Efficacy of Intravenous Glenzocimab in Patients with Anterior Ischemic Stroke and Large Core Eligible for Endovascular Therapy

The primary objective of this study is to evaluate the **efficacy** of intravenous infusion of glenzocimab compared to placebo in patients with acute ischemic stroke (AIS) who have a baseline large ischemic core and are eligible for endovascular therapy (EVT). The focus is on determining the proportion of patients achieving a good functional outcome at 3 months. This is clinically relevant as it aims to improve recovery and quality of life in patients with significant ischemic damage, potentially offering a new therapeutic option.

Secondary objectives include:

• Assessing the rate of no-reflow phenomenon on post-EVT perfusion imaging.
• Evaluating the symptomatic and any intracranial hemorrhage rates at 24-36 hours.
• Determining the all-cause mortality rate and distribution of the modified Rankin Scale (mRS) score at 3 months.
• Assessing favorable functional and cognitive outcomes at 3 and 12 months.
• Evaluating the final post-EVT complete and successful recanalization.
• Assessing the need for decompressive hemicraniectomy surgery and neurological improvement at 24 hours.
• Evaluating infarct growth at 24 hours and the number of EVT passes.
• Assessing the duration of the EVT procedure and the occurrence, nature, and severity of adverse events.
• Evaluating the cost-effectiveness of IV glenzocimab compared to placebo over a 12-month follow-up period.

The clinical trial involves participants diagnosed with **ischemic stroke with large core**. The study population includes both male and female subjects, with an age range of over 18 years. Participants are selected based on their eligibility for endovascular therapy (EVT) within a 0 to 24-hour time window, with or without prior intravenous thrombolysis. The trial population is characterized by individuals presenting with a baseline infarct core volume assessed on MRI or CT scan with an ASPECTS score of less than 6. All women of childbearing potential are required to have a negative pregnancy test at baseline. The trial includes a vulnerable population, and participants must be affiliated with social security or any health insurance. Informed consent is obtained from the patient or a family member/trustworthy person if the patient's condition does not allow for written consent. The sponsor has not provided the total number of participants involved in the study.

The clinical trial is designed to evaluate the efficacy of **glenzocimab** in patients with **ischemic stroke** with a large core, eligible for endovascular therapy. This is a multicentric, randomized, double-blind, placebo-controlled trial, categorized as Phase 4. The primary objective is to assess the efficacy of intravenous infusion of glenzocimab compared to placebo on the proportion of patients achieving a good functional outcome at three months, as measured by the modified Rankin Scale (mRS). The trial is expected to commence recruitment in May 2024 and conclude by June 2027.

Participants will be randomly assigned to receive either glenzocimab, a placebo, or a comparator product. The trial involves a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, stroke characteristics, and baseline infarct core volume. Following randomization, participants will receive the assigned treatment via intravenous infusion or injection. The maximum treatment period is one day, with glenzocimab administered as a solution for infusion, and the comparator as a solution for injection.

Follow-up visits will occur at specified intervals to monitor the participants' health status and collect data on primary and secondary endpoints. These endpoints include the incidence of no-reflow phenomenon, symptomatic intracranial hemorrhage, and overall functional outcomes at three and twelve months. The end-of-study visit will assess the final outcomes, including the mRS score and any adverse events. The expected duration of participant involvement is up to twelve months, with conditions for early termination including withdrawal of consent or significant adverse events.

Inclusion criteria require participants to be over 18 years old, with acute ischemic stroke due to isolated proximal anterior large vessel occlusion, and eligible for endovascular therapy within a 24-hour window. Exclusion criteria are not specified in the provided data. The trial aims to provide comprehensive data on the safety and efficacy of glenzocimab, contributing to the understanding of its potential benefits in treating ischemic stroke with a large core.

**Glenzocimab** is the experimental medication used in this clinical trial. It is formulated as a **solution for infusion** and is administered via **intravenous use**. The maximum daily dose is 1000 mg, with a total dose not exceeding 1000 mg over the treatment period, which is limited to one day. Glenzocimab is a protein-based substance developed by ACTICOR BIOTECH SAS, and it is identified by the sponsor product code ACT017. The administration of Glenzocimab is monitored to ensure compliance with the dosing schedule and to assess its efficacy in patients with acute ischemic stroke (AIS) with a large ischemic core eligible for endovascular therapy (EVT).

**GADOVIST 1,0 mmol/mL**, a non-experimental treatment, serves as a comparator in this study. It is a **solution for injection** containing the active substance **gadobutrol**, a chemical compound. This product is administered via **intravenous injection** with a maximum daily and total dose of 15 mL, also limited to a single day of treatment. Manufactured by BAYER HEALTHCARE, GADOVIST is used as a paramagnetic contrast agent, and its role in the trial is to provide a standard-of-care reference for evaluating the effects of Glenzocimab.

The **0.9% Sodium Chloride solution** is utilized as a placebo in this trial. It is administered via **intravenous use** with a maximum daily and total dose of 100 mL, restricted to one day of treatment. This solution serves as a control to assess the efficacy of Glenzocimab by providing a baseline for comparison. The administration of the placebo is carefully monitored to ensure participant compliance and to maintain the integrity of the trial's double-blind design.

The efficacy of Glenzocimab in patients with acute ischemic stroke (AIS) with a large ischemic core eligible for endovascular therapy (EVT) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the functional outcome at 3 months, evaluated using the modified Rankin Scale (mRS) score, dichotomized into 0 to 3 versus 4 to 6. This assessment will be conducted via phone by trained professionals who are blinded to the treatment allocation.

Secondary endpoints include a variety of measures: the proportion of patients experiencing the No-reflow (NR) phenomenon on post-EVT perfusion imaging, the incidence of symptomatic and any intracranial hemorrhage assessed by the Heidelberg classification on a brain CT scan performed 24-36 hours post-EVT, and the all-cause death rate at 3 months. Additional secondary endpoints involve the distribution of mRS scores at 3 months, the proportion of patients achieving a favorable functional outcome (mRS score 0-2) at 3 and 12 months, and the score of the MoCA 5-minutes at 3 and 12 months.

Further assessments include the incidence of complete and successful recanalization defined by the modified Thrombolysis in Cerebral Infarction (mTICI) score on post-EVT cerebral angiography, the proportion of patients undergoing decompressive hemicraniectomy surgery, and the proportion of patients with neurological improvement indicated by a decrease in NIHSS score greater than 8 points between baseline and 24-36 hours post-EVT. The study will also evaluate cerebral infarct volume growth between baseline and 24-hour brain MRI, the number of EVT passes, and the time between arterial puncture and recanalization occurrence. The incidence of serious and non-serious adverse events, including bleeding-related events, will be monitored, as well as the cost per additional patient with an mRS 0-3 with Glenzocimab use and cost per QALY gained at 12 months.