Characterization of Dopaminergic Network Abnormalities in Comatose Traumatic Brain Injury Patients Using [18F]LBT-999 Radiotracer

The primary objective of this study is to **characterize metabolic abnormalities** of the dopaminergic network within the striatum in comatose patients with severe traumatic brain injury (TC-COMA group) using the radiotracer [18F]LBT-999. This is clinically relevant as it aims to enhance the understanding of dopaminergic disruptions in severe traumatic brain injury, potentially informing therapeutic strategies and improving patient outcomes.

Secondary objectives include:

• Characterizing metabolic abnormalities in the dopaminergic network throughout the network and within the brainstem in severe comatose TC patients (TC-COMA group) using the radiotracer [18F]LBT-999.
• Comparing metabolic abnormalities in the dopaminergic network between patients with severe TC with persistent coma (TC-COMA) and severe TC with recovery of response to simple commands at inclusion (TC-ROS).
• Investigating the potential link between structural and metabolic changes, as well as functional and metabolic changes, within the dopaminergic network in all severe TC patients (TC-COMA and TC-ROS).
• Studying the motor behavioral signatures of metabolic abnormalities within the dopaminergic network in all severe TC patients (TC-COMA and TC-ROS).
• Determining the prognostic value of structural, functional, and metabolic abnormalities within the dopaminergic network on patients' neurological outcomes and quality of life at 3 months, 6 months, and 1 year in all TC patients (TC-COMA and TC-ROS).

The clinical trial involves **Comatose Traumatic Brain Injury patients** and aims to characterize metabolic abnormalities of the dopaminergic network within the striatum using the radiotracer [18F]LBT-999. The study population includes both male and female participants aged between 18 and 65 years. Participants are required to be affiliated with a social security scheme or be beneficiaries of such a scheme. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants were selected based on specific criteria, including being victims of non-penetrating traumatic brain injury (TBI) occurring within less than 30 days, with a traumatic coma defined by a Glasgow Coma Scale (GCS) score of less than 10 and a motor score of less than 6 upon hospital admission. Additionally, patients must have discontinued sedative treatments for more than 48 hours and exhibit clinical stability without haemodynamic, respiratory, or metabolic failure that would contraindicate medical transfer to the imaging center. Control subjects are age and sex-matched to patients in the TC-COMA group. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the **dopaminergic** network abnormalities in patients with **comatose traumatic brain injury** using the radiotracer **[18F]LBT-999**. This study is a randomized, double-blind, controlled trial, with an estimated duration from April 2024 to April 2027. The trial will involve a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, social security affiliation, and clinical stability. Participants will be required to have a Glasgow Coma Scale (GCS) score of less than 10 with a motor score of less than 6 upon hospital admission, and they must have discontinued sedative treatments for more than 48 hours.

Following the screening, eligible participants will undergo a baseline visit where initial assessments, including PET scans, will be conducted to measure the binding potential of **[18F]LBT-999** to presynaptic dopamine membrane transporters in the striatum. Subsequent follow-up visits will occur at specified intervals to monitor changes in the dopaminergic network and assess neurological outcomes using scales such as the CRS-R and DRS. The end-of-study visit will conclude the trial, where final assessments will be made, and data will be collected for analysis.

The expected length of participant involvement is approximately one year, with conditions for early termination including withdrawal of consent, adverse events, or any medical condition that contraindicates continued participation. The primary endpoint is to compare the level of **[18F]LBT-999** binding in the striatum between the TC-COMA group and control subjects. Secondary endpoints include assessing binding levels throughout the dopaminergic network and brainstem, and evaluating the links between metabolic, structural, and functional changes in the brain. The trial aims to provide insights into the metabolic abnormalities of the dopaminergic network in comatose patients, potentially informing future therapeutic strategies.

The clinical trial involves the use of the experimental medication **18F-LBT-999**, a radiotracer designed for the characterization of dopaminergic network abnormalities in patients with severe traumatic brain injury. The pharmaceutical form of **18F-LBT-999** is a **solution for injection**, and it is administered via the **intravenous** route. The dosage is calculated based on the patient's body weight, with a maximum daily dose of 3 megabecquerels per kilogram (MBq/kg). The total dose administered over the course of the treatment period is also capped at 3 MBq/kg. The maximum treatment period is limited to one day. The active substance in **18F-LBT-999** is methyl (1R,2S,3S,5S)-8-[(E)-4-(18F)fluoranylbut-2-enyl]-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate, which is of chemical origin.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the administration of the experimental radiotracer **18F-LBT-999**. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol. The trial aims to provide insights into the metabolic abnormalities of the dopaminergic network within the striatum of comatose patients, utilizing multimodal neuroimaging approaches.

Efficacy in this clinical trial will be assessed by evaluating the **metabolic abnormalities** in the dopaminergic network of patients with traumatic coma (TC-COMA group) using the radiotracer [18F]LBT-999. The primary endpoint involves measuring the level of [18F]LBT-999 binding to presynaptic dopamine membrane transporters located in the striatum, specifically the caudate nuclei and putamen. This will be assessed through PET scans, and the binding level will be expressed as the average Binding Potential (BP) in the striatum. The results will be compared with those of a control group.

Secondary endpoints include assessing the level of [18F]LBT-999 binding throughout the dopaminergic network and brainstem, expressed by the mean BP and the Standard Uptake Value ratio (SUV-r) within each region of interest (ROI), such as the striatum, pallidum, substantia nigra, and brainstem. These measurements will be compared between the TC-COMA group and the control group, as well as between the TC-COMA group and the TC-ROS group. Additionally, the trial will explore the links between metabolic changes in the dopaminergic network and structural and functional changes, using parameters collected by PET and MRI in all traumatic brain injury patients (TC-COMA and TC-ROS).

Motor behavioral signatures will be evaluated using the MDS-UPDRS scale, and patients' neurological outcomes will be assessed at 3 months, 6 months, and 1 year post-CT using the CRS-R and Disability Rating Scale (DRS). Quality of life will be measured using the QOLIBRI. These assessments will provide comprehensive data on the efficacy of the intervention in characterizing dopaminergic pathway abnormalities and recovery biomarkers in the study population.