ACTISAVE: 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 Details
Study Description
Brief Summary
A randomized, double blind, multicenter, multinational, placebo controlled, parallel group, single dose, adaptive phase II/III study (respectively Part 1 and 2).
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2/Phase 3 |
Detailed Description
A randomized, double blind, multicenter, multinational, placebo controlled, parallel group, single dose, adaptive phase II/III study (respectively Part 1 and 2).
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, thrombolysis (IVT with tPA: alteplase) should have been initiated prior to randomization, within 4.5 hrs post onset of acute ischemic stroke symptoms.
Eligible patients will be randomized and the infusion of glenzocimab or of its matching placebo should be administered (infusion initiation) ideally during the tPA infusion but no later than one hour following the end of tPA administration.
Patients will be randomized 1:1 between groups (glenzocimab or placebo). A minimization program will account for the following factors: type of SOC, (IVT alone vs. IVT + MT), Baseline Severity (NIHSS <10 vs. ≥ 10), age group (<65, 65-79, ≥80 years) in order to balance each group composition.
The allocation of each patient in any given center to an active treatment or placebo will strictly follow a central randomization scheme. Clinical supplies allocation to centers should provide the necessary material so that any eligible patient can receive the assigned treatment. An IRT will be used to manage randomization 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.
An Independent Data Monitoring Committee (IDMC) will be composed of at least two clinicians with expertise in the relevant clinical field (a neurologist and a neuroradiologists), and a clinical pharmacologist. They will be supported by a dedicated independent statistician. The statistician will be available to analyze the data for the IDMC (either blinded or unblinded). All cases of intracranial hemorrhage (symptomatic or not) will be thoroughly reviewed, including the radiological images and the pharmacovigilance data.
IDMC members will process the information and will issue their recommendations as per the IDMC Charter. Specific Statistical Analysis Plan (SAP) per each analysis (2 interim and one final) will be made available to the IDMC for each of the 2 interim and final analyses.
Five IDMC meetings are pre-scheduled: 3 of them for a safety evaluation exclusively (after 100, 600 and 800 patients recruited) and 2 of them for efficacy and safety evaluation (after 200 and 400 patients recruited). In case of an urgent safety concern, ad-hoc meetings will be triggered.
Bleeding events are an integral part of these analyses, and a focus on symptomatic/non-symptomatic intra-cranial bleeds is repeatedly considered.
Competent Authorities / Agencies should be notified at the end of the Part 1 and regulatory meetings, such as End-of-Phase II meetings should take place thereafter. Advice from these agencies may be likely to alter Part 2 plans as presented here.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Intravenous glenzocimab (ACT017) 1000 mg Intravenous glenzocimab (ACT017) 1000 mg to be added to a tissue plasminogen activator +/- mechanical thrombectomy |
Drug: Intravenous glenzocimab (ACT017) 1000 mg
Add-on therapy to the standard of Care in the treatment of the acute ischemic stroke symptoms
Other Names:
|
| Placebo Comparator: Intravenous Placebo Intravenous Placebo to be added to a tissue plasminogen activator +/- mechanical thrombectomy |
Drug: Intravenous Placebo
Add-on therapy to the standard of Care in the treatment of the acute ischemic stroke symptoms
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Ordinal modified Ranking Scale (mRS) [Day 90]
To assess the efficacy within the first 4.5 hours following an acute ischemic stroke of a single IV (bolus + infusion) dose of glenzocimab in addition to the pharmacologic standard of care by tissue plasminogen activator (tPA), with or without the addition of mechanical thrombectomy, with a specific focus on the Day 90 modified Rankin Scale (mRS).
Secondary Outcome Measures
- Neurological Status Change as assessed by NIHSS value compared to pre-IVT value [24 hours]
Response defined by a relative decrease (%) in NIHSS value at 24 hours compared to pre-IVT value higher than 30%.
