Combined Thrombectomy for Distal MediUm Vessel Occlusion StroKe

Study Overview
=================
Brief Summary
-----------------
A phase III, randomized, multi-center, investigational, open label clinical trial that will examine whether treatment with endovascular thrombectomy is superior to standard medical therapy alone in patients who suffer a Distal Medium Vessel Occlusion Ischemic Stroke within 12 hours from time last seen well

Detailed Description
-----------------
DUSK is a Phase-3, prospective, multicenter, investigational, randomized, controlled, open-label study with blinded endpoint evaluation (PROBE design) and an adaptive design with population enrichment. The randomization employs a 1:1 ratio of endovascular thrombectomy (EVT) versus standard medical management (SMM) in patients who suffer a distal medium vessel occlusion (DMVO) stroke within 12 hours from time last seen well (TLSW) and have evidence of salvageable brain tissue on perfusion imaging. Randomization will be done under a minimization process using age (≤67 vs. >67 years), baseline NIHSS (≤12 vs. >12), use of IV thrombolysis (none vs. within 120 minutes from randomization vs. > 120 minutes from randomization), site of occlusion (M2 vs. M3 vs. ACA vs. PCA), baseline infarct volume (≤15mL vs. >15-30mL vs. >30-50mL), perfusion mismatch volume (≤15mL vs. >15-30mL vs. >30-50mL), therapeutic window (0-4.5 vs. 4.5-8 or >9-12 hours after TLKW), and participating site. The candidate enriched populations that the trial considers are based on use of intravenous thrombolysis (none vs. within 120 minutes from randomization vs. > 120 minutes from randomization), TLKW to randomization (0-6 vs. 6-12 hours) and mismatch volumes as measured using absolute mismatch (defined as Tmax>6 sec - DWI lesion on MRI or Tmax>6 sec -rCBF<30% lesion on CTP) (>40 cc vs. >30cc vs. >20cc vs. >10cc). The primary endpoint will be a categorical shift across all levels on the modified Rankin Scale (mRS) at 90-days post-randomization. The hypothesis is that EVT will lead to an improved clinical outcome at 90 days. Interim analysis will be performed after the primary endpoint is available for a total of 386 randomized patients.

Official Title
-----------------
A Phase III, Randomized, Multicenter, Investigational, Open Label Clinical Trial That Will Examine Whether Treatment With Endovascular Thrombectomy is Superior to Standard Medical Therapy Alone in Patients Who Suffer a Distal Medium Vessel Occlusion Ischemic Strokes.

Conditions
-----------------
Ischemic Stroke

Intervention / Treatment
-----------------
* Device: Experimental: endovascular thrombectomy in patients who suffer a distal medium vessel occlusion
* Other: Standard medical management


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥18 years (no upper age limit) Acute ischemic stroke where patient is ineligible for or has failed* IV thrombolytic treatment and is ineligible for endovascular treatment under best guideline-based care due to absence of proximal arterial occlusion (e.g. intracranial ICA, MCA-M1 and co-dominant or dominant M2** segments, and vertebrobasilar arteries).*** * IV thrombolytic treatment failure is defined by persistent disabling neurological deficits beyond 60 minutes of completion of thrombolytic infusion in the presence of imaging findings consistent with DMVO. **Dominant M2 segment is defined is a division supplying >50% of the MCA territory vs co-dominant supplying 50% of the MCA territory vs non-dominant supplying <50% of the MCA territory. ***No procedures or tests required by the protocol will delay fastest possible delivery of thrombolytic therapy to potentially eligible subjects. Evidence of a primary (e.g. not secondary to EVT of proximal vessel occlusion) distal medium vascular occlusion defined as occlusion of the non-dominant M2 segment or M3 segment of the MCA, the ACA (A1, A2, or A3 segments), or the PCA (P1, P2 or P3 segments) resulting in significant clinical deficits and expected to be treatable by endovascular thrombectomy. Non dominant M2 segment vessel diameter should not exceed 2.5mm. No significant pre-stroke functional disability (mRS ≤2) Evidence of a disabling stroke defined as follows: Baseline National Institutes of Health Stroke Scale (NIHSS) score >5 at the time of randomization. NIHSS 3-5 with disabling deficit including significant aphasia, neglect, hemianopsia, or hemiparesis/ loss of hand or leg function as established by the treating team in context of the patient's life. The presence of a Target Mismatch defined as: Ischemic Core < 50cc (defined on NCCT/CTP* or DWI-MRI) *Visual or automatedly detected hypodensity on NCCT should be used to exclude or include patients if the investigator believes that their assessment is more reliable than the CTP volume in any particular case. Mismatch Volume (TMax >6sec lesion - Core volume lesion) >10cc Mismatch Ratio >1.4 Patient treatable within 12 hours of symptom onset. Symptoms onset is defined as the point in time the patient was last seen well (at baseline). Treatment start is defined as the time of arterial puncture. Informed consent obtained from patient or acceptable patient surrogate Exclusion Criteria: Any sign of intracranial hemorrhage on baseline CT/MR (SDH/SAH/ICH). Rapidly improving symptoms, particularly if in the judgment of the managing clinician that the improvement is likely to result in the patient having no residual disabling deficits and an NIHSS score of <5 at randomization. Significant ischemic changes in a territory other than the occluded site that in the opinion of the investigator could reduce the benefit of endovascular treatment. Contra indication to imaging with MR or CT with contrast agents. Infarct core >1/3 occluded territory (MCA, ACA, or PCA) qualitatively or >50 mL quantitatively (determined by NCCT, CTP or DWI). Any terminal illness such that patient would not be expected to survive more than 1 year. Recent past history or clinical presentation of ICH, subarachnoid hemorrhage (SAH), arterio-venous (AV) malformation, aneurysm, or cerebral neoplasm other than meningioma. Any imaging findings suggestive of futile recanalization in the judgment of the local investigator. Premorbid disability (mRS ≥3). Inability to initiate endovascular treatment within 12 hours of last known well. Seizures at stroke onset if it precludes obtaining an accurate baseline NIHSS. Baseline blood glucose of <50 mg/dL (2.78 mmol) or >400 mg/dL (22.20 mmol). Known history of hereditary or acquired hemorrhagic diathesis and/or platelet count <100,000/uL. Known renal failure as defined as serum creatinine levels > 3.0 mg/dL. Presumed septic embolus or suspicion of bacterial endocarditis. Any other condition that, in the opinion of the investigator, precludes an endovascular procedure or poses a significant hazard to the subject if an endovascular procedure was performed. History of drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. Subjects with occlusions in multiple vascular territories (e.g., bilateral or multi-territorial anterior circulation, or anterior/posterior circulation) Subject participating in a study involving an investigational drug or device that would impact this study Known pregnancy Prisoner or incarceration Known acute symptomatic COVID-19 infection

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The randomization employs a 1:1 ratio of endovascular thrombectomy (EVT) with the use of Trevo NXT ProVue Retrievers, AXS Vecta 46 Intermediate Catheter and AXS Catalyst 5 Distal Access Catheter, versus standard medical management (SMM) in patients who suffer a distal medium vessel occlusion (DMVO) stroke within 12 hours from time last seen well (TLSW) and have evidence of salvageable brain tissue on perfusion imaging. Randomization will be done under a minimization process using age (≤67 vs. >67 years), baseline NIHSS (≤12 vs. >12), use of IV thrombolysis (none vs. within 120 minutes from randomization vs. > 120 minutes from randomization), site of occlusion (M2 vs. M3 vs. ACA vs. PCA), baseline infarct volume (≤15mL vs. >15-30mL vs. >30-50mL), perfusion mismatch volume (≤15mL vs. >15-30mL vs. >30-50mL), therapeutic window (0-4.5 vs. 4.5-8 or >9-12 hours after TLKW), and participating site.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of Care Treatment<br>Standard medical management in patients who suffer a distal medium vessel occlusion | Other: Standard medical management<br>* All subjects should receive the best standard medical therapy based on current AHA guidelines. Subjects randomized to standard medical management (SMM) will receive standard medical therapy only based on the guidelines. All subjects are expected to be admitted to hospital as part of routine best guideline-based care and treated on a stroke unit or neurointensive care unit or equivalent.<br>* Other names: Active Comparator;|
