Glenzocimab for REperfusion in the Setting of Endovascular Therapy for Brain infarctioN: GREEN Study (GREEN)

Emergent reperfusion is the main goal for acute ischemic stroke therapy (AIS). Endovascular therapy (EVT) is recommended within 6 hrs of stroke onset, and up to 24 hrs following perfusion imaging criteria.

Despite the major benefit associated with MT, more than 50% of the patients remain disabled at 3 months. Reperfusion rates after MT are critical to determine functional outcome. However, complete reperfusion is obtained in only 50 % of the patients, due to, at least in part, erratic emboli and/or no-reflow processes. The aim of this study is to evaluate the efficacy of glenzocimab in addition to EVT and compared to EVT plus placebo, whether or not associated with ntravenous thrombolysis (IVT), on functional outcome at day 90.

Study Overview

• Status: Not yet recruiting
• Conditions: Stroke, Ischemic; Stroke, Acute
• Intervention / Treatment: Drug: Placebo; Drug: Glenzocimab

• Study Type: Interventional
• Enrollment (Anticipated): 260
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: mikael Mazighi, MD PHD; Phone Number: +33 1 49 95 25 97; Email: mikael.mazighi@aphp.fr
• Study Contact Backup: Name: matthieu resche-rigon, MDPHD; Phone Number: +33 142499742; Email: matthieu.resche-rigon@u-paris.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18 years or older (Age≥18 years)
2. 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;
4. Participants presenting with a target mismatch defined by an initial infarct volume (ischemic core) of less than 70 ml, a ratio of volume of ischemic tissue to initial infarct volume of 1.8 or more, and an absolute volume of potentially reversible ischemia (penumbra) of 15 ml or more on magnetic resonance imaging (MRI) or, when this is not possible, on perfusion computed tomography (CTP);
5. Occlusion of the cervical or intracranial internal carotid artery (ICA) or the proximal middle cerebral artery (MCA - M1 and M2), on magnetic resonance angiography (MRA) or, when this is not possible, on CT angiography (CTA);

6. 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.

7. 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.

   Birth control methods which may be considered as highly effective in WOCBP include:

   • combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (intravaginal, transdermal),
   • progestogen-only hormonal contraception associated with inhibition of ovulation (injectable, implantable)
   • intrauterine device (IUD),
   • intrauterine hormone-releasing system (IUS),
   • bilateral tubal occlusion,
   • vasectomized partner,

   Birth control methods which may be considered as highly effective for men and that should last for 4 months after IMP administration include:

   • vasectomy,
   • use of condom combined with a highly effective birth control method for their WOCB partner.

   Please note that hormonal contraception is a risk factor for thromboembolic events and attention should be called to reconsider it passed the acute stroke phase.

8. Women of child-bearing potential must have negative results of a plasma pregnancy test (serum betaHCG).
9. Affiliation to social security or any health insurance

Exclusion Criteria:

1. Contraindications to EVT;
2. Contraindication to contrast agents
3. Pre-existing neurologic and psychiatric disease with mRS ≥ 3;
4. Unknown symptom's onset;
5. Patients under or needing immediate DAPT administration;
6. Patients previously treated by tenecteplase within 24 hrs;
7. Significant mass effect with midline shift as confirmed on CT/MRI;
8. Gastrointestinal or urinary tract hemorrhage in previous 21 days;
9. Patient with intracranial haemorrhage
10. Platelet count <100 000 mm3;
11. Pregnant or breastfeeding woman;
12. Known hypersensitivity to glenzocimab or to any of the excipients;
13. Severe renal insufficiency (Grades 4-5) with a glomerular filtration rate < 30mL/Min/1.73m2;
14. Participation in another interventional clinical trial within 30 days prior to the inclusion.
15. 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)
16. Adults subject to a legal protection measure (L.1121-8)
17. The patient or his/her family (if the patient is unable to give his/her opinion) expresses an inability to return for protocol visits
18. patients receiving anticoagulants, as already mentioned in the non-authorized concomitant treatments
19. patients who have already received another humanized fragment of monoclonal antibody with a suspicion of hypersensitivity

