Effect of xenon on brain injury, neurological outcome and survival in patients after aneurysmal subarachnoid hemorrhage

The primary objective of this study is to explore the **neuroprotective** properties of xenon in patients following aneurysmal subarachnoid hemorrhage (SAH). This is clinically relevant as SAH is a critical condition that can lead to significant neurological damage, and identifying potential neuroprotective agents could improve patient outcomes and survival rates.

Secondary objectives include:

• Exploring the neuroprotective effect of xenon on white matter injury in various brain regions.
• Assessing the incidence and severity of early brain injury (EBI) and delayed cerebral ischemia (DCI) post-SAH.
• Monitoring the incidence of adverse events, serious adverse events, and suspected unexpected serious adverse reactions (SUSARs).
• Investigating the inflammatory process, including microglia activation and cerebrospinal fluid (CSF) cytokine levels.
• Evaluating the need and duration of intracerebral pressure (ICP) treatments.
• Measuring plasma catecholamine levels and the release of biomarkers such as hs troponin-T, neuron-specific enolase (NSE), neurofilament light (NF-L), glial fibrillary acidic protein (GFAP), calcium-binding protein S100B, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), total tau, and cytokines.
• Exploring predictive values of MRI techniques and pathophysiological pathways post-SAH, and developing prognostication models for EBI, DCI, and neurological outcomes.
• Assessing the safety and performance of the xenon delivery device Akzent X Color in comparison to standard ventilatory parameters.

The clinical trial involves participants who have experienced an **aneurysmal subarachnoid hemorrhage** requiring ventilatory care in an intensive care unit. The study population includes both male and female subjects, aged 18 years and older, who have experienced a deterioration of consciousness to Hunt-Hess grades 3-5 and are intubated. Participants must have a Glasgow Coma Scale (GCS) score between 3 and 12, obtained off neuromuscular blocking agents, and xenon treatment must be initiated within 6 hours after the onset of subarachnoid hemorrhage symptoms. The trial population was selected based on these criteria, and informed consent was obtained from the next of kin or legal representative. The sponsor has not provided information regarding the total number of participants. The study includes a vulnerable population, and both genders are represented. No specific lifestyle considerations such as diet or physical activity are mentioned in the trial data.

The clinical trial is designed to evaluate the **neuroprotective** properties of **xenon** in patients who have experienced an aneurysmal subarachnoid hemorrhage (SAH) and require ventilatory care in an intensive care unit. This study is a randomized, double-blind, controlled trial, with a primary objective to assess the effect of xenon on brain injury, neurological outcomes, and survival. The trial is expected to commence on October 1, 2024, with an estimated completion date of December 1, 2035. The trial will involve the administration of xenon via inhalation, with a maximum daily dose of 100 liters and a total dose not exceeding 1000 liters over a treatment period of up to 2 days. The comparator, **oxygen**, will be administered similarly, with a maximum daily dose of 1000 liters and a total dose not exceeding 100,000 liters over a treatment period of up to 3 days.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of SAH, and the ability to initiate xenon treatment within 6 hours of symptom onset. Follow-up visits will be scheduled to monitor safety and efficacy outcomes, including primary and secondary endpoints such as global fractional anisotropy of white matter and safety assessments of xenon. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 14 days post-SAH symptom onset for monitoring purposes. Conditions that may lead to early termination from the study include adverse events, serious adverse events, or any other medical reasons deemed necessary by the investigator.

The clinical trial involves the administration of **XENON**, a **medicinal gas, liquefied**, used as the experimental treatment. The active substance is **xenon**, classified as a noble gas. The pharmaceutical form is a medicinal gas intended for **inhalation use**. The dosage is measured in liters, with a maximum daily dose of 100 liters and a total maximum dose of 1000 liters over the treatment period. The maximum treatment period is set at 2 days. Participant compliance with the inhalation regimen will be monitored throughout the trial to ensure adherence to the dosing schedule.

In addition to the experimental treatment, the trial includes a comparator treatment using **CONOXIA 100%**, a **medicinal gas, cryogenic**. The active substance in this comparator is **oxygen**, provided by Linde Gas. The pharmaceutical form is also a medicinal gas for **inhalation use**. The maximum daily dose for this treatment is 1000 liters, with a total maximum dose of 100,000 liters over a maximum treatment period of 3 days. Compliance with the administration of the comparator treatment will be similarly monitored to ensure accurate dosing and adherence to the trial protocol.

The efficacy of the clinical trial investigating the neuroprotective properties of **xenon** in patients after aneurysmal subarachnoid hemorrhage (SAH) will be assessed using both primary and secondary endpoints. The primary endpoint is the global fractional anisotropy of white matter as measured by diffusion tensor imaging (DTI). It is hypothesized that white matter damage will be less severe in patients treated with xenon, indicated by a significantly higher global fractional anisotropy in the xenon group compared to the control group, as assessed with the first MRI.

Secondary endpoints include fractional anisotropy of white matter at specific brain regions, safety and tolerability of xenon, and a composite of radiological early brain injury (EBI) and delayed cerebral ischemia (DCI). Additional secondary endpoints involve measurements such as intracranial pressure (ICP) levels, need for ICP therapies, plasma catecholamine levels, and differences in biomarkers like neuron-specific enolase (NSE) and neurofilament light (NF-L). The trial will also explore the development of prognostication models using a combination of brain imaging, biomarkers, clinical data, and metabolomics, applying artificial intelligence and machine learning techniques.

Safety assessments will include the evaluation of adverse events, serious adverse events, and suspected unexpected serious adverse reactions (SUSARs) over a one-year follow-up period. The safety of the xenon delivery device, Akzent X Color, will be assessed through ventilator parameters, blood gas values, and related adverse events. Interim and final analyses will compare safety parameters between the xenon and control groups. The trial is set to conclude by December 2035, with recruitment starting in October 2024.