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

Acute Ischemic Stroke Clinical Trial

— ACTISAVE  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05070260
• Other study ID #: ACT-CS-005
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: September 23, 2021
• Est. completion date: January 31, 2024

Study information

• Verified date: August 2023
• Source: Acticor Biotech
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 438
• Est. completion date: January 31, 2024
• Est. primary completion date: January 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Ischemic Stroke
• Cerebral Infarction
• Ischemia
• Ischemic Stroke
• Stroke

Intervention

Drug:
• Intravenous glenzocimab (ACT017) 1000 mg
Add-on therapy to the standard of Care in the treatment of the acute ischemic stroke symptoms
• Intravenous Placebo
Add-on therapy to the standard of Care in the treatment of the acute ischemic stroke symptoms

Locations

Country	Name	City	State
Germany	University Clinic Essen	Essen
United States	Black Medical center	Bradenton	Florida
United States	Nova Clinical Research	Bradenton	Florida
United States	Chattanooga center for neurological research	Chattanooga	Tennessee
United States	University of Chicago	Chicago	Illinois
United States	Miami Valley hospital	Dayton	Ohio
United States	Houston Methodist hospital	Houston	Texas
United States	Memorial Hermann Hospital	Houston	Texas
United States	Washington university	Saint Louis	Missouri
United States	Northside hospital	Saint Petersburg	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Acticor Biotech

Countries where clinical trial is conducted

United States,  Germany, 

References & Publications (2)

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Imaging for exploratory endpoints	• Acute ischemic stroke diagnosis and occluded cerebral vessel identification assessed by CTA or MRA/MRI with Time of Flight (TOF) sequence at Baseline	Baseline
Other	Imaging for exploratory endpoints	Non Symptomatic and Symptomatic intracranial hemorrhage detection assessed by a plain CT-scan or MRI at 24h	24 hours
Primary	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	Key Secondary Efficacy Endpoint - mRS	Binary "Favorable Outcome" on the mRS defined by a score of 0-2 (versus 3-6)	Day 90
Secondary	Mortality	All cause mortality	Day 90
Secondary	mRS	To assess the favorable responses defined as mRS score of 0-1	Day 90
Secondary	mRS	To assess the favorable responses defined as mRS score of 5-6	Day 90
Secondary	Ordinal mRS	To assess the shift analysis	Day 90
Secondary	Utility Weighted mRS	To assess the utility weighted mRS (UW-mRS)	Day 90
Secondary	All cause mortality	To assess all cause mortality	72 hours
Secondary	ICHs	Symptomatic and non-symptomatic ICHs	72 hours
Secondary	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
Secondary	Recanalization rate	To assess recanalization in patients undergoing thrombectomy by eTICI score	Day 90
Secondary	Cerebral tissue reperfusion	To assess Cerebral tissue reperfusion	Day 90
Secondary	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
Secondary	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
Secondary	Incidence of Deaths	Deaths within the first 24 hours and over the whole study period until Day 90 (Kaplan-Meier curve)	Day 90
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in hematology assessments: Hemoglobin at 24 hours as compared to Baseline	% of patient with change in Hemoglobin in g/100ml	24 hours
Secondary	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
Secondary	Change in hematology assessments: Hematocrit at 24 hours as compared to Baseline	% of patient with change in Hematocrit in %	24 hours
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in hematology assessments: Leucocytes(/mm3) at 24 hours as compared to Baseline	% of patient with change in Leucocytes in /mm3	24 hours
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change biochemistry assessments : SGPT at Day 7 or discharge as compared to Baseline	% of patient with change in SGPT in UI/L	Day 7
Secondary	Change biochemistry assessments : SGOT at 24 hours as compared to Baseline	% of patient with change in SGOT in UI/L	24 hours
Secondary	Change biochemistry assessments : SGOT at Day 7 or discharge as compared to Baseline	% of patient with change in SGOT in UI/L	Day 7
Secondary	Change biochemistry assessments: LDH at 24 hours as compared to Baseline	% of patient with change in LDH in UI/l	24 hours
Secondary	Change biochemistry assessments : LDH at Day 7 or discharge as compared to Baseline	% of patient with change in LDH in UI/l	Day 7
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change biochemistry assessments : Serum Glucose at 24 hours as compared to Baseline	% of patient with change in Serum Glucose in g/L	24 hours
Secondary	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
Secondary	Change biochemistry assessments : D-Dimer at 24 hours as compared to Baseline	% of patient with change in D-Dimer in µg/L	24 hours
Secondary	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
Secondary	Change biochemistry assessments : Fibrinogen at 24 hours as compared to Baseline	% of patient with change in Fibrinogen in g/L	24 hours
Secondary	Change biochemistry assessments : Fibrinogen at Day 7 or discharge as compared to Baseline	% of patient with change in Fibrinogen in g/L	Day 7
Secondary	Change biochemistry assessments : INR score at 24 hours as compared to Baseline	% of patient with change in INR Score	24 hours
Secondary	Change biochemistry assessments : INR score at Day 7 or discharge as compared to Baseline	% of patient with change in INR Score	Day 7
Secondary	Change biochemistry assessments : PT score at 24 hours as compared to Baseline	% of patient with change in PT in sec	24 hours
Secondary	Change biochemistry assessments : PT score at Day 7 or discharge as compared to Baseline	% of patient with change in PT in sec	Day 7
Secondary	Change biochemistry assessments : aPTT score at 24 hours as compared to Baseline	% of patient with change in aPTT in sec	24 hours
Secondary	Change biochemistry assessments : aPTT score at Day 7 or discharge as compared to Baseline	% of patient with change in aPTT in sec	Day 7
Secondary	Change in dipstick urinalysis assessments: Turbidity at 24 hours as compared to Baseline	% of patient with change in Change in urinalysis assessments	24 hours
Secondary	Change in dipstick urinalysis assessments: pH at 24 hours as compared to Baseline	% of patient with change in Change in urinalysis assessments	24 hours
Secondary	Change in dipstick urinalysis assessments: Glucose at 24 hours as compared to Baseline	% of patient with change in Change in urinalysis assessments	24 hours
Secondary	Change in dipstick urinalysis assessments: Proteins at 24 hours as compared to Baseline	% of patient with change in Change in urinalysis assessments	24 hours
Secondary	Change in dipstick urinalysis assessments: Blood at 24 hours as compared to Baseline	% of patient with change in Change in urinalysis assessments	24 hours
Secondary	Change in dipstick urinalysis assessments: Leucocytes at 24 hours as compared to Baseline	% of patient with change in Change in urinalysis assessments	24 hours
Secondary	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
Secondary	Change in coagulation parameters (INR, PT, a PTT)	Change in coagulation parameters (INR, PT, aPTT) at 24 hrs	24 hours
Secondary	ECG changes	ECG change from baseline on QT, QTc, PR, ST and QRS intervals at 24 hours as compared to Baseline	24 hours
Secondary	ECG changes	ECG change from baseline on QT, QTc, PR, ST and QRS intervals at Day 7 as compared to Baseline	Day 7
Secondary	ECG changes	ECG change from baseline on QT, QTc, PR, ST and QRS intervals at discharge as compared to Baseline	Day 90