ACTISAVE: ACuTe Ischemic Stroke Study Evaluating Glenzocimab Used as Add-on Therapy Versus placEbo (ACTISAVE)

A Randomized, Double Blind, Multicenter, Multinational, Placebo Controlled, Parallel Group, Single Dose, Adaptive Efficacy and Safety Study of Glenzocimab Used as an add-on Therapy on Top of Standard of Care un the 4.5 Hours Following an Acute Ischemic Stroke

A randomized, double blind, multicenter, multinational, placebo controlled, parallel group, single dose, adaptive phase II/III study (respectively Part 1 and 2). The study evaluates the efficacy and safety of a fixed dose of glenzocimab (1000 mg IV over 6 hrs including initial bolus of 15 minutes) on top of the best standard of care.

A randomized, double blind, multicenter, multinational, placebo controlled, parallel group, single dose, adaptive phase II/III study. The study will be conducted in 3 consecutive parts, each separated from the preceding one by an interim analysis to allow the Independent Data Monitoring Committee (IDMC) to issue recommendations on study conduct, potential early termination or protocol adjustments. The First study part analysis aims to review both safety and efficacy data. The analysis will be performed when at least 100 patients in the MT+ subgroup patients have completed the Day 90 mRS assessment. With regard to the efficacy assessment, this analysis is a futility analysis only, i.e., stopping for an early efficacy claim is not allowable. Rules for claiming the trial futile will be detailed in the SAP. Likewise, a second analysis will be carried out with the aim to review both safety and efficacy data. A SAP for this IA will be finalized before this IA takes place. This analysis will be performed when at least 250 patients in the MT+ subgroup of patients have completed the Day 90 mRS assessment. Assuming a prevalence of 50% of the MT+ patients in the overall population, this second analysis will be performed when around 500 patients have completed the Day 90 mRS assessment. With regard to the efficacy assessment, the second analysis has three different aims: This is the second futility analysis only, i.e., stopping for an early efficacy claim is not allowable. Rules for claiming the trial futile will be detailed in the SAP. Adaptive selection of the population : i.e., either continue to enroll in the overall population or restrict enrolment to the MT+ subgroup. Rules for selecting the population will be further detailed in the SAP of the second interim analysis. Adaptive increase in sample size given the estimated difference between glenzocimab and placebo on each of the dual endpoints at the second IA in the selected population (either the OP or MT+ subgroup). Rules to consider an adaptive increase in the sample size will be further detailed in the Second IA SAP. The method to control the type I error rate at its usual nominal level will be detailed as well. The Third part will embrace the total study population (500 in each treatment arm, and in each type of SoC). The study evaluates the efficacy and safety of a fixed dose of glenzocimab (1000 mg IV over 6 hrs including initial bolus of 15 minutes) on top of the best standard of care. In all patients, the IVT should have been initiated prior to/at randomization, and in any case within 4.5 hrs post onset of acute ischemic stroke symptoms. Eligible patients will be randomized and the infusion of glenzocimab or of its matching placebo should be administered as soon as possible but no later than one hour of the end infusion/injection of the thrombolytic agent. Transferring the patient to the catheterization room should not delay the Investigational Medicinal Product (IMP) administration. Patients will be randomized 1:1 between groups (glenzocimab or placebo). In addition, a 1:1 stratification will allow for an equal balance of treatment allocation in each SoC (thrombolysis alone versus thrombolysis + mechanical thrombectomy (MT+). This stratification will be completed with a centralized capping at 250 patients per SoC for the second futility analysis, so that the final balance between SoCs will be achieved at the study level, whether investigating sites are comprehensive stroke centers or primary stroke centers. In addition, a minimization program will account for the following factors: baseline severity (NIHSS <10 vs. ≥ 10), age group (<65, 65-79, ≥80 years) in order to balance each treatment group composition. The allocation of each patient in all centers to an active treatment or placebo will strictly follow the central randomization/stratification scheme. Clinical supplies allocation to centers should provide the necessary material so that any eligible patient can receive the assigned treatment. A central randomization system (IRT - Interactive Response Technology) will be used to manage randomization/stratification and drug shipment. The whole process will be handled in a manner that it is blinded for the treatment received to all involved study personnel. The IDMC will be composed of 5 independent members (at least 2 clinicians and 1 statistician). IDMC members will process the information and will issue their recommendations as per the IDMC Charter. A specific Statistical Analysis Plan (SAP) per each analysis (2 interim and one final) will be made available to the IDMC for each of the 2 interim and final analyses as well as for the safety analyses. Four IDMC meetings are pre-scheduled: 2 of them for a safety evaluation exclusively (after 100 and 750 patients recruited) and 2 of them for efficacy and safety evaluation (after 200 and 500 patients recruited). In case of any urgent safety concern, ad-hoc meetings will be triggered. This study being adaptive in nature, at the second futility analysis, more precise decision rules will be proposed to the IDMC in the event there would be a clear imbalance in the benefit-to-risk assessment that would warrant focusing on a particular population subset of interest and/or avoiding the undue exposure of some patient categories. In this case, the final sample size should be reassessed accordingly. Competent Authorities / Agencies should be notified at the end of the First study part. Any advice from these agencies may be likely to alter the following part of the study as presented here.

