E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Ischemic Stroke is defined as an acute neurologic deficit caused by vascular occlusion or stenosis |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10055221 |
E.1.2 | Term | Ischemic stroke |
E.1.2 | System Organ Class | 100000004852 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy within the first 4.5 hrs 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). |
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E.2.2 | Secondary objectives of the trial |
Efficacy: • To assess the evolution of the National Institute of Health Stroke Scale (NIHSS) score. Safety: • To assess the number of the following events: o symptomatic and non-symptomatic intracranial hemorrhages, o deaths, o serious adverse events (SAEs), o suspected unexpected serious adverse reactions (SUSARs), o bleeding-related events, o treatment emergent adverse events (TEAEs) Quality of Life: • To evaluate Quality of Life at the end of study follow-up with a recognized QoL scale. Medico-Economics: • To collect care and economic data to support a cost-utility model at the end of Phase III. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 or emergency consent in accordance with local 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 ≥ 4 5. In whom thrombolysis with tPA is or has been initiated, whether or not patients are additionally eligible to mechanical thrombectomy (MT) 6. 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 • intrauterine hormone-releasing system • bilateral tubal occlusion • vasectomized partner • sexual abstinence 7. Women of childbearing potential must have a negative pregnancy test. |
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E.4 | Principal exclusion criteria |
1. Coma, or NIHSS >25 2. Patients < 18 years 3. Prior ischemic stroke within the past 3 months 4. mRS pre-stroke known to be ≥ 2 5. Large (more than 1/3 of the middle cerebral artery) regions of clear hypodensity on Baseline Computed Tomography Angiography (CTA) or Magnetic Resonance Imaging with vascular injection (MRA) 6. 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 9. Known renal insufficiency (Grades 4-5 – severe or terminal) 10. Known allergic reaction to contrast agents 11. Prior cardiopulmonary resuscitation < 10 days 12. Childbirth within < 10 days 13. Epileptic seizure at symptom onset 14. Life expectancy < 3 months 15. Pregnancy or breastfeeding 16. Females of childbearing potential not using effective birth control methods 17. Life expectancy (apart for stroke) greater than 3 months 18. Known current participation in another clinical investigation with experimental drug. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint: Ordinal modified Ranking Scale assessed at Day 90 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Ordinal mRS assessed at Day 90 |
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E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints: • Neurological Status Change as assessed by: o Response defined by a relative decrease (%) in NIHSS value at 24 hrs compared to pre-IVT value higher than 30%. • modified Ranking Scale assessed at Day 90 o Response defined as “0-1 (‘favorable outcome’ i.e., with no symptoms or no significant disability) vs. other categories. o Response defined as “0-2 (functionally independence) vs. other categories. o Utility-weighed mRS assessed at 3 months (the mean utility values (SD) for mRS categories 0 to 6 will be respectively: 0.95 (0.08), 0.93 (0.13), 0.83 (0.21), 0.62 (0.27), 0.42 (0.28), 0.11 (0.28), and 0 (0)). • Neurological Status Change as assessed by: o Response defined by a decrease from pre-IVT value in 24 hrs NIHSS score ≥ 8 points or score = 0) o Response defined by a decrease from pre-IVT value in 24 hrs NIHSS score ≥ 4 points or score = 0) o Worsening defined by an increase from pre-IVT value in 24 hrs NIHSS score ≥ 8 points.) o Worsening defined by an increase from pre-IVT value in 24 hrs NIHSS score ≥ 4 points.) • Quality of Life as assessed at Day 90 by the EuroQol-5 Dimension. A Quality of Life Scale (EQ-5D-5L).
SAFETY Secondary Endpoints: Incidence of the following events: • Deaths within the first 24 hrs and over the whole study period until Day 90 (Kaplan-Meier curve) • 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) • Non-symptomatic hemorrhages, seen on 24-hr plain CT-Scan, not present at baseline assessment, once other diagnoses are excluded • Incidence, nature and severity of Adverse Events, SAEs, bleeding-related events, and Treatment-Emergent Adverse Events (TEAEs) • Change in vital signs at any visit until Day 7 or discharge as compared to Baseline • Change in clinical laboratory assessments (hematology, biochemistry, urinalysis) at 24 hrs and Day 7 or discharge as compared to Baseline • ECG changes at 24 hrs and Day 7 or discharge as compared to Baseline.
Exploratory Endpoints Imaging: • Acute ischemic stroke diagnosis and occluded cerebral vessel identification assessed by CTA/MRA at Baseline • Non-symptomatic intracranial hemorrhage detection assessed by plain CT-Scan or MRI at 24 hrs • Vascular perfusion of the occluded cerebral artery by catheter angiography at the end of the EVT (only in patients undergoing an EVT) assessed by mTICI score measurement It is expected that a similar imaging technique is used for Baseline and 24 hrs evaluation for any given patient (i.e, MRI or CT-Scan) depending on best local experience. Baseline imaging should involve in either case a vascular enhancement with a contrast agent, while 24 hrs evaluation should not
Medico-economics Endpoints Aggregate endpoints: • Incremental cost effectiveness ratio (ICER), stated as cost per quality adjusted life year gained (QALY), using EQ-5D-5L (aggregated) • Incremental cost effectiveness ratio (ICER), stated as cost per quality adjusted life year gained (QALY), using utility-weighted mRS. Other endpoints: • Length of initial hospital stay (subdivided by type) • Death: o Death over the whole study period until Day 90 (Kaplan-Meier curve) o Death within 24 hrs • 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 • Private therapies • Work/productivity/revenue loss • Aids and equipment • Home employment/worker
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
T15min 6 hrs 24 hrs 7 Days 30 Days 60 Days 90 Days |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Russian Federation |
United States |
Belgium |
Denmark |
France |
Germany |
Hungary |
Poland |
Slovakia |
Spain |
United Kingdom |
Czechia |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 3 |