Description

Atherosclerosis is a common disease in which fatty deposits, inflammatory cells, and other material build up in the walls of arteries. It is a major cause of coronary artery disease (CAD), myocardial infarction, stroke, and other cardiovascular diseases. Inflammation within atherosclerotic plaques is thought to contribute to plaque development, progression, and rupture. However, there is currently no established clinical imaging method that can reliably detect and measure inflammatory activity in atherosclerotic plaques throughout the body.

This study investigates vascular inflammation using whole-body positron emission tomography (PET) imaging with a novel folate receptor beta (FR-β)-targeted radiotracer, 18F-AlF-NOTA-Folate. FR-β is expressed by activated macrophages, which are immune cells involved in inflammatory processes. The study aims to determine whether this radiotracer can be used to identify and quantify inflammatory activity in atherosclerotic lesions in humans.

Previous experimental studies have shown that folate receptor beta-targeted radiotracers can accumulate in macrophage-rich atherosclerotic lesions. A related FR-β-targeted PET tracer has also previously been studied in humans with rheumatoid arthritis, where it showed uptake in inflamed joints and a favourable safety profile. The present study is intended to investigate FR-β-targeted PET imaging specifically in patients with coronary artery disease and extracardiac atherosclerosis.

Objectives The main objective is to investigate vascular inflammation using whole-body 18F-AlF-NOTA-Folate PET imaging in patients with atherosclerotic cardiovascular disease.

The specific objectives are:

1. To investigate inflammation in the coronary arteries of patients with chronic or stable coronary artery disease and in a smaller group of patients with a recent myocardial infarction. The study will investigate whether low-grade inflammation can be detected in coronary atherosclerotic lesions.
2. To investigate the relationships between coronary artery inflammation, anatomical plaque characteristics, total coronary atherosclerotic burden, and myocardial perfusion.
3. To determine whether FR-β-targeted PET imaging can detect inflammatory activity in large extracardiac arteries, including the carotid arteries, aorta, renal arteries, and iliac arteries, in patients with chronic coronary syndromes and patients with a recent myocardial infarction.
4. To investigate the relationships between inflammation in extracardiac arteries, plaque characteristics and plaque burden, perfusion of the brain and other organs, and findings in the coronary arteries.
5. To investigate relationships between inflammatory activity in hematopoietic organs, particularly the bone marrow and spleen, vascular inflammation, and blood biomarkers of systemic inflammation.

Study Population: Approximately 90 adult patients will participate in the study.

Group A will consist of approximately 80 patients with suspected or chronic/stable coronary artery disease who have undergone coronary computed tomography angiography (CCTA) and are referred for cardiac 15O-water PET myocardial perfusion imaging based on clinical indications.

Group B will consist of approximately 10 patients with a recent myocardial infarction.

Participants must provide written informed consent before being included in the study.

Patients with unstable angina symptoms or, for Group A, a previous myocardial infarction will be excluded. Other exclusion criteria for both groups include previous coronary artery bypass grafting or percutaneous coronary intervention, severe pulmonary disease, severe symptomatic asthma, severe valvular disease, uncontrolled hypertension or severe hypotension, severe renal failure, pregnancy, age below 50 or above 80 years, certain significant cardiac conduction abnormalities without a pacemaker, allergy to X-ray contrast agents, known inflammatory or autoimmune disease, known infection, use of anti-inflammatory medication or folate antagonists such as corticosteroids or methotrexate, and known cancer.

Study Design:

This is an academic, prospective, open-label, single-dose diagnostic study. Participants will attend two study visits approximately 1 to 4 weeks apart. At Visit 1, participants in Group A will have undergone coronary CT angiography as part of their clinical assessment and will be referred for cardiac 15O-water PET perfusion imaging based on clinical indications. As an additional research procedure, eligible Group A participants will undergo resting total-body 15O-water PET perfusion imaging in addition to the clinically indicated stress PET scan. Participants in Group B will not undergo 15O-water PET perfusion imaging.

Relevant clinical information, including medical history, comorbidities, and medication use, will be collected.

At Visit 2, participants will undergo whole-body PET imaging with the 18F-AlF-NOTA-Folate tracer and contrast-enhanced CT angiography from the neck to the inguinal region. Participants in Group B will also undergo coronary CT angiography as part of the contrast-enhanced CT examination.

Approximately 150 MBq of 18F-AlF-NOTA-Folate will be administered intravenously. The first five participants will undergo a dynamic PET scan lasting approximately 120 minutes. The remaining participants will undergo a static PET scan lasting approximately 20 minutes, performed approximately 60 to 90 minutes after tracer administration.

External ECG recording and, when appropriate, image-based respiratory motion information will be collected to allow cardiac PET data to be gated and improve the assessment of cardiac structures.

Blood samples will also be collected for analysis and storage for exploratory investigations of biomarkers related to atherosclerosis and vascular inflammation.

Imaging Procedures The whole-body PET examination will investigate the distribution and uptake of 18F-AlF-NOTA-Folate in the coronary arteries and other major arteries, including the carotid arteries, aorta and iliac arteries. Uptake will also be assessed in the bone marrow and spleen.

The PET findings will be compared with anatomical information obtained from CT angiography. Coronary CT angiography will be used to assess coronary artery narrowing, plaque burden, and plaque characteristics. CT angiography of the extracardiac arteries will be used to assess plaque volume and characteristics in the carotid arteries, aorta and iliac arteries.

Myocardial and whole-body organ perfusion will be assessed using 15O-water PET in participants for whom this examination is performed. The study will investigate blood flow in the myocardium, brain, and other organs and will examine its relationship with vascular inflammation and atherosclerotic disease.

Image and Laboratory Analysis Coronary CT angiography images will be quantitatively analysed to determine vessel narrowing, plaque burden, plaque volume, vessel and lumen volumes, remodelling characteristics, and plaque type. An artificial intelligence-based quantitative CT analysis method will be used for coronary CT images.

The uptake of 18F-AlF-NOTA-Folate in the coronary arteries will be quantified using PET image analysis. Measurements will include standardized uptake values and target-to-background ratios. A new coronary inflammatory activity measure will also be explored. This measure is intended to represent the overall inflammatory activity in a coronary vessel based on both the amount and intensity of PET tracer activity above the background blood-pool activity.

For the extracardiac arteries, PET tracer uptake will be assessed together with the corresponding anatomical findings on CT angiography. Uptake will be quantified using standardized uptake values and target-to-background ratios.

18F-AlF-NOTA-Folate uptake in the bone marrow and spleen will also be quantified. These measurements will be related to blood biomarkers of inflammation, atherosclerotic plaque characteristics, and vascular inflammation.

Blood samples will be used for analysis of markers of atherosclerosis and systemic inflammation, including lipid-related measurements and other exploratory biomarkers.

Follow-up Participants will be followed for up to 5 years using hospital records and registry information.

The primary clinical composite endpoint during follow-up consists of all-cause death, non-fatal myocardial infarction, unstable angina, late coronary revascularization by percutaneous coronary intervention or coronary artery bypass grafting occurring more than 6 months after study inclusion, ischemic stroke or transient ischemic attack, and peripheral revascularization for claudication or ischemia.

A secondary endpoint is cardiovascular death and resuscitated out-of-hospital cardiac arrest.

The follow-up is intended to allow investigation of whether the imaging measurements of vascular inflammation and atherosclerotic disease are associated with subsequent cardiovascular events.

Risks and Safety The study involves exposure to ionizing radiation from PET and CT imaging and intravenous administration of the 18F-AlF-NOTA-Folate radiotracer and X-ray contrast material.

The amount of 18F-AlF-NOTA-Folate administered is approximately 150 MBq. Based on available estimates in the study protocol, this corresponds to an estimated effective radiation dose of approximately 8.85 mSv. The final administered activity may be adjusted when human dosimetry data become available.

For participants in Group A, the additional radiation exposure associated with study participation is estimated to be approximately 15.1 mSv, including the additional resting 15O-water PET examination, 18F-AlF-NOTA-Folate PET/CT, attenuation CT, and contrast-enhanced body CT angiography.

For participants in Group B, the additional radiation exposure associated with study participation is estimated to be approximately 18.4 mSv, including the 18F-AlF-NOTA-Folate PET/CT and coronary CT angiography performed as part of the contrast-enhanced CT examination.

The study protocol states that the estimated radiation exposure is considered moderate in relation to the age and established cardiovascular disease of the study population. The study also includes appropriate assessment of eligibility and exclusion of participants for whom the imaging procedures or contrast administration may present increased risk.

The folate tracer is administered for imaging purposes and is not intended to produce a pharmacological or therapeutic effect. Based on the study protocol, the very small amount of folate derivative administered is not expected to cause pharmacological effects.

Clinical imaging examinations that are part of routine care will be reviewed and reported according to clinical practice. Research-only imaging and blood tests will not routinely be reviewed or reported for clinical purposes. Contrast-enhanced CT and coronary CT images will be reviewed by an experienced specialist, and clinically important findings will be communicated to the referring physician.

Potential Benefits Participants should not expect a direct therapeutic benefit from taking part in this study. The study is not testing a treatment for coronary artery disease or myocardial infarction.

The study may provide new information about inflammation in atherosclerotic plaques and may help determine whether FR-β-targeted PET imaging can identify and measure vascular inflammation in humans.

In the longer term, improved understanding and imaging of vascular inflammation could contribute to the development of new approaches for assessing cardiovascular risk and investigating inflammation-targeted therapies. However, these potential future benefits are not guaranteed and are not a direct benefit to individual participants.

Scientific Significance This study is designed to provide proof-of-concept information about FR-β-targeted molecular imaging of vascular inflammation in humans. By combining whole-body PET imaging with detailed CT angiography, myocardial and organ perfusion measurements, and blood biomarkers, the study will investigate vascular inflammation at both local and whole-body levels.

The study will assess whether 18F-AlF-NOTA-Folate uptake is associated with atherosclerotic plaque burden, plaque characteristics, myocardial and organ perfusion, and systemic inflammatory markers.

The study may help determine whether activated macrophages and FR-β expression can be visualized in human atherosclerotic lesions and whether molecular imaging of vascular inflammation could provide information beyond conventional anatomical imaging.

The study will also investigate whether imaging findings are associated with subsequent cardiovascular events during long-term follow-up. These findings may contribute to the development and validation of imaging biomarkers for vascular inflammation and may support future research into imaging-guided or inflammation-targeted approaches to cardiovascular disease.

This is a diagnostic imaging research study. The 18F-AlF-NOTA-Folate tracer is being investigated as an imaging agent to study vascular inflammation; it is not being evaluated as a treatment.