A Phase IIa, Randomized, Open-label, Proof-of-Concept Study to Evaluate Safety, Tolerability and Efficacy of Ir CPI in Patients with Spontaneous Intracerebral Haemorrhage - the BIRCH study

The primary objective of this study is to assess the **safety** and **tolerability** profile of Ixodes ricinus Contact Phase Inhibitor (Ir-CPI) in patients with spontaneous intracerebral haemorrhage (ICH). Evaluating the safety and tolerability of Ir-CPI is clinically relevant as it provides essential information on the potential risks and adverse effects associated with the treatment, which is crucial for determining its suitability for further clinical use in this patient population.

Secondary objectives include:

• To obtain the first efficacy estimate of Ir-CPI on the evolution of perihaematomal oedema (PHO) and haemorrhage volumes.
• To evaluate the pharmacokinetics of Ir-CPI in ICH patients.
• To assess the pharmacodynamics of Ir-CPI in ICH patients.

The clinical trial involves participants diagnosed with **spontaneous intracerebral haemorrhage**. The study population includes both male and female patients aged 18 years and older. Participants are required to have a first-ever, spontaneous, supratentorial intracerebral haemorrhage with a volume between 5 mL and 60 mL. The trial includes individuals with a Glasgow Coma Scale best motor score of no less than 5 and a Modified Rankin Scale score ranging from 0 to 2. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on specific inclusion criteria, ensuring that participants have provided written informed consent. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating a careful selection process to ensure participant safety and compliance with ethical standards.

The clinical trial is a **Phase IIa**, randomized, open-label, proof-of-concept study designed to evaluate the safety, tolerability, and efficacy of **Ixodes ricinus contact phase inhibitor** (Ir-CPI) in patients with **spontaneous intracerebral haemorrhage**. The trial is expected to run from April 2023 to May 2028. Participants will be randomly assigned to receive the investigational product, which is administered as a **solution for infusion** via **intravenous use**. The maximum daily dose is 22 mg/kg, with a total dose not exceeding 38.70 mg/kg over a treatment period of up to two weeks.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age (≥18 years), informed consent, and specific clinical parameters like the Glasgow Coma Scale and Modified Rankin Scale scores. Following the screening, participants will undergo regular follow-up visits to assess primary endpoints, including adverse event monitoring, ECGs, vital signs, physical and neurological examinations, and laboratory tests such as biochemistry, haematology, and coagulation profiles. Secondary endpoints will evaluate changes in haemorrhage volumes via CT scans and plasma concentrations of Ir-CPI.

The end-of-study visit will conclude the participant's involvement, summarizing the safety and efficacy data collected throughout the trial. Participant involvement is expected to last for the duration of the treatment period, with additional time allocated for follow-up assessments. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or withdrawal of consent. The trial's design and procedures are meticulously planned to ensure the collection of robust data while prioritizing participant safety and adherence to ethical standards.

The clinical trial involves the administration of **Ixodes ricinus contact phase inhibitor** as the experimental medication. This investigational product is provided in the form of a **solution for infusion**. The active substance, also known by the sponsor product code **Ir-CPI**, is derived from a protein of other origin. The pharmaceutical form is specifically designed for **intravenous use**. The dosing regimen for this trial includes a maximum daily dose of 22 mg/kg and a maximum total dose of 38.70 mg/kg, administered over a treatment period of up to 2 days. The primary objective of the study is to evaluate the safety and tolerability of Ir-CPI in patients with spontaneous intracerebral hemorrhage.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified for this study. The trial is designed as a Phase IIa, randomized, open-label, proof-of-concept study, focusing on the assessment of the investigational product's safety and efficacy. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol. The investigational product is not formulated for pediatric use, and it is not classified as an orphan drug. The study is conducted under the sponsorship of Bioxodes, with the investigational product being authorized for use in this clinical setting.

The efficacy of the investigational product, **Ixodes ricinus contact phase inhibitor** (Ir-CPI), in the clinical trial will be assessed through both primary and secondary endpoints. The primary endpoints focus on safety and tolerability, including monitoring of adverse events and serious adverse events (SAEs), electrocardiograms (ECGs), vital signs, physical examinations, neurological evaluations, and laboratory tests such as biochemistry, hematology, and coagulation (activated partial thromboplastin time, aPTT).

Secondary endpoints are designed to evaluate the efficacy of Ir-CPI in patients with spontaneous intracerebral hemorrhage. These include changes from baseline in perihematomal edema (PHO) and hemorrhage volumes as measured by computed tomography (CT) scans, changes in Ir-CPI plasma concentrations, and changes in aPTT ratio. Additionally, the trial will assess residual activities of coagulation factors XI (FXI) and XII (FXII), as well as the percentages of inhibition of FXI and FXII procoagulant activities. These parameters will be measured at specified timepoints throughout the study to determine the therapeutic impact of Ir-CPI.