A randomized, double blind, multicenter, multinational, placebo controlled, parallel group, single dose, adaptive phase II/III study (respectively Part 1 and 2).

To show the efficacy of glenzocimab vs. placebo, on at least one of the four independent (dual) endpoints, i.e. the ordinal modified Rankin Scale (mRS) assessed at Day 90. Ordinal modified Rankin Scale at Day 90 assessed in the Overall population (OP) Ordinal modified Rankin Scale at day 90 assessed in the MT+ subgroup

Binary "poor outcome" defined as a mRS score of 4-6 (vs 0-3) assessed at Day 90, either in the overall population (denoted as OP) or in the subgroup of patients who received Mechanical Thrombectomy (denoted as MT+). Binary "Poor Outcome" on the mRS defined by a score of 4-6 at Day 90 assessed in the OP Binary "Poor Outcome" on the mRS defined by a score of 4-6 at Day 90 assessed in the MT+subgroup

All-Cause Mortality at Day 90 assessed in the OP All-cause mortality at Day 90 assessed in the MT+ subgroup

To assess the favorable responses defined as mRS score of 0-1 To assess the good responses defined as mRS score 0-2

Response defined by a relative decrease (%) in NIHSS value at 24 hours compared to pre-IVT value higher than 30%. Relative change (%) in NIHSS value at 24 hrs compared to pre-IVT value

To assess the impact on follow up imaging (follow up infarct volume, infarct growth and volume of hemorrhagic transformation)

Symptomatic intracranial hemorrhages, defined by both anatomical imaging (according to Heidelberg's classification) at the time of its occurrence associated with an increase in NIHSS score by 4 points or greater, or death that is not explained otherwise (according to ECASS III study definition (14))

Non-symptomatic hemorrhages, seen on 24-hours plain CT-Scan, not present at baseline assessment, once other diagnoses are excluded

Incidence of Adverse Events, SAEs, bleeding-related events, and Treatment-Emergent Adverse Events (TEAEs)

Incidence, nature and severity of Adverse Events, SAEs, bleeding-related events, and Treatment-Emergent Adverse Events (TEAEs)

Blood Pressure will be assessed every 30 minutes during the 6 hours (infusion) then every 3 hours up to 24 hours.

Heart Rate will be assessed every 30 minutes during the 6 hours (infusion) then every 3 hours up to 24 hours

Change in hematology assessments: RBC (Red Blood Cell Count) at Day 7 or discharge as compared to Baseline

Change in hematology assessments: Hematocrit at 24 hours at Day 7 or discharge as compared to Baseline

Change in hematology assessments: Mean Corpuscular Hemoglobin Volume (MCV) at 24 hours as compared to Baseline

Change in hematology assessments: Mean Corpuscular Hemoglobin Volume (MCV) at Day 7 or discharge as compared to Baseline

