Efficacy and Safety of Glenzocimab as an Adjunct to Mechanical Thrombectomy in Acute Ischemic Stroke: A Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2024-514352-32-00
Protocol: APHP201028
Sponsor: Assistance Publique Hopitaux De Paris

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Diseases & Conditions

Ischaemic stroke

Objectives

The primary objective of this study is to evaluate the **efficacy** of glenzocimab as an adjunct to endovascular therapy (EVT) compared to EVT plus placebo, with or without the addition of intravenous thrombolysis (IVT), on the functional outcome at day 90 in patients with acute ischemic stroke. This is clinically relevant as it aims to determine whether glenzocimab can improve recovery and functional independence in stroke patients, potentially leading to better long-term outcomes.

Secondary objectives include:

Evaluating the impact of glenzocimab on overall survival at day 90 and 1 year.
Assessing its effect on reperfusion at the end of EVT, early clinical improvement at 24 hours, symptomatic and overall intracranial hemorrhage at 24 hours, serious adverse events (SAEs), suspected unexpected serious adverse reactions (SUSARs) at 24 hours and day 90, bleeding-related events (BREs) at 24 hours and day 90, and quality of life at day 90 and 1 year.
Evaluating the cost-effectiveness of glenzocimab in addition to EVT compared to EVT plus placebo.

Participants

The clinical trial involves participants diagnosed with **acute ischemic stroke**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have no significant pre-stroke disability, as indicated by a pre-stroke modified Rankin Scale (mRS) score of 0 or 1. The trial population was selected based on specific clinical criteria, including the indication for endovascular therapy (EVT) within a 0 to 24-hour time window, with or without intravenous thrombolysis, and presenting with a clinico-radiological mismatch. The trial also includes individuals with occlusion of the cervical or intracranial internal carotid artery or the proximal middle cerebral artery, as confirmed by magnetic resonance angiography or CT angiography. The study encompasses a vulnerable population, and informed consent is obtained from participants or their representatives. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include post-menopausal women or women of child-bearing potential with a negative pregnancy test and effective birth control measures. Participants must also be affiliated with social security or any health insurance.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of **glenzocimab** as an add-on therapy to mechanical thrombectomy in patients with **acute ischemic stroke**. The trial will compare the outcomes of patients receiving glenzocimab in addition to endovascular therapy (EVT) against those receiving EVT plus placebo. The primary objective is to assess the functional outcome at day 90, with the primary endpoint being the modified Rankin Scale (mRS) score at day 90 ± 15 days. Secondary endpoints include favorable functional outcomes, overall survival, early reperfusion outcomes, and safety assessments such as the incidence of intracranial hemorrhages and adverse events.

The trial is expected to last until July 23, 2025, with recruitment having commenced on January 3, 2023. Participants will be involved in the study for a period that includes the initial treatment and follow-up assessments up to 90 days post-treatment. The study visits are structured as follows: an initial **screening visit** to confirm eligibility based on criteria such as age, pre-stroke disability, and specific clinical and radiological findings. Following the screening, participants will undergo the treatment phase, which involves the administration of the investigational product or placebo. Subsequent follow-up visits will occur at 24 hours, 7 days or discharge, 30 days, and 90 days to monitor efficacy and safety outcomes. The **end-of-study visit** will coincide with the final assessment at day 90.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial is conducted under strict adherence to ethical guidelines, ensuring informed consent is obtained from all participants or their representatives. The study is not classified as low intervention and is categorized as a Phase 2/3 trial, reflecting its exploratory and confirmatory objectives in evaluating the therapeutic potential of glenzocimab in this patient population.

Treatment

The clinical trial involves the administration of **Glenzocimab**, an experimental medication, which is provided in the form of a **solution for infusion**. Glenzocimab is a protein-based therapeutic agent developed by ACTICOR BIOTECH SAS. The active substance, glenzocimab, is administered intravenously. The maximum daily dose and total dose are both set at 1 gram, with a treatment period limited to one day. The primary objective of the trial is to assess the efficacy of glenzocimab as an add-on therapy to mechanical thrombectomy in patients with acute ischemic stroke.

