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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Drug: Intravenous glenzocimab (ACT017) 1000 mg
* Drug: Intravenous Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A randomized, double blind, multicenter, multinational, placebo controlled, parallel group, single dose, adaptive phase II/III study (respectively Part 1 and 2).
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous glenzocimab (ACT017) 1000 mg<br>Intravenous glenzocimab (ACT017) 1000 mg to be added to thrombolysis +/- mechanical thrombectomy | Drug: Intravenous glenzocimab (ACT017) 1000 mg<br>* Add-on therapy to the standard of Care in the treatment of the acute ischemic stroke symptoms<br>* Other names: Thrombolysis +/- thrombectomy;|
| Placebo Comparator: Intravenous Placebo<br>Intravenous Placebo to be added to thrombolysis +/- mechanical thrombectomy | Drug: Intravenous Placebo<br>* Add-on therapy to the standard of Care in the treatment of the acute ischemic stroke symptoms<br>* Other names: Thrombolysis +/- thrombectomy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Binary Poor Outcome on the mRS defined by a score of 4-6 (versions 0-3) | To show the efficacy of glenzocimab vs. placebo, on the poor outcome defined as a mRS score of 4-6 (vs 0-3) assessed at Day 90 | Day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Key Secondary Efficacy Endpoint - mRS | Binary Favorable Outcome on the mRS defined by a score of 0-2 (versus 3-6) | Day 90 | 
| Mortality | All cause mortality | Day 90 | 
| mRS | To assess the favorable responses defined as mRS score of 0-1 | Day 90 | 
| mRS | To assess the favorable responses defined as mRS score of 5-6 | Day 90 | 
| Ordinal mRS | To assess the shift analysis | Day 90 | 
| Utility Weighted mRS | To assess the utility weighted mRS (UW-mRS) | Day 90 | 
| All cause mortality | To assess all cause mortality | 72 hours | 
| ICHs | Symptomatic and non-symptomatic ICHs | 72 hours | 
| Neurological Status Change as assessed by NIHSS value compared to pre-IVT value | 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 | 24 hours | 
| Recanalization rate | To assess recanalization in patients undergoing thrombectomy by eTICI score | Day 90 | 
| Cerebral tissue reperfusion | To assess Cerebral tissue reperfusion | Day 90 | 
| Infarct volume progression and hemorrhagic transformation | To assess the impact on follow up imaging (follow up infarct volume, infarct growth and volume of hemorrhagic transformation) | 24 hrs | 
| Measure of Quality of Life by EuroQol-5 Dimension-5 Level (EQ-5D-5L) | Quality of Life as assessed by the EuroQol-5 Dimension-5 Level. A Quality-of-Life Scale (EQ-5D-5L) | Day 90 | 
| Incidence of Deaths | Deaths within the first 24 hours and over the whole study period until Day 90 (Kaplan-Meier curve) | Day 90 | 
| Incidence of Symptomatic intracranial hemorrhages | 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)) | 24 hours | 
| Incidence of Non-symptomatic hemorrhages | Non-symptomatic hemorrhages, seen on 24-hours plain CT-Scan, not present at baseline assessment, once other diagnoses are excluded | 24 hours | 
| 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) | Day 90 | 
| Change in vital signs (Blood Pressure) at any visit or discharge as compared to Baseline | Blood Pressure will be assessed every 30 minutes during the 6 hours (infusion) then every 3 hours up to 24 hours. | 24 hours | 
| Change in vital signs (Heart Rate) at any visit or discharge as compared to Baseline | Heart Rate will be assessed every 30 minutes during the 6 hours (infusion) then every 3 hours up to 24 hours | 24 hours | 
| Change in hematology assessments: RBC (Red Blood Cell Count) at 24 hours as compared to Baseline | % of patient with change in RBC (Red Blood Cell Count) in million/mm3 | 24 hours | 
| Change in hematology assessments: RBC (Red Blood Cell Count) at Day 7 or discharge as compared to Baseline | % of patient with change in RBC (Red Blood Cell Count) in million/mm3 | Day 7 | 
| Change in hematology assessments: Hemoglobin at 24 hours as compared to Baseline | % of patient with change in Hemoglobin in g/100ml | 24 hours | 
