Role of Neuroinflammation and Blood-Brain Barrier Breakdown in Intracerebral Hemorrhage. The INFINITE Study

The primary objective is to evaluate the effect of perihematomal neuroimmune response, assessed by quantitative measurement of 18F-DPA-714 PET radiotracer uptake (binding within perihematomal edema) at day 10 ±2 after spontaneous intracerebral hemorrhage, on the functional outcome (poor versus favorable) at 6 months. This objective addresses the clinical relevance of neuroinflammatory processes in the perihematomal region and their potential impact on long-term neurological recovery following spontaneous intracerebral hemorrhage.

The secondary objectives include:

• To evaluate the effect of perihematomal neuroimmune response assessed by other PET-derived quantitative measures of 18F-DPA-714 radiotracer uptake at day 10 ±2 after spontaneous intracerebral hemorrhage on the functional outcome at 6 months.

• To evaluate the effect of perihematomal neuroimmune response as assessed by PET-derived quantitative measures of 18F-DPA-714 uptake at day 10 ±2 after intracerebral hemorrhage on early (within 14 days) neurological deterioration, early (within 30 days) death, functional outcome at 6 months, and mortality at 6 months.

• To evaluate at day 10 ±2 after intracerebral hemorrhage the correlations of perihematomal neuroimmune response as assessed with 18F-DPA-714 PET with other measures of neuroimmune response: blood-brain barrier breakdown as assessed with DCE-MRI and the level of a panel of inflammatory (pro- and anti-) biomarkers.

• To evaluate the effect of blood-brain barrier breakdown and inflammatory plasma biomarkers at day 10 ±2 after intracerebral hemorrhage onset on the functional outcome (poor versus favorable) at 6 months.

• To compare the performance of 18F-DPA-714 PET, DCE-MRI and inflammatory plasma biomarkers at day 10 ±2 after intracerebral hemorrhage onset to predict the functional outcome (poor versus favorable) at 6 months.

• To identify baseline clinical and imaging variables associated with increased neuroimmune response (TSPO PET) and blood-brain barrier breakdown (DCE-MRI) at day 10 ±2 after intracerebral hemorrhage.

The sponsor did not provide information regarding the total number of participants for this clinical trial. The study population includes **adults** aged 18 years and older of both **male** and **female** gender. Participants are individuals presenting with symptomatic spontaneous **supratentorial intracerebral hemorrhage** (ICH) confirmed by brain imaging, with symptom onset occurring within 48 hours prior to enrollment (or last seen well). The trial focuses on patients classified within the clinical trial group category. No vulnerable populations are included in this study. The selection criteria require that participants be affiliated with or beneficiaries of a social security scheme, and informed consent must be documented prior to enrollment.

This clinical trial investigates the role of neuroinflammation and blood-brain barrier breakdown in patients with spontaneous supratentorial **intracerebral hemorrhage**. The study is designed as a Phase IV trial evaluating the effect of perihematomal neuroimmune response on functional outcomes. The primary objective is to assess the relationship between **18F-DPA-714** **PET** radiotracer uptake in the perihematomal area at day 10 ±2 after hemorrhage onset and functional outcome at 6 months. The investigational medicinal product 18F-DPA-714 is administered as a solution for injection via **intravenous administration** at a maximum dose of 3.5 MBq/kg, with a single-day treatment period. The radiotracer binds to activated microglia and macrophages, allowing quantitative measurement of neuroinflammation through **positron emission tomography** imaging.

Eligible participants include adults aged 18 years or older presenting with symptomatic spontaneous supratentorial intracerebral hemorrhage within 48 hours of symptom onset or last seen well, confirmed by brain imaging. Participants must provide informed consent and be affiliated with or beneficiaries of a social security scheme. The trial is expected to commence recruitment in September 2025 and conclude in September 2028, spanning an estimated duration of 3 years.

The study protocol includes several scheduled visits throughout the participant involvement period. Following confirmation of eligibility criteria at the screening visit, participants undergo baseline clinical and imaging assessments. The key imaging visit occurs at day 10 ±2 after intracerebral hemorrhage onset, during which participants receive the 18F-DPA-714 radiotracer and undergo PET imaging to quantify neuroinflammation in the **perihematomal edema**. Concurrent **magnetic resonance imaging** is performed to assess blood-brain barrier breakdown using contrast agent transfer coefficient (Ktrans) mapping. Blood samples are collected at this timepoint to measure plasma levels of inflammatory biomarkers including **MMP9**, **TNF alpha**, **IL-6** and **IL-10**, soluble **TLR 2/4**, and **Neutrophil Extracellular Traps**. Clinical monitoring continues through day 14 to detect neurological deterioration, defined as a ≥4-point increase on the **National Institutes of Health Stroke Scale** or ≥2-point decrease on the **Glasgow Coma Scale** compared to baseline. An assessment at day 30 evaluates early mortality. The end-of-study visit occurs at 6 months post-hemorrhage, at which time functional outcome is assessed using the **modified Rankin scale**, ranging from 0 (no symptoms) to 6 (death). The total participant involvement period is approximately 6 months.