In addition to the experimental treatment, the study utilizes a **0.9% Sodium Chloride Solution** as a placebo. This solution is also administered as a solution for infusion. The placebo serves as a comparator to evaluate the efficacy and safety of glenzocimab when used in conjunction with endovascular therapy (EVT), with or without intravenous thrombolysis (IVT). The use of the placebo is integral to maintaining the double-blind nature of the trial, ensuring unbiased assessment of the treatment outcomes.

Efficacy

The efficacy of Glenzocimab as an add-on therapy to mechanical thrombectomy for acute ischemic stroke will be assessed through a series of predefined endpoints. The primary efficacy endpoint is the functional outcome at day 90, evaluated using the modified Rankin Scale (mRS) at day 90, with an allowable variation of plus or minus 15 days. Secondary efficacy endpoints include a favorable functional outcome defined by an mRS score of 2 or less at day 90, the proportion of patients with severe handicap (mRS 4-6) at day 90, overall survival at day 90 and one year, and early reperfusion outcomes. These early outcomes will be measured by stroke volume via brain imaging at 24 hours, reperfusion at the end of the mechanical thrombectomy procedure assessed by the expanded Thrombolysis in Cerebral Infarction (eTICI) score, and early neurological improvement as indicated by the National Institutes of Health Stroke Scale (NIHSS) at 24 hours. Additionally, patient-reported outcomes will be collected using the EQ-5D-5L at day 90 and one year.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age 18 years or older (Age≥18 years)
No significant pre-stroke disability (pre-stroke mRS must be equal to 0 or 1);
3.Indication of EVT within the time-window of 0 to 24 hrs in participants, treated with or without intravenous thrombolysis, and presenting with a clinico-radiological mismatch (defined by a NIHSS≥10 and an ASPECT score≥6)
Occlusion of the cervical or intracranial internal carotid artery (ICA) or the proximal middle cerebral artery (MCA - M1 and/or M2), on magnetic resonance angiography (MRA) or, when this is not possible, on CT angiography (CTA);
Informed consent signed: • By the patient, • Or informed consent signed by a family members/trustworthy person if his condition does not allow him to express his consent by written as per L. 1111-6, • In a situation urgently and in the absence of family members/trustworthy person, the patient can be enrolled. The consent to participate to the research will be requested as soon as the condition of the patient will allow him to consent.
Post-menopausal women defined as not having menses for 12 months without an alternative medical cause. For WOCBP, a highly effective birth control method should be in place that can achieve a failure rate of less than 1% per year that should last for at least 2 months after IMP administration.
Women of child-bearing potential (WOCBP) must have a negative serum/urine pregnancy test at baseline. Women of childbearing potential, i.e., fertile, are defined as women following menarche and until becoming post-menopausal unless permanently sterile, i.e., having undergone hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Affiliation to social security or any health insurance

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Exclusion Criteria

Contraindications to EVT;
Contraindication to contrast agents
Pre-existing neurologic and psychiatric disease with mRS ≥ 2;
Unknown symptom’s onset or last seem well > 24 hours;
Patients under or needing immediate DAPT administration;
Significant mass effect with midline shift as confirmed on CT/MRI;
Gastrointestinal or urinary tract hemorrhage in previous 21 days;
Patient with intracranial haemorrhage
Known Platelet count <100 000 mm3
Pregnant or breastfeeding woman;
Known hypersensitivity to glenzocimab or to any of the excipients;
Known Severe renal insufficiency (Grades 4-5) with a glomerular filtration rate < 30mL/Min/1.73m2;
Participation in another interventional clinical trial within 30 days prior to the inclusion.
Persons deprived of their liberty by a judicial or administrative decision, persons subject to psychiatric care under sections L.3212-1 et L.3213-1 and persons admitted to a health or social institution for purposes other than research (L.1121-6)
Adults subject to a legal protection measure (L.1121-8)
The patient or his/her family (if the patient is unable to give his/her opinion) expresses an inability to return for protocol visits
patients receiving anticoagulants (i.e. heparin within 48 hours and an elevated aPTT -greater than upper limit of normal for laboratory-; (current use of oral anticoagulants (ex: warfarin) and INR >1.7; Current use of direct thrombin inhibitors or direct factor Xa inhibitors, as already mentioned in the non-authorized concomitant treatments
patients who have already received another humanized fragment of monoclonal antibody with a suspicion of hypersensitivity