| Change in hematology assessments: Hemoglobin at Day 7 or discharge as compared to Baseline | % of patient with change in Hemoglobin in g/100ml | Day 7 | 
| Change in hematology assessments: Hematocrit at 24 hours as compared to Baseline | % of patient with change in Hematocrit in % | 24 hours | 
| Change in hematology assessments: Hematocrit at 24 hours at Day 7 or discharge as compared to Baseline | % of patient with change in Hematocrit in % | Day 7 | 
| Change in hematology assessments: Mean Corpuscular Hemoglobin Volume (MCV) at 24 hours as compared to Baseline | % of patient with change in Mean Corpuscular Hemoglobin Volume (MCV) in µ3 | 24 hours | 
| Change in hematology assessments: Mean Corpuscular Hemoglobin Volume (MCV) at Day 7 or discharge as compared to Baseline | % of patient with change in Mean Corpuscular Hemoglobin Volume (MCV) in µ3 | Day 7 | 
| Change in hematology assessments: Mean corpuscular hemoglobin content (MCHC) at 24 hours as compared to Baseline | % of patient with change in Mean corpuscular hemoglobin content (MCHC) in pg | 24 hours | 
| Change in hematology assessments: Mean corpuscular hemoglobin content (MCHC) at Day 7 or discharge as compared to Baseline | % of patient with change in Mean corpuscular hemoglobin content (MCHC) in pg | Day 7 | 
| Change in hematology assessments: Corpuscular hemoglobin concentration (CHC) at 24 hours as compared to Baseline | % of patient with change in Corpuscular hemoglobin concentration (CHC) in % | 24 hours | 
| Change in hematology assessments: Corpuscular hemoglobin concentration (CHC) at Day 7 or discharge as compared to Baseline | % of patient with change in Corpuscular hemoglobin concentration (CHC) in % | Day 7 | 
| Change in hematology assessments: Leucocytes(/mm3) at 24 hours as compared to Baseline | % of patient with change in Leucocytes in /mm3 | 24 hours | 
| Change in hematology assessments: Leucocytes(/mm3) at Day 7 or discharge as compared to Baseline | % of patient with change in Leucocytes in /mm3 | Day 7 | 
| Change in hematology assessments: Platelets x 10^9 /L at 24 hours as compared to Baseline | % of patient with change in Platelets x 10^9 /L | 24 hours | 
| Change in hematology assessments: Platelets x 10^9 /L at 24 hours at Day 7 or discharge as compared to Baseline | % of patient with change in Platelets x 10^9 /L | Day 7 | 
| Change biochemistry assessments : SGPT (Sérum Glutamate Pyruvate Transaminase) at 24 hours as compared to Baseline | % of patient with change in SGPT in UI/L | 24 hours | 
| Change biochemistry assessments : SGPT at Day 7 or discharge as compared to Baseline | % of patient with change in SGPT in UI/L | Day 7 | 
| Change biochemistry assessments : SGOT at 24 hours as compared to Baseline | % of patient with change in SGOT in UI/L | 24 hours | 
| Change biochemistry assessments : SGOT at Day 7 or discharge as compared to Baseline | % of patient with change in SGOT in UI/L | Day 7 | 
| Change biochemistry assessments: LDH at 24 hours as compared to Baseline | % of patient with change in LDH in UI/l | 24 hours | 
| Change biochemistry assessments : LDH at Day 7 or discharge as compared to Baseline | % of patient with change in LDH in UI/l | Day 7 | 
| Change biochemistry assessments : Cholesterol at 24 hours as compared to Baseline | % of patient with change in Cholesterol in g/L or mmol/L | 24 hours | 
| Change biochemistry assessments : Cholesterol at Day 7 or discharge as compared to Baseline | % of patient with change in Cholesterol in g/L or mmol/L | Day 7 | 
| Change biochemistry assessments : Triglycerid at 24 hours as compared to Baseline | % of patient with change in Triglycerid in g/L or mmol/L | 24 hours | 
| Change biochemistry assessments : Triglycerid at Day 7 or discharge as compared to Baseline | % of patient with change in Triglycerid in g/L or mmol/L | Day 7 | 
| Change biochemistry assessments : Urea at 24 hours as compared to Baseline | % of patient with change in Urea in g/L or mmol/L | 24 hours | 
| Change biochemistry assessments : Urea at Day 7 or discharge as compared to Baseline | % of patient with change in Urea in g/L or mmol/L | Day 7 | 
