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

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.

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.

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. IVT should mandatorily be used according to the approved dosing regimen as described in the product information/SmPC/USPI.

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 two hours from the start of the thrombolytic agent administration. Transferring the patient to the catheterization room should not delay the Investigational Medicinal Product (IMP) administration.

Patients will be randomized in a 1:1 ratio allocation either to glenzocimab or placebo. Randomization will be minimized for factors as follows: (NIHSS <10 vs. ≥ 10), age group (<65, 65-79, ≥80 years), and type of thrombolytic agent (alteplase vs. tenecteplase) 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 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.

One interim analysis after 100 patients recruited and treated is planned for safety evaluation only.

In case of any urgent safety concern, ad-hoc meetings will be triggered.

Inclusion Criteria:

1. Adult male or female patients ≥ 18 years (i.e., at least 18 years old at time of randomization)

2. Having given their own written consent, or legal representative consent, and in any case, in strict accordance with country-specific legal requirements,

3. 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

4. Presenting with a pre-IVT NIHSS ≥ 6

5. 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),

6. 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

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 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.

8. Patients affiliated to a health insurance - modality depending on country legal requirement

Exclusion Criteria:

1. Coma, or NIHSS >25,
2. Patients < 18 years,
3. Protected adults under guardianship or curatorship,
4. Prior ischemic stroke within the past 3 months,
5. mRS pre-stroke known to be ≥ 2,
6. 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),
7. Significant mass effect with midline shift,
8. Stroke of hemorrhagic origin,
9. 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,
10. Known renal insufficiency (Grades 4-5 - severe or terminal with a creatinine clearance < 30 mL/min using Cockroft formula),
11. Known allergic reaction to contrast agents,
12. Patients under anti-coagulant therapy, except preventative doses of injectable low molecular weight heparin (LMWH),
13. Known ongoing treatment with a mAb,
14. Prior cardiopulmonary resuscitation < 10 days,
15. Childbirth within < 10 days,
16. Seizures at stroke onset if it precludes obtaining an accurate baseline (pre-IVT) NIHSS,
17. Life expectancy (except for stroke) < 3 months,
18. Pregnancy or breastfeeding,
19. Females of childbearing potential not using effective birth control methods,
20. Known current participation in another clinical investigation with experimental drug.