The primary endpoint measures 18F-DPA-714 binding by calculating the mean **standard uptake value ratio** within the perihematomal edema using the mirror region of interest in the contralateral hemisphere as reference. Poor functional outcome is defined as a modified Rankin scale score ≥3 at 6 months. Secondary endpoints include the volume of brain tissue with increased 18F-DPA-714 binding, voxel-wise radiotracer levels based on SuperVised Cluster Analysis, and associations between PET-derived measures and clinical outcomes including neurological deterioration, early death at 30 days, distribution of modified Rankin scale scores, and mortality at 6 months. Additional secondary analyses examine correlations between PET imaging findings, MRI-derived blood-brain barrier breakdown measures, and plasma inflammatory biomarker levels. The predictive performance of these biomarkers for functional outcome at 6 months is evaluated using **receiver operating characteristic curve** analyses and **area under curve** values. Baseline clinical and imaging variables are also analyzed for associations with PET and MRI quantitative measures.

Participants may be withdrawn from the study under specific conditions that compromise safety, data integrity, or protocol compliance. Early termination may occur due to withdrawal of consent, loss to follow-up, significant protocol violations, or adverse events requiring discontinuation. Clinical and imaging data collected up to the point of early termination are retained for analysis when applicable.

The experimental investigational medicinal product utilized in this clinical trial is 18F-DPA-714, a radiopharmaceutical agent containing the active substance N,N-diethyl-(2-(4-(2-(18F)fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidine-3-yl)acetamide, which is of chemical origin. This compound is also known by the synonyms BAY 85-8102 and DPA-714 F-18. The investigational product is formulated as a solution for injection and is administered via intravenous administration. The maximum daily dose is established at 3.5 megabecquerels per kilogram (MBq/kg), which also represents the maximum total dose per treatment period. The maximum treatment period is defined as 1 day. The sponsor product code assigned to this investigational medicinal product is CHUTLSE003. This radiopharmaceutical serves as a PET radiotracer designed to assess perihematomal neuroimmune response through quantitative measurement of uptake binding within the perihematomal edema region at day 10 ±2 following spontaneous intracerebral hemorrhage.

Efficacy will be assessed through the evaluation of perihematomal neuroimmune response and its effect on functional outcome following spontaneous intracerebral hemorrhage. The primary efficacy parameter is 18F-DPA-714 binding, measured by the mean standard uptake value ratio (SUVR) within the perihematomal edema at day 10 ±2 after ICH onset, using the mirror region of interest in the contralateral hemisphere as reference. Functional outcome at 6 months after ICH will be quantified using the modified Rankin scale, which ranges from 0 (no symptoms) to 6 (death). Poor functional outcome is defined as a modified Rankin scale score of ≥3.

Secondary efficacy parameters include the volume of brain tissue within the perihematomal area with increased 18F-DPA-714 binding and voxel-wise 18F-DPA-714 levels based on SuperVised Cluster Analysis. Additional assessments will evaluate associations between PET-derived quantitative measures of 18F-DPA-714 radiotracer uptake and several clinical endpoints: neurological deterioration within 14 days after ICH onset (defined as a ≥4-point increase on the National Institutes of Health Stroke Scale or ≥2-point decrease on the Glasgow Coma Scale compared to baseline scores), early death at day 30, clinical outcome at 6 months assessed by the distribution of modified Rankin scale scores, and mortality at 6 months. MRI-derived quantitative measures of blood-brain barrier breakdown based on maps of the contrast agent transfer coefficient (Ktrans) in the perihematomal area at day 10 ±2 after ICH will be analyzed. Plasma levels of inflammatory biomarkers, including MMP9, TNF alpha, IL-6 and IL-10, soluble TLR 2/4, and Neutrophil Extracellular Traps, will be measured at day 10 ±2 after ICH onset. Comparisons of MRI-derived quantitative measures of blood-brain barrier breakdown and plasma levels of inflammatory biomarkers between patients with poor versus favorable functional outcome at 6 months will be performed. The performance of PET-derived quantitative measures of 18F-DPA-714 radiotracer uptake, MRI-derived quantitative measures of blood-brain barrier breakdown, and plasma levels of inflammatory biomarkers to predict functional outcome at 6 months will be assessed using receiver operating characteristic curve analyses and area under curve values. Associations of baseline clinical and imaging variables with PET-derived quantitative measures of 18F-DPA-714 radiotracer uptake and MRI-derived quantitative measures of blood-brain barrier breakdown will also be evaluated.