Evaluation of Cholinergic and Dopaminergic Pathway Integrity in Post-Stroke Apathy Using Fluoroethoxybenzovesamicol F-18 and Fluorodopa (18F)

The primary objective of this study is to compare the integrity of **cholinergic** and **dopaminergic** pathways in patients exhibiting apathy versus those without apathy, 3 to 7 months post-stroke. This comparison will be conducted by evaluating the binding intensity of cholinergic and dopaminergic tracers between the two groups, matched for age and sex. Understanding these differences is clinically relevant as it may elucidate the pathophysiological mechanisms underlying apathy, potentially guiding future therapeutic strategies.

Secondary objectives include:

• Assessing whether modifications in cholinergic and dopaminergic activities correlate with the clinical expression of apathy.
• Evaluating the link between cholinergic and dopaminergic dysfunctions and alterations in the functional organization of the resting brain.
• Investigating the association between changes in cholinergic and dopaminergic activities and specific local changes in white matter microstructure.
• Exploring whether the binding intensity of cholinergic and dopaminergic tracers is influenced by cerebral blood flow disorders, as indicated by arterial spin labeling sequences.

The clinical trial involves a total of 30 participants, divided into two groups: 15 **apathetic** and 15 unapathetic patients. The study population consists of both male and female subjects, aged between 18 and 74 years, who have experienced a stroke 3 to 7 months prior to the study. Participants were selected based on specific criteria, including a Rankin score of less than or equal to 2, and the presence or absence of apathy as demonstrated by AI scales. All participants are required to be affiliates or beneficiaries of a social security scheme and must use highly effective contraceptive methods. The trial includes a vulnerable population, and informed consent is mandatory. The sponsor has not provided information on the general health status or lifestyle considerations of the participants.

The clinical trial is designed to evaluate the **in vivo** involvement of the cholinergic and dopaminergic systems in the pathophysiology of apathy. This study is a randomized, double-blind, controlled trial involving 30 participants, divided into two groups: apathetic and non-apathetic patients, 3 to 7 months post-stroke. The primary objective is to compare the binding intensities of cholinergic and dopaminergic tracers, specifically **[18F]-FEOBV** and **[18F]-FDOPA**, between these groups. Secondary endpoints include assessing the clinical severity of apathy, functional connectivity parameters via MRI, diffusion tensor imaging parameters, and cerebral blood flow.

The trial is expected to last approximately four years, with an estimated recruitment start date of April 13, 2021, and an estimated end date of May 13, 2025. Participants will be involved in the study for a maximum treatment period of one day, with the primary intervention being the administration of the investigational products, **Fluoroethoxybenzovesamicol F-18** and **Dopacis 90 MBq/mL**, both in solution for injection form. The inclusion visit will involve screening for eligibility based on criteria such as age, Rankin score, and apathy status, as well as obtaining informed consent. Follow-up visits will be scheduled to monitor the participants' response to the intervention and to collect data on the primary and secondary endpoints. The end-of-study visit will conclude the participants' involvement, ensuring all necessary data is collected and any adverse events are addressed.

Participant involvement may be terminated early if they withdraw consent, experience adverse events that contraindicate continued participation, or if they fail to comply with the study protocol. The trial is not classified as a low-intervention study and is categorized as a therapeutic confirmatory clinical trial. The study aims to provide insights into the neurobiological mechanisms underlying apathy, potentially informing future therapeutic strategies.

The clinical trial involves the administration of **Fluoroethoxybenzovesamicol F-18**, a radiopharmaceutical used to assess the integrity of cholinergic pathways. This experimental medication is provided in the form of a **solution for injection**. The active substance, **fluoroethoxybenzovesamicol F-18**, is of chemical origin. The maximum daily and total dose is 262.5 MBq, administered as a single injection. The administration route is intravenous, and the treatment period is limited to one day. The product is manufactured by the Centre Hospitalier Universitaire de Bordeaux. Participant compliance with the dosing schedule will be monitored through direct observation during administration.

The comparator treatment in this study is **Dopacis 90 MBq/mL, solution injectable**, which contains the active substance **Fluorodopa (18F)**. This non-experimental treatment is also a **solution for injection** and is used to evaluate dopaminergic pathways. The maximum daily and total dose is 2 MBq/kg, administered intravenously. The treatment period is similarly restricted to one day. This product is manufactured by CIS BIO INTERNATIONAL. As with the experimental medication, compliance will be ensured through direct observation during administration.

Efficacy in this clinical trial will be assessed by evaluating the integrity of cholinergic and dopaminergic pathways in patients with and without apathy, 3 to 7 months post-stroke. The primary endpoint for efficacy evaluation is the binding intensities of **[18F]-FEOBV** and **[18F]-FDOPA** tracers. These tracers will be used to compare the binding intensity between apathetic and non-apathetic patients, matched by age and sex.

Secondary endpoints include the clinical severity of apathy, functional connectivity parameters measured with MRI, diffusion tensor imaging parameters such as fractional anisotropy and mean diffusivity, and cerebral blood flow. These parameters will provide additional insights into the functional and structural changes associated with apathy post-stroke. The assessments will be conducted using validated imaging techniques and scales to ensure accurate and reliable data collection and analysis.