Randomization of Endovascular Treatment in Acute Ischemic Stroke in the Extended Time Window

Study Overview
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Brief Summary
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A phase III, randomized, multi-center, open label clinical trial that will examine whether endovascular treatment is superior to standard medical therapy alone in patients who suffer a large vessel anterior circulation ischemic stroke within 8-24 hours from time last seen well

Detailed Description
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Prospective, multi-center, randomized, controlled, open-label, blinded-endpoint trial with a sequential design. The randomization employs a 1:1 ratio of mechanical thrombectomy with stent-retriever and/or thromboaspiration versus medical management alone in patients who suffer a large vessel anterior circulation ischemic stroke between 8 and 24 hours from time last seen well. Randomization will be done under a minimization process using age (≤68 vs. >68 years), baseline NIHSS (<17 v. ≥17), ASPECTS (5-7 vs. 8-10), therapeutic window (6-12 or 12-24 hours after TLKW), occlusion site (Intracranial ICA or M1), and clinical site. For the primary endpoint, subjects will be followed for 90 days post-randomization. Sham endovascular procedure has been rejected due to the medical risk of the angiography and practical issues that difficult to maintain blindness of investigators.

Official Title
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Randomization of Endovascular Treatment With Stent-retriever and/or Thromboaspiration vs. Best Medical Therapy in Acute Ischemic Stroke Due to Large VEssel OcclusioN Trial in the Extended Time Window

Conditions
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Stroke, Ischemic

Intervention / Treatment
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* Device: Thrombectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute ischemic stroke where patient is ineligible for IV thrombolytic treatment or the treatment is contraindicated (e.g., subject presents beyond recommended time from symptom onset), or where patient has received IV thrombolytic therapy without clinical improvement. No significant pre-stroke functional disability (mRS ≤2) Baseline NIHSS score obtained prior to randomization must be equal or higher than 8 points (assessed within one hour prior to qualifying imaging) Age ≥18 years (no upper age limit) Occlusion (TICI 0-1) of the intracranial ICA (distal ICA or T occlusions) and/or MCA-M1 segment suitable for endovascular treatment, as evidenced by CTA, MRA or angiogram, with or without concomitant cervical carotid occlusion or stenosis. The presence of Age-Adjusted modified Clinical ASPECTS Mismatch (mCAM) defined as ASPECTS 5-10 and one of the following criteria: NIHSS ≥ 8 and >50% involvement in 0-1 Cortical (e.g. M1-6) ASPECTS areas (any age); NIHSS ≥ 8 and >50% involvement in 0-2 Cortical (e.g. M1-6) ASPECTS areas (and age < 80 years old); NIHSS ≥ 15 and >50% involvement in 0-3 Cortical (e.g. M1-6) ASPECTS areas (and age < 80 years old). Patient treatable within 6-24 hours of symptom onset. Symptoms onset is defined as point in time the patient was last seen well (at baseline). Treatment start is defined as arterial puncture. Informed consent obtained from patient or acceptable patient surrogate Exclusion Criteria: -Clinical criteria Known hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR > 3.0 Baseline platelet count < 30.000/µL Baseline blood glucose of < 50mg/dL Severe, sustained hypertension (SBP > 185 mm Hg or DBP > 110 mm Hg) NOTE: If the blood pressure can be successfully reduced and maintained at the acceptable level using AHA guidelines recommended medication (including iv antihypertensive drips), the patient can be enrolled. Patients in coma defined as totally unresponsive; responding only with reflexes or being areflexic (Intubated patients for transfer could be randomized only in case an NIHSS is obtained by a neurologist prior transportation). Seizures at stroke onset which would preclude obtaining a baseline NIHSS Serious, advanced, or terminal illness with anticipated life expectancy of less than one year. History of life-threatening allergy (more than rash) to contrast medium Subjects who has received IV t-PA treatment beyond 4.5 hours from the beginning of the symptoms Woman of childbearing potential who is known to be pregnant or who has a positive pregnancy test on admission. Subject participating in a study involving an investigational drug or device that would impact this study. Cerebral vasculitis Patients with a pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations, mRS score at baseline must be ≤2. This excludes patients who are severely demented, require constant assistance in a nursing home type setting or who live at home but are not fully independent in activities of daily living (toileting, dressing, eating, cooking and preparing meals, etc.) Unlikely to be available for 90-day follow-up (e.g. no fixed home address, visitor from overseas). - Neuroimaging criteria Hypodensity on CT or restricted diffusion on MRI amounting to an ASPECTS score of <5. Complete involvement of more than 3 cortical ASPECTS areas (e.g. M1, M2, M3, M4, M5, or M6). Complete absence of leptomeningeal collaterals on CT angiography (e.g. Malignant CTA pattern or score 0). CT or MR evidence of hemorrhage (the presence of GRE microbleeds is allowed). Significant mass effect with midline shift. Evidence of ipsilateral carotid occlusion, high grade stenosis or arterial dissection in the extracranial or petrous segment of the internal carotid artery that cannot be treated or will prevent access to the intracranial clot or excessive tortuosity of cervical vessels precluding device delivery/deployment Subjects with occlusions in multiple vascular territories (e.g., bilateral anterior circulation, or anterior/posterior circulation) Evidence of intracranial tumor (except small meningioma).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The randomization employs a 1:1 ratio of mechanical thrombectomy with stent-retriever and/or thromboaspiration versus medical management alone
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: thrombectomy<br>mechanical thrombectomy with stent-retriever and/or thromboaspiration | Device: Thrombectomy<br>* Endovascular treatment of large vessel occlusion (mechanical thrombectomy) with stent-retriever and/or thromboaspiration (neurointerventionalist choice)<br>* Other names: Endovascular treatment;|
| Active Comparator: Clinical treatment<br>Best Medical treatment | Device: Thrombectomy<br>* Endovascular treatment of large vessel occlusion (mechanical thrombectomy) with stent-retriever and/or thromboaspiration (neurointerventionalist choice)<br>* Other names: Endovascular treatment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Rankin Scale scores | Distribution of the modified Rankin Scale scores at 90 days (shift analysis). The score range from zero to 6 with higher values indicating a worst functional outcome at 90 days | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients with Functional independence in 90 days | Functional independence defined as mRS ≤2 | 90 days | 
| Disability on the utility-weighted modified Rankin scale (UW-mRS) | Mean score for disability on the utility-weighted modified Rankin scale (UW-mRS). The score range from 1 to zero with higher values indicating a better functional outcome at 90 days | 90 days | 
| Quality of life measured by EuroQol Group 5-Dimension Self-Report Questionnaire (EuroQol / EQ5D) | Quality of life analysis as measured by EuroQol/EQ5D 5-Dimension Self-Report Questionnaire, on which scores range from -0.176 to 1, with higher values indicating a better quality of life]) at 90 days | 90 days and 1 year | 
| Mortality at 90 days | Mortality at 90 days | 90 days | 
| Proportion of patients with Intracranial Hemorrhage at 24 hours | Clinically significant ICH rates at 24 (-2/+12) hours. All intracerebral hemorrhages will be classified by a central core-lab using the Heidelberg criteria. Symptomatic ICH will be defined as per the SITS-MOST definition: deterioration in NIHSS score of ≥4 points within 24 hours from treatment and evidence of intraparenchymal hemorrhage type 2 in the 22 to 36 hours follow-up imaging scans. | 24 hours | 
| Procedural related complications | Procedural related complications: arterial perforation, arterial dissection, and embolization in a previously uninvolved vascular territory | immediately after procedure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stroke, ischemic stroke, thrombectomy, treatment, acute stroke