- Measure of Quality of Life by EuroQol-5 Dimension-5 Level (EQ-5D-5L) [Day 90]
Quality of Life as assessed by the EuroQol-5 Dimension-5 Level. A Quality-of-Life Scale (EQ-5D-5L)
- Incidence of Deaths [Day 90]
Deaths within the first 24 hours and over the whole study period until Day 90 (Kaplan-Meier curve)
- Incidence of Symptomatic intracranial hemorrhages [24 hours]
Symptomatic intracranial hemorrhages, defined by both anatomical imaging (according to Heidelberg's classification) AND an increase in NIHSS score by 4 points or greater, or death that is not explained otherwise (according to ECASS III study definition)
- Incidence of Non-symptomatic hemorrhages [24 hours]
Non-symptomatic hemorrhages, seen on 24-hours plain CT-Scan, not present at baseline assessment, once other diagnoses are excluded
- Incidence of Adverse Events, SAEs, bleeding-related events, and Treatment-Emergent Adverse Events (TEAEs) [Day 90]
Incidence, nature and severity of Adverse Events, SAEs, bleeding-related events, and Treatment-Emergent Adverse Events (TEAEs)
- Change in vital signs (Blood Pressure) at any visit or discharge as compared to Baseline [24 hours]
Blood Pressure will be assessed every 30 minutes during the 6 hours (infusion) then every 3 hours up to 24 hours.
- Change in vital signs (Heart Rate) at any visit or discharge as compared to Baseline [24 hours]
Heart Rate will be assessed every 30 minutes during the 6 hours (infusion) then every 3 hours up to 24 hours
- Change in hematology assessments: RBC (Red Blood Cell Count) at 24 hours as compared to Baseline [24 hours]
% of patient with change in RBC (Red Blood Cell Count) in million/mm3
- Change in hematology assessments: RBC (Red Blood Cell Count) at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in RBC (Red Blood Cell Count) in million/mm3
- Change in hematology assessments: Hemoglobin at 24 hours as compared to Baseline [24 hours]
% of patient with change in Hemoglobin in g/100ml
- Change in hematology assessments: Hemoglobin at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in Hemoglobin in g/100ml
- Change in hematology assessments: Hematocrit at 24 hours as compared to Baseline [24 hours]
% of patient with change in Hematocrit in %
- Change in hematology assessments: Hematocrit at 24 hours at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in Hematocrit in %
- Change in hematology assessments: Mean Corpuscular Hemoglobin Volume (MCV) at 24 hours as compared to Baseline [24 hours]
% of patient with change in Mean Corpuscular Hemoglobin Volume (MCV) in µ3
- Change in hematology assessments: Mean Corpuscular Hemoglobin Volume (MCV) at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in Mean Corpuscular Hemoglobin Volume (MCV) in µ3
- Change in hematology assessments: Mean corpuscular hemoglobin content (MCHC) at 24 hours as compared to Baseline [24 hours]
% of patient with change in Mean corpuscular hemoglobin content (MCHC) in pg
- Change in hematology assessments: Mean corpuscular hemoglobin content (MCHC) at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in Mean corpuscular hemoglobin content (MCHC) in pg
- Change in hematology assessments: Corpuscular hemoglobin concentration (CHC) at 24 hours as compared to Baseline [24 hours]
% of patient with change in Corpuscular hemoglobin concentration (CHC) in %
- Change in hematology assessments: Corpuscular hemoglobin concentration (CHC) at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in Corpuscular hemoglobin concentration (CHC) in %
- Change in hematology assessments: Leucocytes(/mm3) at 24 hours as compared to Baseline [24 hours]
% of patient with change in Leucocytes in /mm3
- Change in hematology assessments: Leucocytes(/mm3) at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in Leucocytes in /mm3
- Change in hematology assessments: Platelets x 10^9 /L at 24 hours as compared to Baseline [24 hours]
% of patient with change in Platelets x 10^9 /L
- Change in hematology assessments: Platelets x 10^9 /L at 24 hours at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in Platelets x 10^9 /L
- Change biochemistry assessments : SGPT (Sérum Glutamate Pyruvate Transaminase) at 24 hours as compared to Baseline [24 hours]
% of patient with change in SGPT in UI/L
- Change biochemistry assessments : SGPT at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in SGPT in UI/L
- Change biochemistry assessments : SGOT at 24 hours as compared to Baseline [24 hours]
% of patient with change in SGOT in UI/L
- Change biochemistry assessments : SGOT at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in SGOT in UI/L
- Change biochemistry assessments: LDH at 24 hours as compared to Baseline [24 hours]
% of patient with change in LDH in UI/l
- Change biochemistry assessments : LDH at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in LDH in UI/l
- Change biochemistry assessments : Cholesterol at 24 hours as compared to Baseline [24 hours]
% of patient with change in Cholesterol in g/L or mmol/L
- Change biochemistry assessments : Cholesterol at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in Cholesterol in g/L or mmol/L
- Change biochemistry assessments : Triglycerid at 24 hours as compared to Baseline [24 hours]
% of patient with change in Triglycerid in g/L or mmol/L
- Change biochemistry assessments : Triglycerid at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in Triglycerid in g/L or mmol/L
- Change biochemistry assessments : Urea at 24 hours as compared to Baseline [24 hours]
% of patient with change in Urea in g/L or mmol/L
- Change biochemistry assessments : Urea at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in Urea in g/L or mmol/L
- Change biochemistry assessments : Creatinin at 24 hours as compared to Baseline [24 hours]
% of patient with change in Creatinin in mg/L or µM/L
- Change biochemistry assessments : Creatinin at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in Creatinin in mg/L or µM/L
- Change biochemistry assessments : GFR at 24 hours as compared to Baseline [24 hours]
% of patient with change in GFR in mL/min/1,73 m²
- Change biochemistry assessments : GFR at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change inGFR in mL/min/1,73 m²
- Change biochemistry assessments : Serum Glucose at 24 hours as compared to Baseline [24 hours]
% of patient with change in Serum Glucose in g/L
- Change biochemistry assessments : Serum Glucose at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in Serum Glucose in g/L
- Change biochemistry assessments : D-Dimer at 24 hours as compared to Baseline [24 hours]
% of patient with change in D-Dimer in µg/L
- Change biochemistry assessments : D-Dimer at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in D-Dimer in µg/L
- Change biochemistry assessments : Fibrinogen at 24 hours as compared to Baseline [24 hours]
% of patient with change in Fibrinogen in g/L
- Change biochemistry assessments : Fibrinogen at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in Fibrinogen in g/L
- Change biochemistry assessments : INR score at 24 hours as compared to Baseline [24 hours]
% of patient with change in INR Score
- Change biochemistry assessments : INR score at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in INR Score
- Change biochemistry assessments : PT score at 24 hours as compared to Baseline [24 hours]
% of patient with change in PT in sec
- Change biochemistry assessments : PT score at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in PT in sec
- Change biochemistry assessments : aPTT score at 24 hours as compared to Baseline [24 hours]
% of patient with change in aPTT in sec
- Change biochemistry assessments : aPTT score at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in aPTT in sec
- Change in dipstick urinalysis assessments: Turbidity at 24 hours as compared to Baseline [24 hours]
% of patient with change in Change in urinalysis assessments
- Change in dipstick urinalysis assessments: pH at 24 hours as compared to Baseline [24 hours]
% of patient with change in Change in urinalysis assessments
- Change in dipstick urinalysis assessments: Glucose at 24 hours as compared to Baseline [24 hours]
% of patient with change in Change in urinalysis assessments
- Change in dipstick urinalysis assessments: Proteins at 24 hours as compared to Baseline [24 hours]
% of patient with change in Change in urinalysis assessments
- Change in dipstick urinalysis assessments: Blood at 24 hours as compared to Baseline [24 hours]
% of patient with change in Change in urinalysis assessments
- Change in dipstick urinalysis assessments: Leucocytes at 24 hours as compared to Baseline [24 hours]
% of patient with change in Change in urinalysis assessments
- Change in dipstick clinical laboratory assessments (urinalysis) at Day 7 or discharge as compared to Baseline [Day 7]
% of patient with change in Change in urinalysis assessments
- ECG changes [24 hours]
ECG change from baseline on QT, QTc, PR, ST and QRS intervals at 24 hours as compared to Baseline
- ECG changes [Day 7]
ECG change from baseline on QT, QTc, PR, ST and QRS intervals at Day 7 as compared to Baseline
- ECG changes [Day 90]
ECG change from baseline on QT, QTc, PR, ST and QRS intervals at discharge as compared to Baseline
Other Outcome Measures
- Imaging for exploratory endpoints [Baseline]
Acute ischemic stroke diagnosis and occluded cerebral vessel identification assessed by CT/CTA/MRI/MRA
- Imaging for exploratory endpoints [24 hours]
Non-symptomatic intracranial hemorrhage detection assessed by plain CT-scan or MRI
- Medico-economics endpoints [Day 90]
- Incremental cost effectiveness ratio (ICER), stated as cost per quality adjusted life year gained (QALY), using EQ-5D-5L (aggregated)
- Medico-economics endpoints [Day 90]
- Incremental cost effectiveness ratio (ICER), stated as cost per quality adjusted life year gained (QALY), using EQ-5D-5L (aggregated) DeathoverthewholestudyperioduntilDay90(Kaplan- Meier curve) Death within 24 hours Rehabilitation (% and length, % of in and out-patient status) Re-hospitalization within the Day 90 period following initial event (length of stay(s)) Imaging techniques used Other explorations done Medications
