Effects of ziltivekimab versus placebo on coronary atherosclerosis in patients with acute myocardial infarction. A serial, multivessel, intravascular ultrasound, near-infrared spectroscopy and optical coherence tomography imaging study

The primary objective of this study is to demonstrate the superiority of ziltivekimab versus placebo administered once-monthly, added to standard of care therapy, in inducing favorable effects on change in percent atheroma volume in participants with acute myocardial infarction. This objective addresses the critical need to evaluate the impact of targeted anti-inflammatory therapy on coronary atherosclerotic plaque burden following acute myocardial infarction, which remains a significant predictor of recurrent cardiovascular events.

The secondary objectives include:

• To demonstrate the superiority of ziltivekimab versus placebo once-monthly, added to standard of care therapy, in inducing favorable effects on lipid core burden index and fibrous cap thickness in participants with acute myocardial infarction.

• To demonstrate the superiority of ziltivekimab versus placebo once-monthly, added to standard of care therapy, in inducing favorable effects on change in plaque burden as assessed by key metrics from intravascular ultrasound, near-infrared spectroscopy, and optical coherence tomography in participants with acute myocardial infarction.

• To compare the effects of ziltivekimab versus placebo once-monthly, both added to standard of care therapy, on inflammatory and lipid biomarkers, as well as the relationship between levels of biomarkers and changes in plaque characteristics.

• To compare the effects of ziltivekimab versus placebo once-monthly, both added to standard of care therapy, on risk of cardiovascular events in participants with acute myocardial infarction.

This clinical trial enrolled a total of **118 participants** who experienced an **acute myocardial infarction**. The study population included both **male and female** subjects comprising **adults** and **elderly** individuals. Participants were selected based on having sustained an acute myocardial infarction with at least one coronary segment treated with **percutaneous coronary intervention (PCI)** within 48 hours. Eligible subjects presented with either **ST-segment elevation myocardial infarction (STEMI)** characterized by specific ECG changes and symptom onset within 24 hours of index angiography, or **non-ST segment elevation myocardial infarction (NSTEMI)** with elevated cardiac troponin levels. A key requirement for inclusion was the presence of at least two major native **coronary arteries** suitable for intracoronary imaging, each demonstrating angiographic evidence of luminal reduction between 20% and 50% and accessible for imaging in the proximal 50 mm segment. These study vessels could not be bypass grafts, bypassed native vessels, or vessels previously treated with PCI in the study segment. Participants were required to demonstrate **hemodynamic stability** sufficient to tolerate repetitive administration of **nitroglycerin** during imaging procedures. The trial population was categorized as a **vulnerable population**.

This is a **randomized**, **double-blind**, **placebo-controlled** clinical trial evaluating the effects of **ziltivekimab** compared to placebo on **coronary atherosclerosis** in participants with **acute myocardial infarction**. The trial is designed as a Phase III/IV integrated study. The primary objective is to demonstrate the superiority of ziltivekimab administered once-monthly, added to **standard of care** therapy, in inducing favorable effects on change in **percent atheroma volume** in participants with acute myocardial infarction. The investigational medicinal product, ziltivekimab, is a solution for injection administered via the **subcutaneous** route. The maximum treatment period is 12 months. The trial is estimated to commence recruitment in October 2025, with an estimated end date in February 2029.

Eligible participants must have experienced acute myocardial infarction, with at least one coronary segment treated with **percutaneous coronary intervention** within 48 hours. This includes participants with **ST-segment elevation myocardial infarction** presenting with onset of relevant pain suggestive of cardiac ischemia within 24 hours of index angiography and specific ECG changes, or participants with **non-ST segment elevation myocardial infarction** with rise and/or fall in cardiac **troponin** I or T with at least one value above the 99th percentile upper reference limit. Additionally, participants must have at least two major native coronary arteries meeting specific criteria for intracoronary imaging immediately following the qualifying percutaneous coronary intervention procedure, including angiographic evidence of lumen diameter reduction between 20% and 50%, suitability for imaging in the proximal 50 mm segment, and absence of previous percutaneous coronary intervention within the study segment. Hemodynamic stability allowing repetitive administration of **nitroglycerine** during the study-specific imaging procedure is also required.