| Experimental: Endovascular Thrombectomy<br>Endovascular thrombectomy in patients who suffer a distal medium vessel occlusion. | Device: Experimental: endovascular thrombectomy in patients who suffer a distal medium vessel occlusion<br>* The AXS Catalyst Distal Access Catheter is indicated for use in facilitating the insertion and guidance of appropriately sized interventional devices into a selected blood vessel in the peripheral and neurovascular systems, and is also indicated for use as a conduit for retrieval devices. The AXS Vecta Intermediate Catheter, as part of the AXS Vecta Aspiration System, is indicated in the revascularization of patients with acute ischemic stroke. Patients who are ineligible for intravenous tissue plasminogen activator (IV t-PA) or who failed IV t-PA therapy are candidates for treatment. The Trevo® Retriever is indicated for use to restore blood flow in the neurovasculature by removing thrombus for the treatment of acute ischemic stroke to reduce disability in patients with a persistent, proximal anterior circulation, large vessel occlusion, and smaller core infarcts who have first received intravenous tissue plasminogen activator (IV t-PA).<br>* Other names: NXT ProVue Retriever;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Shift in distribution of all levels of the 90-day modified Rankin Scale with levels 5-6 combined (mRS; 0, 1, 2, 3, 4, 5-6) as assessed by structured assessment | Modified Rankin Scale measurement (mRS): 0=no symptoms, 1= no significant disablity despite symptoms, able to carry out all usual duties. 2= slight disability, unable to carry out all previous activities, but able to look after own affairs without assistance. 3=moderate disability, requiring some help, able to walk without assistance. 4=moderatly severe disability, unable to walk and attend to bodily needs without assistance. 5=severe disability, bedridden, incontinent and requiring total nursing care. 6=dead | 90-day follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Shift in distribution of the 90-day mRS (0;1;2;3;4;5;6) as assessed by structured assessment | Modified Rankin Scale measurement (mRS)0=no symptoms, 1= no significant disablity despite symptoms, able to carry out all usual duties. 2= slight disability, unable to carry out all previous activities, but able to look after own affairs without assistance. 3=moderate disability, requiring some help, able to walk without assistance. 4=moderatly severe disability, unable to walk and attend to bodily needs without assistance. 5=severe disability, bedridden, incontinent and requiring total nursing care. 6=dead | 90-day follow-up | 
| Rates of Independent Outcome defined as mRS ≤2 and/ or equal to Baseline mRS at 90 days | Independant outcome: 0=no symptoms, 1= no significant disablity despite symptoms, able to carry out all usual duties. 2= slight disability, unable to carry out all previous activities, but able to look after own affairs without assistance. 3=moderate disability, requiring some help, able to walk without assistance. 4=moderatly severe disability, unable to walk and attend to bodily needs without assistance. 5=severe disability, bedridden, incontinent and requiring total nursing care. 6=dead | 90-day follow-up | 
| Rates of Excellent Outcome defined as mRS ≤1 and/ or equal to Baseline mRS at 90 days | Excellent outcome: 0=no symptoms, 1= no significant disablity despite symptoms, able to carry out all usual duties. 2= slight disability, unable to carry out all previous activities, but able to look after own affairs without assistance. 3=moderate disability, requiring some help, able to walk without assistance. 4=moderatly severe disability, unable to walk and attend to bodily needs without assistance. 5=severe disability, bedridden, incontinent and requiring total nursing care. 6=dead. | 90-day follow-up | 
