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

Acticor Biotech438 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

438

Conditions

Acute Ischemic Stroke

Interventions

Intravenous glenzocimab (ACT017) 1000 mgDRUG

Add-on therapy to the standard of Care in the treatment of the acute ischemic stroke symptoms

Intravenous PlaceboDRUG

Add-on therapy to the standard of Care in the treatment of the acute ischemic stroke symptoms

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (10)

Black Medical center

Bradenton, Florida, United States

Nova Clinical Research

Bradenton, Florida, United States

Northside hospital

St. Petersburg, Florida, United States

University of Chicago

Outcomes

Primary Outcomes

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

Time frame: Day 90

Secondary Outcomes

Key Secondary Efficacy Endpoint - mRS

Binary "Favorable Outcome" on the mRS defined by a score of 0-2 (versus 3-6)

Time frame: Day 90

Mortality

All cause mortality

Time frame: Day 90

mRS

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

Time frame: Day 90

mRS

To assess the favorable responses defined as mRS score of 5-6

Time frame: Day 90

Ordinal mRS

To assess the shift analysis

Time frame: Day 90

Utility Weighted mRS

To assess the utility weighted mRS (UW-mRS)

Time frame: Day 90

All cause mortality

To assess all cause mortality

Time frame: 72 hours

ICHs

Symptomatic and non-symptomatic ICHs

Time frame: 72 hours

Data from ClinicalTrials.gov

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Chicago, Illinois, United States

Washington university

St Louis, Missouri, United States

Miami Valley hospital

Dayton, Ohio, United States

Chattanooga center for neurological research

Chattanooga, Tennessee, United States

Houston Methodist hospital

Houston, Texas, United States

Memorial Hermann Hospital

Houston, Texas, United States

University Clinic Essen

Essen, Germany

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

Time frame: 24 hours

Recanalization rate

To assess recanalization in patients undergoing thrombectomy by eTICI score

Time frame: Day 90

Cerebral tissue reperfusion

To assess Cerebral tissue reperfusion

Time frame: 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)

Time frame: 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)

Time frame: Day 90

Incidence of Deaths

Deaths within the first 24 hours and over the whole study period until Day 90 (Kaplan-Meier curve)

Time frame: 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))

Time frame: 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

Time frame: 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)

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Day 7

Change in hematology assessments: Hemoglobin at 24 hours as compared to Baseline

% of patient with change in Hemoglobin in g/100ml

Time frame: 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

Time frame: Day 7

Change in hematology assessments: Hematocrit at 24 hours as compared to Baseline

% of patient with change in Hematocrit in %

Time frame: 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 %

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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 %

Time frame: 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 %

Time frame: Day 7

Change in hematology assessments: Leucocytes(/mm3) at 24 hours as compared to Baseline

% of patient with change in Leucocytes in /mm3

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 24 hours

Change biochemistry assessments : SGPT at Day 7 or discharge as compared to Baseline

% of patient with change in SGPT in UI/L

Time frame: Day 7

Change biochemistry assessments : SGOT at 24 hours as compared to Baseline

% of patient with change in SGOT in UI/L

Time frame: 24 hours

Change biochemistry assessments : SGOT at Day 7 or discharge as compared to Baseline

% of patient with change in SGOT in UI/L

Time frame: Day 7

Change biochemistry assessments: LDH at 24 hours as compared to Baseline

% of patient with change in LDH in UI/l

Time frame: 24 hours

Change biochemistry assessments : LDH at Day 7 or discharge as compared to Baseline

% of patient with change in LDH in UI/l

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Day 7

Change biochemistry assessments : Serum Glucose at 24 hours as compared to Baseline

% of patient with change in Serum Glucose in g/L

Time frame: 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

Time frame: Day 7

Change biochemistry assessments : D-Dimer at 24 hours as compared to Baseline

% of patient with change in D-Dimer in µg/L

Time frame: 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

Time frame: Day 7

Change biochemistry assessments : Fibrinogen at 24 hours as compared to Baseline

% of patient with change in Fibrinogen in g/L

Time frame: 24 hours

Change biochemistry assessments : Fibrinogen at Day 7 or discharge as compared to Baseline

% of patient with change in Fibrinogen in g/L

Time frame: Day 7

Change biochemistry assessments : INR score at 24 hours as compared to Baseline

% of patient with change in INR Score

Time frame: 24 hours

Change biochemistry assessments : INR score at Day 7 or discharge as compared to Baseline

% of patient with change in INR Score

Time frame: Day 7

Change biochemistry assessments : PT score at 24 hours as compared to Baseline

% of patient with change in PT in sec

Time frame: 24 hours

Change biochemistry assessments : PT score at Day 7 or discharge as compared to Baseline

% of patient with change in PT in sec

Time frame: Day 7

Change biochemistry assessments : aPTT score at 24 hours as compared to Baseline

% of patient with change in aPTT in sec

Time frame: 24 hours

Change biochemistry assessments : aPTT score at Day 7 or discharge as compared to Baseline

% of patient with change in aPTT in sec

Time frame: Day 7

Change in dipstick urinalysis assessments: Turbidity at 24 hours as compared to Baseline