Clinical trial NCT05070260: ACTISAVE: ACuTe Ischemic Stroke Study Evaluating Glenzocimab Used as Add-on Therapy Versus placEbo
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Acute Ischemic Stroke
Keywords: Haemorrhages GPVI
Thrombolysis
Thrombectomy
Anti-platelet
glenzocimab
ACT017
stroke
GPVI
Lead sponsor: Acticor Biotech
Sponsor class: INDUSTRY
First posted: 2021-10-07
Enrollment: 438
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomized, double blind, multicenter, multinational, placebo controlled, parallel group, single dose, adaptive phase II/III study (respectively Part 1 and 2).
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Binary Poor Outcome on the mRS defined by a score of 4-6 (versions 0-3)
timeFrame: Day 90
Secondary outcomes:
measure: Key Secondary Efficacy Endpoint - mRS
timeFrame: Day 90
measure: Mortality
timeFrame: Day 90
measure: mRS
timeFrame: Day 90
measure: mRS
timeFrame: Day 90
measure: Ordinal mRS
timeFrame: Day 90
measure: Utility Weighted mRS
timeFrame: Day 90
measure: All cause mortality
timeFrame: 72 hours
measure: ICHs
timeFrame: 72 hours
measure: Neurological Status Change as assessed by NIHSS value compared to pre-IVT value
timeFrame: 24 hours
measure: Recanalization rate
timeFrame: Day 90
measure: Cerebral tissue reperfusion
timeFrame: Day 90
measure: Infarct volume progression and hemorrhagic transformation
timeFrame: 24 hrs
measure: Measure of Quality of Life by EuroQol-5 Dimension-5 Level (EQ-5D-5L)
timeFrame: Day 90
measure: Incidence of Deaths
timeFrame: Day 90
measure: Incidence of Symptomatic intracranial hemorrhages
timeFrame: 24 hours
measure: Incidence of Non-symptomatic hemorrhages
timeFrame: 24 hours
measure: Incidence of Adverse Events, SAEs, bleeding-related events, and Treatment-Emergent Adverse Events (TEAEs)
timeFrame: Day 90
measure: Change in vital signs (Blood Pressure) at any visit or discharge as compared to Baseline
timeFrame: 24 hours
measure: Change in vital signs (Heart Rate) at any visit or discharge as compared to Baseline
timeFrame: 24 hours
measure: Change in hematology assessments: RBC (Red Blood Cell Count) at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change in hematology assessments: RBC (Red Blood Cell Count) at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change in hematology assessments: Hemoglobin at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change in hematology assessments: Hemoglobin at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change in hematology assessments: Hematocrit at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change in hematology assessments: Hematocrit at 24 hours at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change in hematology assessments: Mean Corpuscular Hemoglobin Volume (MCV) at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change in hematology assessments: Mean Corpuscular Hemoglobin Volume (MCV) at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change in hematology assessments: Mean corpuscular hemoglobin content (MCHC) at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change in hematology assessments: Mean corpuscular hemoglobin content (MCHC) at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change in hematology assessments: Corpuscular hemoglobin concentration (CHC) at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change in hematology assessments: Corpuscular hemoglobin concentration (CHC) at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change in hematology assessments: Leucocytes(/mm3) at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change in hematology assessments: Leucocytes(/mm3) at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change in hematology assessments: Platelets x 10^9 /L at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change in hematology assessments: Platelets x 10^9 /L at 24 hours at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change biochemistry assessments : SGPT (Sérum Glutamate Pyruvate Transaminase) at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change biochemistry assessments : SGPT at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change biochemistry assessments : SGOT at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change biochemistry assessments : SGOT at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change biochemistry assessments: LDH at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change biochemistry assessments : LDH at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change biochemistry assessments : Cholesterol at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change biochemistry assessments : Cholesterol at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change biochemistry assessments : Triglycerid at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change biochemistry assessments : Triglycerid at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change biochemistry assessments : Urea at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change biochemistry assessments : Urea at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change biochemistry assessments : Creatinin at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change biochemistry assessments : Creatinin at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change biochemistry assessments : GFR at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change biochemistry assessments : GFR at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change biochemistry assessments : Serum Glucose at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change biochemistry assessments : Serum Glucose at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change biochemistry assessments : D-Dimer at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change biochemistry assessments : D-Dimer at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change biochemistry assessments : Fibrinogen at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change biochemistry assessments : Fibrinogen at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change biochemistry assessments : INR score at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change biochemistry assessments : INR score at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change biochemistry assessments : PT score at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change biochemistry assessments : PT score at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change biochemistry assessments : aPTT score at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change biochemistry assessments : aPTT score at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change in dipstick urinalysis assessments: Turbidity at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change in dipstick urinalysis assessments: pH at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change in dipstick urinalysis assessments: Glucose at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change in dipstick urinalysis assessments: Proteins at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change in dipstick urinalysis assessments: Blood at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change in dipstick urinalysis assessments: Leucocytes at 24 hours as compared to Baseline
timeFrame: 24 hours
measure: Change in dipstick clinical laboratory assessments (urinalysis) at Day 7 or discharge as compared to Baseline
timeFrame: Day 7
measure: Change in coagulation parameters (INR, PT, a PTT)
timeFrame: 24 hours
measure: ECG changes
timeFrame: 24 hours
measure: ECG changes
timeFrame: Day 7
measure: ECG changes
timeFrame: Day 90
Other outcomes:
measure: Imaging for exploratory endpoints
timeFrame: Baseline
measure: Imaging for exploratory endpoints
timeFrame: 24 hours
Locations:
city: Bradenton
country: United States
facility: Black Medical center
state: Florida
city: Bradenton
country: United States
facility: Nova Clinical Research
state: Florida
city: Saint Petersburg
country: United States
facility: Northside hospital
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Saint Louis
country: United States
facility: Washington university
state: Missouri
city: Dayton
country: United States
facility: Miami Valley hospital
state: Ohio
city: Chattanooga
country: United States
facility: Chattanooga center for neurological research
state: Tennessee
city: Houston
country: United States
facility: Houston Methodist hospital
state: Texas
city: Houston
country: United States
facility: Memorial Hermann Hospital
state: Texas
city: Essen
country: Germany
facility: University Clinic Essen
Study officials:
affiliation: Acticor Biotech
name: Andrea Comenducci, MD
role: STUDY_DIRECTOR
References:
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.
citation: 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.