Change in hematology assessments: Mean corpuscular hemoglobin content (MCHC) at 24 hours as compared to Baseline

Change in hematology assessments: Mean corpuscular hemoglobin content (MCHC) at Day 7 or discharge as compared to Baseline

Change in hematology assessments: Corpuscular hemoglobin concentration (CHC) at 24 hours as compared to Baseline

Change in hematology assessments: Corpuscular hemoglobin concentration (CHC) at Day 7 or discharge as compared to Baseline

Change in hematology assessments: Platelets x 10^9 /L at 24 hours at Day 7 or discharge as compared to Baseline

Change biochemistry assessments : SGPT (Sérum Glutamate Pyruvate Transaminase) at 24 hours as compared to Baseline

Change in dipstick clinical laboratory assessments (urinalysis) at Day 7 or discharge as compared to Baseline

• Acute ischemic stroke diagnosis and occluded cerebral vessel identification assessed by CTA or MRA/MRI with Time of Flight (TOF) sequence at Baseline

Non Symptomatic and Symptomatic intracranial hemorrhage detection assessed by a plain CT-scan or MRI at 24h

Inclusion Criteria: Adult male or female patients ≥ 18 years (i.e., at least 18 years old at time of randomization) Having given their own written consent, or legal representative consent, and in any case, in strict accordance with country-specific legal requirements, Presenting with an acute disabling ischemic stroke either in the anterior or in posterior circulation, with or without visible occlusion, with a known time of onset, that is ≤ 4.5 hrs Presenting with a pre-IVT NIHSS ≥ 6 In whom IVT is or has been initiated, whether or not patients are additionally eligible to mechanical thrombectomy (MT+ IVT), according to the recommendation of the last guidelines (ASA and ESO recommandations), Women of childbearing 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 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 WOCBP 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. Patients affiliated to a health insurance - modality depending on country legal requirement Exclusion Criteria: Coma, or NIHSS >25, Patients < 18 years, Protected adults under guardianship or curatorship, Prior ischemic stroke within the past 3 months, mRS pre-stroke known to be ≥ 2, Large (more than 1/3 of the middle cerebral artery) regions of clear hypodensity on Baseline Computed Tomography Angiography (CTA) or Magnetic Resonance Imaging (MRI) or with vascular injection (MRA), Significant mass effect with midline shift, Stroke of hemorrhagic origin, Patients likely to require dual antiplatelet therapy (DAPT) within the first 24 hrs after cessation of glenzocimab or placebo infusion for e.g., carotid stenting, Known renal insufficiency (Grades 4-5 - severe or terminal with a creatinine clearance < 30 mL/min using Cockroft formula), Known allergic reaction to contrast agents, Patients under anti-coagulant therapy, except preventative doses of injectable low molecular weight heparin (LMWH), Known ongoing treatment with a mAb, Prior cardiopulmonary resuscitation < 10 days, Childbirth within < 10 days, Seizures at stroke onset if it precludes obtaining an accurate baseline (pre-IVT) NIHSS, Life expectancy (except for stroke) < 3 months, Pregnancy or breastfeeding, Females of childbearing potential not using effective birth control methods, Known current participation in another clinical investigation with experimental drug.

Voors-Pette C, Lebozec K, Dogterom P, Jullien L, Billiald P, Ferlan P, Renaud L, Favre-Bulle O, Avenard G, Machacek M, Pletan Y, Jandrot-Perrus M. Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT017, an Antiplatelet GPVI (Glycoprotein VI) Fab. Arterioscler Thromb Vasc Biol. 2019 May;39(5):956-964. doi: 10.1161/ATVBAHA.118.312314.

Renaud L, Lebozec K, Voors-Pette C, Dogterom P, Billiald P, Jandrot Perrus M, Pletan Y, Machacek M. Population Pharmacokinetic/Pharmacodynamic Modeling of Glenzocimab (ACT017) a Glycoprotein VI Inhibitor of Collagen-Induced Platelet Aggregation. J Clin Pharmacol. 2020 Sep;60(9):1198-1208. doi: 10.1002/jcph.1616. Epub 2020 Jun 4.