| Rates of Good Functional Outcomes adjusted for the baseline mRS and stroke severity (NIHSS) according to the modified Rankin Scale scores at 90 days as following: | NIHSS and mRS scores MRS: 0=no symptoms, 1= no significant disablity despite symptoms, able to carry out all usual duties. 2= slight disability, unable to carry out all previous activities, but able to look after own affairs without assistance. 3=moderate disability, requiring some help, able to walk without assistance. 4=moderatly severe disability, unable to walk and attend to bodily needs without assistance. 5=severe disability, bedridden, incontinent and requiring total nursing care. 6=dead NIHSS: 0=no stroke symptoms, 1-4=minor stroke, 5-15 moderate stroke, 16-20 moderate to sever stroke, 21-42- severe stroke. If NIHSS <10 and Baseline mRS 0 or 1: 90-day mRS ≤1 If NIHSS <10 and Baseline mRS 2: 90-day mRS ≤2 If NIHSS ≥10 and Baseline mRS 0 or 1: 90-day mRS ≤2 If NIHSS ≥10 and Baseline mRS 2: 90-day mRS ≤3 | 90-day follow-up | 
| EVT arm only: Final reperfusion grades according to the extended Thrombolysis in Cerebral Infarction (eTICI) scale and the rates of First Pass Effect (eTICI ≥2c) and Modified First Pass Effect (eTICI ≥2b50) | Reprofusion grades :TICI scores:grade 0: no perfusion noted (0% reperfusion) grade 1: reduction in thrombus but without any resultant filling of distal arterial branches grade 2 grade 2a: reperfusion of 1-49% of the territory grade 2b50: reperfusion of 50-66% of the territory grade 2b67: reperfusion of 67-89% of the territory grade 2c: extensive reperfusion of 90-99% of the territory grade 3: complete or full reperfusion (100% reperfusion). | 90-day follow-up | 
| EVT arm only: Final reperfusion grades according to the rates of First Pass Effect (eTICI ≥2c) | Reprofusion grades :TICI scores:grade 0: no perfusion noted (0% reperfusion) grade 1: reduction in thrombus but without any resultant filling of distal arterial branches grade 2 grade 2a: reperfusion of 1-49% of the territory grade 2b50: reperfusion of 50-66% of the territory grade 2b67: reperfusion of 67-89% of the territory grade 2c: extensive reperfusion of 90-99% of the territory grade 3: complete or full reperfusion (100% reperfusion). | 90-Day follow up | 
| EVT arm only: Final reperfusion grades according to the Modified First Pass Effect (eTICI ≥2b50) | Reprofusion grades :TICI scores:grade 0: no perfusion noted (0% reperfusion) grade 1: reduction in thrombus but without any resultant filling of distal arterial branches grade 2 grade 2a: reperfusion of 1-49% of the territory grade 2b50: reperfusion of 50-66% of the territory grade 2b67: reperfusion of 67-89% of the territory grade 2c: extensive reperfusion of 90-99% of the territory grade 3: complete or full reperfusion (100% reperfusion). | 90 day follow up | 
| Mean score for disability on the utility-weighted modified Rankin scale (UW-mRS) at 90 days | utility weighted mRS 0=no symptoms, 1= no significant disablity despite symptoms, able to carry out all usual duties. 2= slight disability, unable to carry out all previous activities, but able to look after own affairs without assistance. 3=moderate disability, requiring some help, able to walk without assistance. 4=moderatly severe disability, unable to walk and attend to bodily needs without assistance. 5=severe disability, bedridden, incontinent and requiring total nursing care. 6=dead | 90-day follow-up | 
| Final infarct volume (FIV) (FIV - baseline infarct on CTP or DWI) evaluated on CT or MRI at 24 hours (-2/+12 hours) | Infarct volume at 24 hours will be measured on CT or MRI. | 24 hours (-2hours /+12 hours) | 
| Final infarct growth (FIV - baseline infarct on CTP or DWI) | Infarct volume at 24 hours will be measured on CT or MRI, growth of infarct from baseline to 24 hours will be captured. | 24 hours (-2 hours/+12 hours) | 
| Final infarct volume (FIV) and infarct growth (FIV - baseline infarct on CTP or DWI) evaluated on CT or MRI at 3-5 days (if available) | Infarct volume at 3-5 days will be measured on CT or MRI. | 3-5 days | 
| Final infarct growth (FIV - baseline infarct on CTP or DWI) evaluated on CT or MRI at 3-5 days (if available) | Infarct volume at 3-5 days will be measured on CT or MRI, growth of infarct will be compared to baseline. | 3 to 5 days | 