The primary endpoint is the change in percent atheroma volume as determined by **greyscale intravascular ultrasound** in matched regions of interest, measured from randomization to end-of-study. Secondary endpoints include changes in maximum **lipid core burden index** in any 4-mm segment as determined by **near-infrared spectroscopy**, changes in minimal **fibrous cap thickness** as determined by **optical coherence tomography**, changes in total lipid core burden index, changes in average angular extension of macrophages, changes in normalized total atheroma volume, and changes in mean fibrous cap thickness, all measured in matched regions of interest from randomization to end-of-study. Additional secondary endpoints include changes in biomarkers such as **IL-6**, **hs-CRP**, **hs-TnT**, **NT-pro-BNP**, and other lipid and inflammatory markers measured from randomization to week 4 and week 52. Time to first occurrence of major cardiovascular events, including all-cause death, cardiac death, non-fatal spontaneous myocardial infarction, any **coronary revascularization**, non-fatal **stroke**, and **transient ischemic attack**, measured from randomization to end-of-study, is also evaluated.

The study involves serial, multivessel intracoronary imaging procedures utilizing intravascular ultrasound, near-infrared spectroscopy, and optical coherence tomography. Participants undergo a screening visit following the qualifying percutaneous coronary intervention procedure, at which time baseline intracoronary imaging is performed. Following randomization, participants receive either ziltivekimab or placebo once-monthly for a treatment period of up to 12 months. Follow-up visits are scheduled at week 4 and week 52 for assessment of biomarkers and clinical status. The end-of-study visit includes repeat intracoronary imaging to assess changes in atherosclerotic parameters. The expected length of participant involvement is approximately 12 months from randomization to the end-of-study assessment. Conditions that may lead to early termination from the study include withdrawal of consent, adverse events requiring discontinuation, hemodynamic instability precluding imaging procedures, or need for revascularization in study vessels as determined by the investigator.

The experimental treatment consists of **ziltivekimab**, a protein-based **active substance** manufactured by Novo Nordisk A/S. Ziltivekimab is formulated as a **solution for injection** administered via the **subcutaneous route**. The treatment is administered once-monthly over a maximum treatment period of 12 months. Ziltivekimab is added to **standard of care therapy** in participants with **acute myocardial infarction**.

The comparator treatment is **placebo** matching ziltivekimab. The placebo is administered to maintain blinding in the study and is given in addition to standard of care therapy. The administration schedule and route of the placebo correspond to those of the active treatment to ensure consistency across treatment groups.

Efficacy will be assessed through multiple imaging and biomarker parameters measured from randomization to end-of-study. The primary endpoint is the change in **percent atheroma volume** (PAV) as determined by greyscale intravascular ultrasound (IVUS) in matched regions of interest. Secondary endpoints include changes in maximum **lipid core burden index** (LCBI) in any 4-mm segment (maxLCBI4mm) as determined by near-infrared spectroscopy (NIRS) in matched regions of interest, and changes in minimal **fibrous cap thickness** as determined by optical coherence tomography (OCT) in matched regions of interest. Additional secondary endpoints encompass changes in LCBI total as determined by NIRS in matched regions of interest, changes in average angular extension (AAE) of macrophages as determined by OCT in matched regions of interest, and changes in normalized total atheroma volume (NTAV) by IVUS in matched regions of interest. Changes in mean fibrous cap thickness as determined by OCT in matched regions of interest will also be evaluated.

Biomarker assessments will be performed at specific timepoints, including changes in **interleukin-6** (IL-6), high-sensitivity C-reactive protein (hs-CRP), high-sensitivity troponin T (hs-TnT), and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) measured from randomization to week 4 and week 52. Changes in lipid and inflammatory markers will be assessed from randomization to week 4 and week 52. Clinical outcomes will be evaluated through time to first occurrence of all-cause death, cardiac death, non-fatal spontaneous **myocardial infarction**, any coronary revascularization, non-fatal stroke, and transient ischemic attack, measured from randomization to end-of-study.