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo of glenzocimab is 0.9%NaCl (Acticor Biotech) for IV administration. It is supplied for clinical trial use in vials of 50 mL. Two vials of placebo of glenzocimab should be administered concomitantly for eligible patients.
Experimental: Glenzocimab	Drug: Glenzocimab; Glenzocimab (ACT-017, Acticor Biotech) is formulated for IV administration as a sterile product with 20 mM sodium citrate and 130 mM sodium chloride buffer at pH of 5.0. It is supplied for clinical trial use in vials containing 50 mL of the drug product at a concentration of 10 mg/mL. Each vial contains 500 mg of glenzocimab. Two vials (2x500 mg) of glenzocimab should be administered concomitantly for eligible patients for a total daily dose of 1g. Glenzocimab is intended to be administered as an IV infusion over 6 hrs, with 1/4 of the dose administered by a 15-minute bolus and 3/4 of the dose administered by 5h45min-slow infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy mRS 90	The primary efficacy endpoint is the functional outcome assessed by the modified Rankin Scale (mRS) at day 90 +/- 15 days. The Modified Rankin Scale (mRS) is used to measure the degree of disability in patients who have had a stroke. The scale runs from 0-6, running from perfect health without symptoms to death. 0 - No symptoms.; - No significant disability. Able to carry out all usual activities, despite some symptoms.; - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.; - Moderate disability. Requires some help, but able to walk unassisted.; - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.; - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.; - Dead.	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Favorable functional outcome	Favorable functional outcome defined by a mRS ≤ 2 at day 90 +/- 15 days	90 days
Severe handicap	Proportion of patients with a severe handicap: mRS equal to 4, 5 or 6 at day 90 +/- 15 days	90 days
Survival	Overall survival at 90 days and 1 year	90 days and 1 year
Early reperfusion outcomes : volume	Stroke volume by MRI at 24 hrs	24 hours
Early reperfusion outcomes : eTICI	Reperfusion at the end of procedure assessed by the expanded treatment in cerebral infarction (eTICI) score.The eTICI is defined as follows : grade 0: no perfusion noted (0% reperfusion) grade 1: reduction in thrombus but without any resultant filling of distal arterial branches grade 2a: reperfusion of 1-49% of the territory grade 2b50: reperfusion of 50-66% of the territory grade 2b67: reperfusion of 67-89% of the territory grade 2c: extensive reperfusion of 90-99% of the territory grade 3: complete or full reperfusion (100% reperfusion)	24 hours
Early reperfusion outcomes NIHSS	Early neurological improvement by National Institutes of Health Stroke Scale, or NIH Stroke Scale (NIHSS) at 24 hrs. The NIHSS is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a patient's total NIHSS score. The maximum possible score is 42, with the minimum score being a 0.	24 hours
Quality of life	EQ5D-5L at day 90 and at 1 year. EQ-5D is a standardised measure of health-related quality of life. The EQ-5D-5L descriptive system uses five dimensions. The five levels in each dimension are worded as (1) 'not /no problems', (2) 'slight problems', (3) 'moderate problems', (4) 'severe problems', and (5) 'unable to' (mobility, self-care, usual activities), 'extreme' (pain/depression), or 'extremely' (anxiety/depression). EQ-5D-5L is the sum of the five dimensions.	90 days and 1 year
IntraCranial Hemorrhages	Incidence of symptomatic or non-symptomatic IntraCranial Hemorrhages (ICH) at 24 hrs	24 hours
Symptomatic IntraCranial Hemorrhages	Incidence of symptomatic IntraCranial Hemorrhages (ICH) at 24 hrs	24 hours
Non-Symptomatic IntraCranial Hemorrhages	Incidence of non-symptomatic IntraCranial Hemorrhages (ICH) at 24 hrs	24 hours
Adverse event	Incidence, nature and severity of Adverse Events, SAEs, SUSARs, Bleeding-Related Events (BREs) and/or Treatment-Emergent Adverse Events (TEAEs), at 24 hrs, at D7/discharge, 30 days and 90 days	24 hours, 7 days, 30 days, 90 days
Bleeding relating events	Incidence of bleeding-related events at 90 days	90 days
Anti-glenzocimab antibodies	Anti-glenzocimab antibodies (ADA) blood concentration at 3 months for 50 patients.	3 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Anticipated): October 10, 2022
• Primary Completion (Anticipated): October 10, 2025
• Study Completion (Anticipated): October 10, 2026

Study Registration Dates

• First Submitted: September 26, 2022
• First Submitted That Met QC Criteria: September 26, 2022
• First Posted (Actual): September 29, 2022

Study Record Updates

• Last Update Posted (Actual): September 29, 2022
• Last Update Submitted That Met QC Criteria: September 26, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Endovascular therapy; Platelet glycoprotein VI
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Infarction; Stroke; Ischemic Stroke; Brain Infarction; Anticoagulants; Glenzocimab
• Other Study ID Numbers: APHP 201028 / ACT-CS-004; 2021-000889-16 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No