| Clinical improvement at 24 hours calculated as the difference between 24-hour and baseline NIHSS score | NIHSS score at 24hours :NIHSS: 0=no stroke symptoms, 1-4=minor stroke, 5-15 moderate stroke, 16-20 moderate to sever stroke, 21-42- severe stroke. | 24 hours | 
| Cost effectiveness analysis of endovascular thrombectomy vs standard medical therapy | Assessment of costs from the time of randomization to the 90 day follow up. This includes Costs of hospitalization, institutional living and outpatient care will be assessed and compared for each arm. | 90-day follow-up | 
| Brain tissue reperfusion evaluated by CT or MRI perfusion at 24 hours in both treatment groups (if available) | CT or MRI results at 24 hours | 24 hours | 
| Vessel patency evaluated by CTA or MRA perfusion at 24 hours in both treatment groups (if available) | CTA or MRA perfusion results at 24 hours | 24 hours | 
| Patient reported outcomes (EQ-5D) | Questionnaires assessed by blinded assessor at 90 days. EQ-5D measures mobility, self care, usual activities, pain and anxiety, overall heath is measured on a scale of 0 (worst health state) to 100 best health state. | 90-day follow-up | 
| Patient reported outcomes (PROMIS Global-10) | Questionnaires assessed by blinded assessor at 90 days. Promise Global Health measures current health status on a scale of 1=poor, 2=fair, 3=good, 4=very good, 5=excellent. The scale is from 1-5 with 1 being the poorest health outcome and 5 the best. | 90 day follow up | 
| Patient reported outcomes (PROMIS Fatigue) | Questionnaires assessed by blinded assessor at 90 days. Promise Fatigue will measure degree of fatigue on a scale of 1=not at all, 2=a little bit, 3=somewhat, 4= quite a bit, 5=very much. The scale is from 1-5 with 1 being the least fatigued and 5 the greatest feeling of fatigue. | 90 day follow up | 
| Patient reported outcomes ( IADL) | Questionnaires assessed by blinded assessor at 90 days. IADL measures the ability to use a telephone, shop prepare food, do housekeeping, laundry, mode of transportation, medications and handle finances. The subject will answer the questions and answer as for how they are able to accomplish their ADLs. | 90 day follow up | 
| Patient reported outcomes ( MoCa) | Questionnaires assessed by blinded assessor at 90 days. MoCa measures the patient's ability to draw(visuospatial), name items, memory, attention, language, and abstraction. There are several questions that the subject will answer for each category. | 90 day follow up | 
| All cause mortality | All-cause mortality within 90 days | 90 day follow up | 
| Mortality due to stroke | Mortality within 90 days due to index stroke | 90 day follow up | 
| Intracranial hemorrhage | Symptomatic intracranial hemorrhage (SICH) defined as per the modified SITS-MOST definition:local or remote parenchymal hemorrhage type 2, subarachnoid hemorrhage, and/or intraventricular hemorrhage on the post-treatment imaging scan, combined with a neurological deterioration of 4 points or more on the NIHSS from baseline, or from the lowest NIHSS value between baseline and 24 h (-2/+12), or leading to death that the CEC/DSMB judges is causative of the deterioration. (https://www.sitsinternational.org/research/studies/sits-most-ii/) | 90 day follow up | 
| Intracranial hemorrhage | The incidence of any intracranial hemorrhage measured at 24 (-2/+12) hours as graded by the central core-lab using the Heidelberg classification criteria. | 24 hours (-2 hours /+12 hours) | 
| Procedure-related vessel perforation. | Perforation of the artery related to the procedure. | 24 hours (-2 hours /+12 hours) | 
| Procedure-related vessel dissection | Dissection of an artery related to the procedure. | 24 hours (-2 hours/+12 hours) | 
| Embolization to a new territory during mechanical thrombectomy (MT) procedure | New emboli to a different area of the brain during the MR procedure. | 24 hours (-2 hours/+12hours) | 
| Significant extracranial hemorrhage (e.g., access site, retroperitoneal hematoma) requiring blood transfusion and/or surgical intervention. | Hemorrhage in other areas besides the brain such as the arterial access site or retroperitoneum. | 24 hours (-2 hours/+12 hours) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Stroke, Ischemic