| Change biochemistry assessments : Creatinin at 24 hours as compared to Baseline | % of patient with change in Creatinin in mg/L or µM/L | 24 hours | 
| Change biochemistry assessments : Creatinin at Day 7 or discharge as compared to Baseline | % of patient with change in Creatinin in mg/L or µM/L | Day 7 | 
| Change biochemistry assessments : GFR at 24 hours as compared to Baseline | % of patient with change in GFR in mL/min/1,73 m² | 24 hours | 
| Change biochemistry assessments : GFR at Day 7 or discharge as compared to Baseline | % of patient with change inGFR in mL/min/1,73 m² | Day 7 | 
| Change biochemistry assessments : Serum Glucose at 24 hours as compared to Baseline | % of patient with change in Serum Glucose in g/L | 24 hours | 
| Change biochemistry assessments : Serum Glucose at Day 7 or discharge as compared to Baseline | % of patient with change in Serum Glucose in g/L | Day 7 | 
| Change biochemistry assessments : D-Dimer at 24 hours as compared to Baseline | % of patient with change in D-Dimer in µg/L | 24 hours | 
| Change biochemistry assessments : D-Dimer at Day 7 or discharge as compared to Baseline | % of patient with change in D-Dimer in µg/L | Day 7 | 
| Change biochemistry assessments : Fibrinogen at 24 hours as compared to Baseline | % of patient with change in Fibrinogen in g/L | 24 hours | 
| Change biochemistry assessments : Fibrinogen at Day 7 or discharge as compared to Baseline | % of patient with change in Fibrinogen in g/L | Day 7 | 
| Change biochemistry assessments : INR score at 24 hours as compared to Baseline | % of patient with change in INR Score | 24 hours | 
| Change biochemistry assessments : INR score at Day 7 or discharge as compared to Baseline | % of patient with change in INR Score | Day 7 | 
| Change biochemistry assessments : PT score at 24 hours as compared to Baseline | % of patient with change in PT in sec | 24 hours | 
| Change biochemistry assessments : PT score at Day 7 or discharge as compared to Baseline | % of patient with change in PT in sec | Day 7 | 
| Change biochemistry assessments : aPTT score at 24 hours as compared to Baseline | % of patient with change in aPTT in sec | 24 hours | 
| Change biochemistry assessments : aPTT score at Day 7 or discharge as compared to Baseline | % of patient with change in aPTT in sec | Day 7 | 
| Change in dipstick urinalysis assessments: Turbidity at 24 hours as compared to Baseline | % of patient with change in Change in urinalysis assessments | 24 hours | 
| Change in dipstick urinalysis assessments: pH at 24 hours as compared to Baseline | % of patient with change in Change in urinalysis assessments | 24 hours | 
| Change in dipstick urinalysis assessments: Glucose at 24 hours as compared to Baseline | % of patient with change in Change in urinalysis assessments | 24 hours | 
| Change in dipstick urinalysis assessments: Proteins at 24 hours as compared to Baseline | % of patient with change in Change in urinalysis assessments | 24 hours | 
| Change in dipstick urinalysis assessments: Blood at 24 hours as compared to Baseline | % of patient with change in Change in urinalysis assessments | 24 hours | 
| Change in dipstick urinalysis assessments: Leucocytes at 24 hours as compared to Baseline | % of patient with change in Change in urinalysis assessments | 24 hours | 
| Change in dipstick clinical laboratory assessments (urinalysis) at Day 7 or discharge as compared to Baseline | % of patient with change in Change in urinalysis assessments | Day 7 | 
| Change in coagulation parameters (INR, PT, a PTT) | Change in coagulation parameters (INR, PT, aPTT) at 24 hrs | 24 hours | 
| ECG changes | ECG change from baseline on QT, QTc, PR, ST and QRS intervals at 24 hours as compared to Baseline | 24 hours | 
| ECG changes | ECG change from baseline on QT, QTc, PR, ST and QRS intervals at Day 7 as compared to Baseline | Day 7 | 
| ECG changes | ECG change from baseline on QT, QTc, PR, ST and QRS intervals at discharge as compared to Baseline | Day 90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Haemorrhages GPVI, Thrombolysis, Thrombectomy, Anti-platelet, glenzocimab, ACT017, stroke, GPVI