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).~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.