E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute ischemic stroke |
Accident vasculaire cérébrale ischémique aigu |
|
E.1.1.1 | Medical condition in easily understood language |
Acute ischemic stroke |
Accident vasculaire cérébrale ischémique aigu |
|
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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10055221 |
E.1.2 | Term | Ischemic stroke |
E.1.2 | System Organ Class | 100000004852 |
|
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 |
The primary objective of this trial to assess the effect of unfractionated heparin and acetylsalicylic acid, alone, or in combination on functional outcome at 3 months in patients with AIS caused by a confirmed intracranial large vessel occlusion of the anterior circulation, who undergo intra-arterial treatment with or without prior intravenous thrombolysis according to standard care. Control patients will receive usual care alone (EVT with or without IVT), without additional periprocedural use of unfractioned heparin or acetylsalicylic acid, followed by analysis for stroke etiology, secondary preventive measures and rehabilitation. |
L’objectif primaire est d’évaluer l’effet de l’héparine non fractionnée et de l’acide acétylsalicylique, seuls ou en association, sur l’évolution fonctionnelle à 3 mois chez les patients ayant eu un AVC ischémique aigu dû à l’occlusion confirmée d’un vaisseau intracrânien antérieur de large calibre et ayant reçu un traitement intra-artériel précédé ou pas par une thrombolyse selon la pratique courante. Les patients contrôle recevront le traitement habituel seul (traitement endovasculaire avec ou sans thrombolyse intraveineuse), sans administration additionnelle péri-interventionnelle d'héparine non fractionnée ou d'acide acétylsalicylique suivie par l'analyse étiologique de l'AVC, des mesures préventives secondaires et de la réhabilitation. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objective is to assess the safety and effect of unfractionated heparin and acetylsalicylic acid, alone, or in combination, on neurological outcome, revascularization and infarct size in patients who undergo intra-arterial treatment for AIS caused by a confirmed intracranial large vessel occlusion of the anterior circulation. |
L’objectif secondaire est d’évaluer la sécurité et l’effet de l’héparine non fractionnée et de l’acide acétylsalicylique, seuls ou en association, sur l’évolution neurologique, la revascularisation et la taille de l’infarctus chez les patients ayant reçu un traitement intra-artériel pour AVC ischémique aigu dû à l’occlusion confirmée d’un vaisseau intracrânien antérieur de large calibre. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- a clinical diagnosis of acute ischemic stroke; - caused by intracranial large vessel occlusion of the anterior circulation (distal intracranial carotid artery or middle (M1/proximal M2) cerebral artery confirmed by neuro-imaging (CTA or MRA); - CT or MRI ruling out intracranial hemorrhage; - treatment possible (groin puncture) within 6 hours from symptom onset or last seen well; - a score of at least 2 on the NIH Stroke Scale; - age of 18 years or older; - written informed consent (deferred). |
- Diagnostic d’AVC ischémique aigu - Causé par l’occlusion d’un vaisseau intracrânien antérieur de large calibre (artère carotide intracrânienne distale ou artère cérébrale moyenne (segments M1/M2 proximal)) confirmée par neuro-imagerie (angio-scanner ou angio-IRM) ; - Scanner ou IRM éliminant une hémorragie intracrânienne ; - Traitement possible (ponction de l’aine) dans les 6 heures depuis le début des symptômes ou la dernière fois en bon état ; - Score NIHSS ≥ 2 ; - Age ≥ 18 ans ; - Ayant signé le consentement éclairé écrit (différé). |
|
E.4 | Principal exclusion criteria |
- Pre-stroke disability which interferes with the assessment of functional outcome at 90 days, i.e. mRS >2 - (Relative) contra-indications for ASA/unfractionated heparin, including: allergy, recent surgery, heparin induced thrombocytopenia, pregnancy - INR exceeding 3.0 - Known hemorrhagic diathesis or known thrombopenia (<90^9/L) - Treatment with IV alteplase despite the following contra-indications for IV alteplase: o cerebral infarction in the previous 6 weeks with residual neurological deficit or signs of recent infarction on neuroimaging, o previous intracerebral hemorrhage within the previous 3 months, o INR exceeding 1.7, o prior use of direct oral anticoagulant (DOAC), - IV alteplase infusion >4.5 hours after symptom onset. - therapeutic heparin use - Participation in medical or surgical intervention trials other than current (or MR ASAP / ARTEMIS) |
