Quantification of Neuroinflammation in Multiple Sclerosis Using [18F]-DPA-714 PET Imaging: A Multicenter Study Comparing Lesion Activity in Patients and Healthy Controls

The primary objective of this study is to quantify the **smoldering component** of white matter lesions in individuals with **multiple sclerosis** (MS) using [18F]-DPA-714 PET imaging. This is compared to the [18F]-DPA-714 binding in the white matter of healthy controls, with both groups undergoing PET acquisition using the same camera at each center. This objective is clinically relevant as it aims to enhance the understanding of neuroinflammatory processes in MS, potentially leading to improved diagnostic and therapeutic strategies.

Secondary objectives include:

• Quantifying the regional neuroinflammatory load, measured as [18F]-DPA-714 DVR, in specific regions of interest such as the total brain, normal appearing white matter, cortex, thalami, and deep grey matter for each patient.
• Assessing the clinical relevance of inflammatory profiles derived from PET MR acquisitions in conjunction with clinical and neuropsychological scores collected at baseline.
• Improving the methodological workup for the quantification of multicenter PET data.
• Exploring and assessing the MRI signatures of each lesional subtype and the correlation between MRI metrics (T1, T2, FLAIR, SWI, QSM, MTR, ihMT, diffusion) and [18F]-DPA-714 DVR in each region of interest, including the evaluation of novel algorithms generated through deep learning to reproduce PET using multimodal MRI datasets.

The clinical trial involves participants diagnosed with **multiple sclerosis** and healthy volunteers, with an age range of 18 to 55 years. Both male and female subjects are included in the study, and the population is not considered vulnerable. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants with relapsing-remitting multiple sclerosis (RRMS) are selected based on the 2017 McDonald criteria, requiring at least nine supra-tentorial white matter lesions on T2/FLAIR MRI. They must not be on current disease-modifying therapy and should have an indication for highly active disease-modifying treatment. Healthy volunteers are required to be free from any evolutive pathology and capable of understanding the study objectives and procedures. All participants must be affiliated with a social security scheme, excluding those under "Aide Médicale d’État." Lifestyle considerations such as diet, physical activity, or habits are not detailed in the provided data.

The clinical trial is designed to evaluate the **neuroinflammation** in patients with **multiple sclerosis** (MS) using [18F]-DPA-714 PET imaging. This is a multicentric, prospective, non-randomized, non-blinded, interventional study. The trial aims to quantify the smoldering component of white matter lesions in people with MS compared to healthy controls. The study will involve the administration of two products: 18F-DPA-714, a radiotracer, and DOTAREM 0.5 mmol/mL, a solution for injection, both delivered via **intravenous infusion**. The trial is expected to commence recruitment on May 1, 2024, and conclude by January 1, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, disease status, and treatment history. Eligible participants will be either patients with relapsing-remitting multiple sclerosis (RRMS) or healthy volunteers. The primary endpoint is the classification of lesions as homogeneously active, rim active, or inactive, based on predefined thresholds. Secondary endpoints include regional mean and voxel-wise maps of innate immune cell activation, clinical and neuropsychological scores, and MRI data.

The expected duration of participant involvement is up to two years, with the possibility of early termination if participants do not adhere to the study protocol or if adverse events occur. Follow-up visits will be scheduled to monitor the participants' health and collect necessary data. The end-of-study visit will conclude the trial for each participant, ensuring all data is collected and any remaining health concerns are addressed. The study is not classified as low intervention, given the use of a radiotracer and the comprehensive data collection involved.

The clinical trial involves the use of **18F-DPA-714**, an experimental radiotracer, to assess neuroinflammation in patients with multiple sclerosis. **18F-DPA-714** is administered in the form of an **injection**. The active substance is **N,N-diethyl-2-(2-(4-(2[(18)F]-fluoroethoxy)phenyl)5,7dimethylpyrazolo[1,5a]pyrimidin-3-yl)acetamide**. The administration route is **intravenous infusion**. The maximum daily dose is 300 MBq, with a total maximum dose of 600 MBq over a treatment period of up to 2 days. The formulation is not pediatric, and the product is classified as a radiotracer.

In addition to the experimental treatment, the trial utilizes **DOTAREM 0.5 mmol/mL, solution injectable**, as a comparator treatment. This product contains the active substance **gadoteric acid** and is also administered via **intravenous infusion**. The pharmaceutical form is a **solution for injection**. The maximum dose is 0.2 mL/kg, with a total maximum dose of 0.2 mL/kg over a treatment period of 1 day. This product is not a pediatric formulation and is used as an auxiliary treatment in the trial.

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint involves evaluating the proportion of **lesions** classified as homogeneously active, rim active, and inactive in each patient with multiple sclerosis (MS). This classification will be based on a predefined data-driven threshold of activity in lesion subareas, as referenced in Hamzaoui et al., 2023.

Secondary endpoints include the analysis of regional mean and voxel-wise individual maps of innate immune cell activation derived from baseline [18F]-DPA-714 PET scans. These will be expressed as mean distribution volume ratio (DVR) values and as a percentage of voxels classified as "DPA+" for each region of interest, including the whole brain, normal-appearing white matter (NAWM), grey matter, cortex, thalami, deep grey matter, white matter T2 lesions, and white matter T1 lesions. Additionally, clinical and neuropsychological scores will be collected at baseline, and an accessible pipeline for processing DPA-714 data will be developed. MRI data will also be utilized in the assessment of efficacy.