Assessment of [18F]Befiradol in PET-MRI for Pathophysiological Analysis of Episodic Cluster Headache in Active vs. Inactive Disease Phases

The primary objective of this study is to assess the difference in **[18F]F13640** fixation, perfusion, brain activity, and functional connectivity between the active and inactive periods of episodic cluster headache (AVF) in patients. This evaluation is clinically relevant as it aims to enhance the understanding of the pathophysiology of cluster headaches, potentially leading to improved diagnostic and therapeutic strategies.

Secondary objectives include:

• Evaluation of the availability of 5-HT1A receptors in patients during active periods in the crisis and inter-crisis phases using PET data.
• Assessment of the difference in density of functional 5-HT1A receptors in patients during inactive periods compared to controls using PET data.
• Comparison of the density of functional 5-HT1A receptors in patients during active periods in crisis and inter-crisis phases with the control group using PET data.
• Evaluation of brain activity in patients during active periods in seizure and inter-seizure phases using activation fMRI data.
• Comparison of cerebral perfusion and functional connectivity networks in patients during inactive periods compared to the control group using fMRI data.
• Comparison of cerebral perfusion and functional connectivity networks in active patients during seizure and inter-seizure phases compared to the control group using fMRI data.

The clinical trial focuses on **nervous system diseases**, specifically targeting a population of male patients diagnosed with episodic autonomic vascular function (AVF). The study includes participants aged between 20 and 45 years, with a weight range of 50 to 110 kg. Participants were selected based on specific criteria, including the occurrence of algic crises between 11:00 a.m. and 9:00 p.m., and the absence of any psychiatric or neurological history other than AVF. Additionally, individuals with a history of head trauma resulting in loss of consciousness for more than 30 minutes were excluded. All participants are required to be affiliated with a social security or similar system and must not be under any legal protection measures. The trial does not include female subjects or vulnerable populations. The sponsor has not provided information regarding the total number of participants involved in the study.

The clinical trial is designed to explore the pathophysiology of **cluster headache** using PET-MRI technology with the investigational product **befiradol (18F)**. This trial is a Phase 4, randomized, double-blind, controlled study, aiming to assess differences in PET and MRI data between active and inactive periods of the disease in patients with episodic cluster headaches. The trial is expected to commence recruitment on January 1, 2025, and conclude by January 1, 2028. Participants will be involved in the study for a maximum treatment period of one day, with a total dose of 150 MBq of the investigational product administered via injection.

The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, weight, and medical history, followed by study visits during both active and inactive periods of the disease. The primary endpoints include the comparison of functional receptor density maps and regional cerebral blood flow maps between these periods, as well as the analysis of functional connectivity through BOLD signal fluctuations. Secondary endpoints will further explore these parameters before, during, and after headache attacks. The end-of-study visit will involve a final assessment to gather comprehensive data for analysis.

Participants are expected to meet specific inclusion criteria, such as being male, aged between 20 and 45 years, and having no significant psychiatric or neurological history other than cluster headaches. Conditions that may lead to early termination from the study include non-compliance with study procedures or the emergence of any exclusion criteria during the trial. The trial's methodology ensures rigorous data collection and analysis to achieve its objectives, contributing valuable insights into the pathophysiology of cluster headaches.

The clinical trial involves the administration of **befiradol (18F)**, an experimental radiopharmaceutical agent, utilized for the exploration of the pathophysiology of cluster headache. The active substance, also known by its synonyms **[18F]-NLX-112**, **[18F]-F13640**, and **BEFIRADOL F-18**, is a chemically synthesized compound. The pharmaceutical form of the medication is **injectable**, and it is administered via **injection**. The maximum daily dose is set at 150 MBq (megabecquerel), with the same amount being the maximum total dose permissible within a single treatment period, which is limited to one day. The administration of the drug is conducted under the auspices of Hospices Civils de Lyon, ensuring adherence to the specified dosing regimen.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are employed. The focus remains solely on the investigational use of **befiradol (18F)** to assess its fixation in patients with episodic cluster headache during both active and inactive periods of the disease. Participant compliance with the dosing schedule is monitored to ensure the integrity of the trial data and the safety of the participants. The trial does not include any pediatric formulations, and the investigational product is not classified as an orphan drug.

Efficacy in this clinical trial will be assessed by evaluating the differences in **functional receptor density maps** and **regional cerebral blood flow maps** between the active and inactive periods of **cluster headache**. The primary endpoints include the comparison of these maps and the correlations of BOLD (Blood Oxygen Level Dependent) fluctuations between distant brain regions, which reflect the functional connectivity of patients during the two periods. Secondary endpoints involve similar comparisons and correlations, but they are further detailed to include assessments before, during, and after a headache attack. The variation of the BOLD signal during the active period will also be analyzed. These assessments will be conducted using PET-MRI imaging techniques, which allow for the detailed observation of brain activity and connectivity. The trial aims to provide insights into the pathophysiology of cluster headaches by examining these parameters in a controlled clinical setting.