- Medico-economics endpoints [Day 90]
Length of initial hospital stay (subdivided by type) o Death within 24 hours Rehabilitation (% and length, % of in and out-patient status) Re-hospitalization within the Day 90 period following initial event (length of stay(s)) Imaging techniques used Other explorations done Medications
- Medico-economics endpoints [Day 90]
Death over the whole study period until Day90 (Kaplan- Meier curve)
- Medico-economics endpoints [24 hours]
Death Rehabilitation (% and length, % of in and out-patient status) Re-hospitalization within the Day 90 period following initial event (length of stay(s)) Imaging techniques used Other explorations done Medications
- Medico-economics endpoints [Day 90]
Rehabilitation (% and length, % of in and out-patient status) Re-hospitalization within the Day 90 period following initial event (length of stay(s)) Imaging techniques used Other explorations done Medications
- Medico-economics endpoints [Day 90]
Re-hospitalization following initial event (length of stay(s)) Imaging techniques used Other explorations done Medications
- Medico-economics endpoints [Day 90]
Imaging techniques used Other explorations done Medications
Eligibility Criteria
Criteria
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 or emergency consent in accordance with local 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 ≥ 4
-
In whom thrombolysis with tPA is or has been initiated, whether or not patients are additionally eligible to mechanical thrombectomy (MT)
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With an effective birth control method (if relevant) that should last for at least 2 months for non-menopausal women, and 4 months for men after IMP administration if applicable according to local regulatory requirement; birth control methods which may be considered as highly effective include:
-
intrauterine device
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intrauterine hormone-releasing system
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bilateral tubal occlusion
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vasectomized partner
-
sexual abstinence
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Women of childbearing potential must have a negative pregnancy test
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Patients affiliated to social security insurance (if applicable, in accordance to local regulations)
Exclusion Criteria:
-
Coma, or NIHSS >25.
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Patients < 18 years.
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Prior ischemic stroke within the past 3 months. 4. mRS pre-stroke known to be ≥ 2.
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Large (more than 1/3 of the middle cerebral artery) regions of clear hypodensity on Baseline Computed Tomography or Computed Tomography Angiography (CT/CTA) or Magnetic Resonance Imaging with/without vascular injection (MRA/MRI).
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Significant mass effect with midline shift. 7. Stroke of hemorrhagic origin. 8. Patients likely to require dual antiplatelet therapy within the 12 hrs after cessation of glenzocimab or placebo infusion for e.g., carotid stenting.
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Known renal insufficiency (Grades 4-5 - severe or terminal). 10. Known allergic reaction to contrast agents.
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Known ongoing anti-coagulant therapy. 12. Known ongoing treatment with a mAb. 13. Prior cardiopulmonary resuscitation < 10 days. 14. Childbirth within < 10 days.
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Epileptic seizure at symptom onset. 16. Life expectancy (except for stroke) < 3 months.
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Pregnancy or breastfeeding.
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Females of childbearing potential not using effective birth control methods.
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Known current participation in another clinical investigation with experimental drug.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Centre Hospitalier Universitaire de Bordeaux, | Bordeau | France | 33404 |
Sponsors and Collaborators
- Acticor Biotech
Investigators
- Study Director: Andrea Comenducci, MD, Acticor Biotech
Study Documents (Full-Text)
None provided.More Information
Additional Information:
- Design, development and characterization of ACT017, a humanized Fab that blocks platelet's glycoprotein VI function without causing bleeding risks
- Quality and cost assessment of a recombinant antibody fragment produced from mammalian, yeast and prokaryotic host cells: A case study prior to pharmaceutical development
Publications
- 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.
- Voors-Pette C, Lebozec K, Dogterom P, Jullien L, Billiald P, Ferlan P, Renaud L, Favre-Bulle O, Avenard G, Machacek M, Plétan 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.
- ACT-CS-005