- Handicap pré-infarctus qui interfère avec l’évaluation fonctionnelle à 90 jours, ex. mRS > 2 ; - Traitement avec alteplase intraveineuse malgré les contrindications suivantes pour l’alteplase intraveineuse : o Infarctus cérébral dans les 6 semaines précédentes avec déficit neurologique résiduel ou signes d’infarctus récent sur la neuroimagerie ; o Hémorragie intracérébrale dans les 3 mois précédents ; o INR dépassant 1,7 ; o Précédente administration d’anticoagulants oraux directs (AOD) ; o Perfusion d’alteplase intraveineuse > 4,5 heures après le début des symptômes. - (Relative) Contrindications pour acide acétylsalicylique/héparine non fractionnée, incluant : allergie, chirurgie récente, thrombocytopénie induite par l’héparine, grossesse ; - Utilisation d’héparine thérapeutique ; - INR dépassant 3,0 ; - Diathèses hémorragique ou thrombocytopénie (<909/L) connues ; - Participation à une recherche clinique interventionnelle de type médicament ou chirurgicale autre que la présente (ou MR ASAP / ARTEMIS aux Pays-Bas). |
|
E.5 End points |
E.5.1 | Primary end point(s) |
90 days (± 14 days).30 The mRS is the preferred disability parameter of clinical trials in stroke. The mRS is an ordinal hierarchical scale incorporating six categories from 0 up to and including 5, and describes the range of disability encountered post stroke. 'Death' is assigned a score of 6. |
Le critère d’évaluation principal est le score de Rankin modifié (mRs) à 90 jours (± 14 jours) après l’inclusion dans l’étude. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
- Extended treatment in cerebral ischaemia (eTICI) score on final angiography of IAT (Table 2) - Recanalization rate at 24 hours, assessed with CTA - Score on the NIHSS at 24 hours and 5-7 days, or at discharge - Final infarct volume at 5-7 days, assessed with NCCT or MRI in a subset of 600 patients. Final infarct volume will be assessed with the use of an automated, validated algorithm. Infarct size at day 5-7 will be compared with plain CT and perfusion CT results (if available) at baseline. - Dichotomized mRS of 0-1 vs. 2-6 at 90 days (± 14 days) - Dichotomized mRS of 0-2 vs. 3-6 at 90 days (± 14 days) - Dichotomized mRS of 0-3 vs. 4-6 at 90 days (± 14 days) - Score on the EQ-5D-5L and Barthel index at 90 days (± 14 days) Safety endpoints are the following: - Intracerebral hemorrhage according to the Heidelberg Bleeding Classification - Symptomatic intracerebral hemorrhage (sICH) scored according to the Heidelberg Bleeding Classification, with the addition of sICH that led to death and that was identified as the predominant cause of the neurologic deterioration - Major extracranial hemorrhages requiring transfusion or resulting in death - Embolization in new territory on angiography during IAT - Infarction in new territory within 5-7 days |
Les critères d’évaluation secondaire incluent la mortalité à 90 jours, la gravité de l’AVC mesurée par le score National Institutes of Health Stroke (NIHSS) à 24 heures et 5-7 jours, la recanalisation via l’angiographie de soustraction digitale postinterventionnelle (mesurée par le score de recanalisation eTICI) et via le scanner à 24 +/- 12 heures ou IRM à 24-48 heures et la taille de l’infarctus à 5-7 jours, ou 24-48 heures si IRM effectuée, et mRS dichotomisé, décès, score du EQ-5D-5L et index de Barthel à 90 jours. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Mostly at 90 days |
Majoritairement à 90 jours |
|
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 | Yes |
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 | No |
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) | No |
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 | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Prise en charge habituelle |
Standard care |
|
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
|
LVLS and The study will only be terminated prematurely if the Data Safety Monitoring Board recommends stopping. In case of premature termination of the study the database will be closed after 90 days assessment of the last enrolled patient and results will be reported |
Dernière visite dernier patient et L'étude sera arrêtée prématurément uniquement si le Comité de Surveillance Indépendant propose l’arrêt. En cas d’arrêt prématuré de l'étude, la base de données sera clôturée après l'évaluation à 90 jours du dernier patient inclus et les résultats seront colligés. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |