Large Stroke Therapy Evaluation

Study Overview
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Brief Summary
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Stroke represents the fourth leading cause of death in industrialized nations, after heart disease, cancer, and chronic lower respiratory disease. The overall burden of stroke will rise dramatically in the next 20 years due to an ageing population. Approximately one-quarter of the patients suffering a stroke die within one year after the initial event and stroke is a leading cause of serious long-term disability. Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a potentially devastating event, with a poor prognosis in the absence of timely revascularization. Whether in patients with large anterior circulation stroke, direct mechanical intervention is equally effective, superior or inferior to bridging thrombolysis remains a matter of debate. Thus, this procedure, is now the recommended standard of care for selective patients with LVO in the anterior circulation. When performed with newer generation devices (mainly stent retrievers), more stringent imaging selection criteria and more efficient workflow than in previous trials, significantly reduces disability rates after AIS caused by LVO in the anterior circulation. The STAIR (Stroke Treatment Academic Industry Roundtable) meeting aims to advance acute stroke therapy development through collaboration between academia, industry, and regulatory institutions. In pursuit of this goal and building on the available level I evidence of benefit from endovascular therapy (EVT) in large vessel occlusion stroke, STAIR IX consensus recommendations were developed that outline priorities for future research in EVT.

Detailed Description
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The LASTE hypothesis is that patient harbouring a large ischemic core stroke at presentation, may still benefit from mechanical thrombectomy, given the very poor natural history of patient managed by a standalone medical therapy. The threshold of ASPECTS 5 to set a benefit for treatment was inspired by initial large medical trials using IV t-PA25-27 (Samurai-CT ALBERTA Score IV cohort). In the paradigm of acute and complete reperfusion, radiographic infarct stroke volume may be partially reversible and thus the resulting final infarct may be smaller compared to the one in non-re-perfused patients who will consequently have poorer clinical outcomes. By now, large core patients defined as ASPECTS 0-5 were excluded from most randomized clinical trials resulting in a lack of unequivocal evidence of benefit in this patient population. Analyses of several prospective cohorts suggest signals of benefit in favor of thrombectomy in patients with large baseline core. In the prospective cohort ETIS, LAPERGUE et al reported a rate of good outcome of 34% in the subgroup of patient with ASPECT 4-5. In the prospective cohort analysis RECOST, a mean mRS score of 34% in a group of patient presenting ASPECT 0-5 treated with mechanical thrombectomy, versus 9% of good outcome in the medical group, suggesting a benefit to treat LVO harbouring a large core. The strongest argument in favor of benefit of EVT even in patients with large core is provided by the six completed randomized endovascular stroke trials. These trials did prove that Combined Approach Mechanical + IV t-PA, is superior to standalone IV lytics, mRs score ≤ 2 ranging from 33% and up to 72%, but Large Core Infarction were largely excluded. Nonetheless a pooled analysis of these trials revealed that a minority of patients with large baseline core were still randomized. In MR CLEAN study, despite no exclusion criteria defined in the initial protocol, the median ASPECT score of the cohort was 9 out of 10. In SWIFT-PRIME study, the mean ASPECT score of the cohort was 7, and in REVASCAT study it was 6.8. The LASTE protocol Large Stroke Therapy Evaluation aims to study the efficacy and safety of mechanical thrombectomy in the acute phase of cerebral infarction less than 7 hours for patients with a large volume of necrosis defined by a score ASPECT from 0 to 5. The patients will be followed 6 months after the stroke.

Official Title
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Evaluation of Acute Mechanical Revascularisation in Large Stroke (ASPECTS 0-5) With Large Vessel Occlusion Within 7 Hours After Stroke Onset or Last Known Well

Conditions
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Stroke

Intervention / Treatment
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* Other: Best Medical Therapy
* Procedure: Mechanical Thrombectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is ≥ 18 years old at inclusion (no upper age limit) Clinical signs consistent with acute ischemic stroke with symptoms onset or time last known well (TLKW) ≤ 6.5 h from randomization (With the goal of remaining within 7 hours from TLKW till treatment), or with negative FLAIR on MRI, if TLKW is unknown Proven Large Ischemic Core defined as: ASPECT Score 0 to 5 on non-contrast CT or Diffusion Weighted Imaging (DWI)-MRI. In patients ≥ 80 years : ASPECT score 4 or 5. (ASPECTS on MRI will be calculated in the following way: an ASPECTS region will considered to be affected if > 30% of its area demonstrates restricted diffusion) Proved anterior circulation intracranial large vessel occlusion on CTA or MRA (intracranial ICA, M1, M1-M2) Patient or patient's representative has received information about the study and has signed and dated the appropriate Informed Consent Form, or fulfilling the criteria for emergent consent Selection imaging performed maximum 3 hours from randomization Anticipated possibility to start the procedure (arterial access) within 30 minutes after randomization Pre stroke mRS ≤ 1 Subjects receiving antiaggregant and/or anticoagulant agents (at any mode of administration) within the last 24 hours from screening are eligible for participation General Exclusion Criteria: Anticipated impossibility to start the procedure (arterial access) within 30 minutes after randomization. Known absence of vascular access. Known contrast or endovascular product life-threatening allergy. Female who is known to be pregnant or lactating at time of admission Patient presents severe or fatal co-morbidities or life expectancy under 6 months that will likely interfere with the improvement or follow-up or that will render the procedure unlikely to benefit the patient. Patient unable to present or be available for follow-up. Pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations. Evidence of vessel recanalization prior to randomization. Seizures at stroke onset if it makes the diagnosis of stroke doubtful and precludes obtaining an accurate baseline NIHSS assessment. Current participation in another investigational drug study. Suspicion of aortic dissection based on medical history, clinical evaluation or/and imaging. Major patients under guardianship. Imaging Exclusion Criteria: Evidence of intracranial haemorrhage on CT/MRI Excessive tortuosity of cervical vessels on CTA/MRA that would likely result in unstable access platform High Suspicion of underlying intracranial stenosis on CTA/MRA/digital subtraction angiography (DSA) Suspected cerebral vascular disease (e.g. vasculitis) based on medical history and CTA/MRA/DSA Presumed calcified Embolus or Intracranial Stenosis decompensation Intracranial stent implanted in the same vascular territory that would preclude the safe deployment/removal of the stentriever device Occlusions in multiple vascular territories (e.g.: bilateral anterior circulation, or anterior circulation/vertebrobasilar system) confirmed on CTA/MRA/DSA. Significant mass effect with midline shift as confirmed on CT/MRI Any cervical ICA lesion (Tandem), that requires stent placement Isolated proximal cervical ICA occlusions

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Best Medical Therapy (BMT)<br>Best treatment medical probably associated to the rescue endovascular treatment in case of neurological deterioration | Other: Best Medical Therapy<br>* The administration of medications is at the treating physician's discretion (for example intravenous fibrinolysis, anticoagulants or antiplatelet) according to local standards of care but may NOT include any intra-arterial therapies.<br>|
| Other: Mechanical Thrombectomy (MT)<br>Endovascular treatment (thrombectomy) associated with the best medical treatment | Procedure: Mechanical Thrombectomy<br>* MT in the Experimental Arm can be performed with any thrombectomy (CE labeled) device usually used at study site. For the subjects randomized to the MT plus BMT arm start of treatment is defined as the date and time of groin puncture (arterial access).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of functional outcome | Shift on the Modified Rankin Scale (mRS) at 90 days in experimental group vs the control group | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of all-cause mortality at 90 days | Evaluation of mortality at 90 days | 3 months | 
| Incidence of symptomatic intracerebral hemorrhage | Incidence of symptomatic intracerebral hemorrhage according to HEIDELBERG at imaging at 24 (-6/+12) hours post randomization | 1 day | 
| Deterioration of patient's condition | National Institutes of Health Stroke Scale (NIHSS) ≥ 10 points during hospitalization. This scale is construed by 15 items and the minimum score is 1 and the maximum score is 20. | 6 months | 
| Incidence of procedure/device-related adverse events | Incidence of procedure/device-related adverse events (in patients treated by mechanical treatment) | 1 day | 
| Evaluation of the degree of disability | The degree of disability at 180 days (shift on the mRS combining scores of 5 and 6) | 6 months | 
| Evaluation of functional outcome (mRS 0-2) | Rate of patients with a good functional outcome at 90 days and 180 days, defined as mRS 0-2 | 3 and 6 months | 
| Evaluation of functional outcome (mRS 0-3) | Rate of patients with a favorable outcome at 90 and 180 days, defined as Modified Rankin Scale (mRS) 0-3 | 3 and 6 months | 
| Distribution of utility weighted Modified Rankin Scale (mRS) | Distribution of utility weighted mRS (UW mRS) at 90 and 180 days | 3 and 6 months | 
| Quality of life of the patient | Quality of life at 90 and 180 days assessed by EuroQol 5D-5L (5-level EQ-5-Dimension) scale | 3 and 6 months | 
| Rate of patients with secondary decompressive craniectomy | Rate of patients with secondary decompressive craniectomy | 6 months | 
| Improvement of patient's condition | Rate of patients with early good response at Day 5-7/Discharge (whichever is earlier), defined as a NIHSS drop of ≥ 8 points from baseline or NIHSS score 0 or 1 | 7 days | 
| Medico-economic study | Cost-effectiveness analysis (number of patients functionally independent : mRS =< 2), cost of devices and drugs, staff hourly cost, operating room cost | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Large vessel occlusion, Mechanical thrombectomy, Stroke, Proximal intracranial arterial occlusions