Assessment of Ficolin-2 Levels and Carotid and Brain Inflammation in Symptomatic Carotid Stenosis Using [18F]DPA-714 PET/MRI in Stroke or Transient Ischemic Attack

The primary objective of this study is to evaluate the association between circulating levels of **ficolin-2** and inflammation in the carotid artery and brain, as observed through [18F]DPA-714 PET/MRI, in patients who have experienced a transient ischemic attack or acute ischemic stroke due to carotid stenosis. This is clinically relevant as it may provide insights into the inflammatory processes involved in these conditions, potentially guiding therapeutic strategies and improving patient outcomes.

Secondary objectives include assessing whether plasma levels of ficolin-2 correlate with: morphological data of the plaque, such as the presence of intraplaque hemorrhage, lipid-rich necrotic core, and thinning or rupture of the fibrous cap on carotid plaque MRI; morphological data of the brain, including infarct size, presence of hemorrhagic transformation, or blood-brain barrier leakage; and histological data of the retrieved plaque, such as hemorrhagic content, lipid core, cholesterol cleft areas, the ratio between the thickness of tunica media and total thickness of tunica, including infiltration of cellular debris and cholesterol, rupture, intraplaque deposition of ficolin-2, and macrophages and neutrophils infiltration.

The clinical trial involves participants diagnosed with **stroke** or transient ischemic attack, focusing on individuals with atherosclerotic carotid stenosis. The study population includes both male and female subjects aged 18 years and older. Participants are required to have experienced a probable ipsilateral transient ischemic attack, retinal artery occlusion, or ischemic stroke within 48 hours from onset. The trial population was selected based on specific inclusion criteria, such as the presence of carotid stenosis between 50% and 99% confirmed by imaging examinations. The sponsor has not provided information regarding the total number of participants. The study includes a vulnerable population, and participants must have signed written informed consent prior to any study-specific intervention. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the association between circulating levels of **ficolin-2** and carotid and brain inflammation in patients who have experienced a **transient ischemic attack** or acute **ischemic stroke** due to carotid stenosis. This study employs a randomized, double-blind, controlled methodology to ensure the reliability and validity of the results. The trial is expected to run from August 2023 to December 2024, with participant involvement lasting approximately one month. The primary endpoint is the correlation between plasma levels of ficolin-2 and metabolic data obtained from [18F]DPA-714 PET/MRI scans, specifically focusing on the standardized uptake value and Logan distribution volume ratio in the carotids and brain.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, informed consent, and specific medical history related to carotid stenosis. The initial visit will involve imaging examinations to confirm atherosclerotic carotid stenosis between 50% and 99% using methods like Doppler ultrasound or MR angiography. Follow-up visits will occur on day 5 and day 15, where plasma levels of ficolin-2 will be measured, and PET/MRI scans will be conducted to assess inflammation and morphological changes. The end-of-study visit will conclude the trial, summarizing the findings and ensuring participant safety.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include the identification of alternative causes for the transient ischemic attack or ischemic stroke, adverse reactions to the investigational products, or withdrawal of consent. The investigational products used in the trial include **18F-DPA-714** and **GADOTERIC ACID**, both administered via injection. The trial is categorized as a Phase 4 study, focusing on the safety and efficacy of these products in the specified patient population.

The clinical trial involves the use of **18F-DPA-714**, an experimental radiopharmaceutical agent. This compound is chemically identified as **N,N-diethyl-2-(2-(4-(2[(18)F]-fluoroethoxy)phenyl)5,7dimethylpyrazolo[1,5a]pyrimidin-3-yl)acetamide**. It is administered in the form of an **injection**. The maximum daily and total dose is set at 215 MBq (megabecquerels), with a treatment period limited to a single day. The administration route is via **injection**, and the formulation is not designed for pediatric use. Compliance with dosing schedules will be monitored throughout the trial to ensure accurate data collection and participant safety.

In addition to the experimental treatment, the study utilizes **Gadoteric Acid** as a non-experimental auxiliary agent. Gadoteric Acid is provided as a **solution for injection** and serves as a contrast agent in imaging procedures. The maximum daily and total dose is 500,000 nmol/ml (nanomoles per milliliter), also administered over a single day. The route of administration is **intravenous use**. This agent is not a pediatric formulation and is used to enhance the imaging quality during the trial. Monitoring of participant compliance with the administration of Gadoteric Acid will be conducted to ensure the integrity of the imaging results.

Efficacy in this clinical trial will be assessed by evaluating the correlation between circulating levels of **ficolin-2** and metabolic data obtained from [18F]DPA-714 PET/MRI imaging in patients with transient ischemic attack or acute ischemic stroke due to carotid stenosis. The primary endpoint involves measuring plasma levels of **ficolin-2** at day 5 and correlating these with the standardized uptake value (SUV) and Logan distribution volume ratio (DVR) of [18F]DPA-714 in the carotids and brain at the time of the PET-Scan imaging, also on day 5.

Secondary endpoints include the correlation of plasma levels of **ficolin-2** at day 5 with morphological data and at day 15 with histological data. Morphological data will be evaluated by the Central Image Reading Board at day 5, focusing on carotid plaque PET/MRI to assess the presence of intraplaque hemorrhage, lipid-rich necrotic core, and thinning/rupture of the fibrous cap on carotid plaque MRI. Additionally, brain PET/MRI will be used to evaluate infarct size, hemorrhagic transformation, and blood-brain barrier leakage. These assessments will provide comprehensive insights into the efficacy of the intervention in addressing inflammation associated with carotid stenosis.