and 4. All subjects had established Atherosclerotic cardiovascular disease and met laboratory and clinical definitions of chronic kidney disease (eGFR ≥ 15 < 60 mL/min/1.73 m² or UACR ≥ 200 mg/g with eGFR ≥ 60 mL/min/1.73 m²) and demonstrated persistent systemic inflammation indicated by serum hs-CRP ≥ 2 mg/L. Evidence of ASCVD was required, including documented myocardial infarction, coronary revascularisation, ≥50 % coronary stenosis, prior atherosclerotic stroke, carotid revascularisation, ≥50 % carotid stenosis, or symptomatic peripheral artery disease as defined by standard imaging or clinical criteria. Participants were selected from patients receiving standard of care who fulfilled these inclusion criteria; no additional lifestyle restrictions such as specific diet or physical‑activity regimens were imposed. The primary efficacy focus of the study was the superiority of the investigational agent in reducing the risk of MACE compared with placebo, both added to standard therapy.

The study is a randomized, double-blind, placebo-controlled trial evaluating subcutaneous administration of ziltivekimab once monthly versus matching placebo in addition to standard of care for participants with established ASCVD, chronic kidney disease and systemic inflammation. After an initial screening visit to confirm eligibility criteria—including eGFR, UACR, hs‑CRP and documented atherosclerotic disease—eligible individuals are randomized and receive the first dose. Subsequent study visits occur monthly for drug administration, safety assessment, and collection of laboratory and imaging data; additional visits at 6‑month intervals include assessments of renal function, inflammatory markers, and quality‑of‑life questionnaires. The primary endpoint is time to first occurrence of a 3‑point MACE (cardiovascular death, non‑fatal myocardial infarction, or non‑fatal stroke) measured from randomization to the end‑of‑study visit, which is scheduled after approximately two years of follow‑up. Secondary endpoints encompass expanded MACE, heart‑failure hospitalizations, renal composite outcomes, mortality, and various biomarker changes over the same period. Participant involvement therefore extends for roughly 24 months. Early termination may occur if a participant experiences a serious adverse event related to study drug, withdraws consent, fails to meet adherence requirements, or is lost to follow‑up, in which case all collected data up to the point of discontinuation are retained for analysis.

The investigational agent, ziltivekimab, is supplied as a sterile solution for injection intended for subcutaneous administration. Participants receive a single 0 Other dose administered subcutaneously once monthly throughout the study period. Dosing is performed by qualified study personnel at scheduled clinic visits, and the injection site is rotated according to protocol specifications.

The control comparator is a matching placebo (ziltivekimab), provided as an identical‑appearing solution for injection. The placebo is administered subcutaneously once monthly using the same volume, injection technique, and schedule as the active product to maintain blinding.

All subjects continue to receive appropriate standard of care therapy for established atherosclerotic cardiovascular disease, chronic kidney disease, and systemic inflammation, in accordance with current clinical guidelines. Concomitant medications are recorded at each visit, and adherence to both study and background therapies is monitored through pill counts, injection logs, and scheduled compliance assessments.

Efficacy will be evaluated primarily by the time to first occurrence of a 3-point MACE composite endpoint, which includes cardiovascular death, non‑fatal myocardial infarction, and non‑fatal stroke. The event time will be measured from randomisation until the end of the study.

Key secondary efficacy parameters include time‑to‑first event analyses of an expanded MACE composite (adding hospitalisation for unstable angina requiring urgent coronary revascularisation), the number of heart‑failure hospitalisations or urgent visits or cardiovascular deaths, a composite kidney endpoint (cardiovascular death, ≥40 % persistent decline in eGFR, or kidney failure), all‑cause mortality, individual components of the expanded MACE and kidney composites, myocardial infarction, stroke, a composite of all‑cause mortality with non‑fatal MI and stroke, a four‑component kidney endpoint, coronary revascularisation, and the annual rate of change in eGFR. Additional efficacy assessments comprise changes from baseline to two years in urinary albumin‑to‑creatinine ratio, eGFR, high‑sensitivity C‑reactive protein, NT‑pro‑BNP, left ventricular ejection fraction, haemoglobin, and the Short Form‑36 Physical Component Score, as well as the number of atrial‑fibrillation events and infection‑related hospitalisations or deaths.

All time‑to‑event endpoints will be captured from randomisation through the study’s follow‑up period. Laboratory biomarkers (eGFR, hs‑CRP, NT‑pro‑BNP, UACR) and imaging parameters (LVEF) will be obtained at baseline and at prespecified intervals up to the two‑year mark, with final assessments at study completion. Patient‑reported outcomes (SF‑36 PCS) will be collected using the validated questionnaire at baseline and at two years. Data will be analysed using standard survival‑analysis techniques for time‑to‑event outcomes and appropriate statistical models for continuous changes, consistent with the study’s analytical plan.