Phase II Evaluation of Anakinra on Cerebral Edema Post-Spontaneous Supratentorial Intracerebral Hemorrhage

The primary objective of this phase II clinical trial is to evaluate the effect of **high-dose** versus low-dose **anakinra** compared to standard medical management on the development of cerebral oedema following spontaneous supratentorial **intracerebral haemorrhage**. This is clinically relevant as cerebral oedema can exacerbate neurological damage and worsen patient outcomes. By assessing the efficacy of anakinra, a potential therapeutic strategy may be identified to mitigate secondary injury resulting from neuroinflammation in this patient population.

The clinical trial focuses on patients with **intracerebral haemorrhage**, specifically targeting individuals aged 18 years and older. The study population includes both male and female participants, with no specific exclusion based on gender. Participants are required to have a supratentorial non-traumatic intracerebral haemorrhage confirmed by CT, with a minimum haemorrhage volume of 10 mL, and the intervention must commence within 8 hours of symptom onset. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection process involves obtaining informed consent from the patient or their legal representative. The study population may include vulnerable individuals, although specific lifestyle considerations such as diet or physical activity are not detailed. The trial aims to assess the impact of high-dose versus low-dose anakinra on cerebral oedema development following spontaneous supratentorial intracerebral haemorrhage.

The clinical trial is designed to evaluate the effect of high-dose versus low-dose **anakinra** compared to standard medical management on cerebral oedema development following spontaneous supratentorial **intracerebral haemorrhage**. This is a phase II, randomized, double-blind, controlled trial. The trial is expected to commence recruitment on November 1, 2024, and conclude by September 30, 2025. Participants will be randomly assigned to receive either high-dose or low-dose anakinra, administered via injection, or standard medical management. The maximum treatment period for participants is three days, with a maximum daily dose of 2 mg/kg/h.

The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥ 18 years), confirmed supratentorial non-traumatic intracerebral haemorrhage by CT, and the ability to start the intervention within eight hours of symptom onset. Informed consent from the patient or their legal representative is required. Follow-up visits will be scheduled to monitor the primary endpoint, oedema extension distance (OED) determined by MRI, and secondary endpoints, including serious adverse events, serum inflammatory markers, and functional outcomes measured by mRS, Barthel index, and EQ-5D-5L score. The end-of-study visit will assess the overall outcomes and any long-term effects of the treatment.

Participant involvement is expected to last for the duration of the treatment period and follow-up assessments. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or withdrawal of consent by the participant or their legal representative. The trial aims to provide valuable insights into the therapeutic potential of anakinra in managing cerebral oedema post-intracerebral haemorrhage, contributing to the development of improved treatment protocols.

The clinical trial involves the administration of **anakinra**, a recombinant human interleukin-1 receptor antagonist, as the experimental medication. Anakinra is provided in a subcutaneous solution form, which is diluted in sodium chloride to create an intravenous solution for administration. The pharmaceutical form is identified as PHF00231MIG. The dosing regimen for anakinra is specified as a maximum daily dose of 2 mg/kg/h, with a total maximum dose of 2 mg/kg/h. The treatment period is limited to a maximum of 3 days. The route of administration is via injection, specifically intravenous, following dilution. The trial aims to evaluate the effects of high-dose versus low-dose anakinra on cerebral edema development after spontaneous supratentorial intracerebral hemorrhage.

In addition to the experimental treatment, participants will receive standard medical management as a non-experimental treatment. This standard-of-care therapy serves as a comparator to assess the efficacy of anakinra in the context of the trial. The study does not involve the use of a placebo. Compliance with the dosing schedule and administration protocol will be monitored throughout the trial to ensure adherence to the study design and to accurately assess the outcomes related to anakinra administration.

Efficacy in the clinical trial titled "Anakinra in Cerebral haemorrhage to Target secondary Injury resulting from Neuroinflammation - a phase II clinical trial" will be assessed using both primary and secondary endpoints. The primary endpoint is the **Oedema extension distance (OED)**, which will be determined using MRI. This measurement will provide insight into the development of cerebral oedema following spontaneous supratentorial intracerebral haemorrhage.

Secondary endpoints include the evaluation of (serious) adverse events, serum inflammatory markers such as IL-1β, IL-6, hsCRP, neutrophil, and total white blood cell counts. Additionally, the DCE-MRI measurement of the blood-brain barrier transfer constant (Ktrans) will be conducted. Functional outcomes will be assessed using the modified Rankin Scale (mRS), Barthel Index, and EQ-5D-5L score. These parameters will collectively provide a comprehensive assessment of the therapeutic effects of high-dose versus low-dose **anakinra** compared to standard medical management.