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.
Overview
- Phase
- Not Applicable
- Intervention
- Standard medical management
- Conditions
- Ischemic Stroke
- Sponsor
- Raul Nogueira
- Enrollment
- 584
- Locations
- 4
- Primary Endpoint
- 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
- Status
- Recruiting
- Last Updated
- 2 months ago
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.
Investigators
Raul Nogueira
Director, UPMC Stroke Institute
University of Pittsburgh
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. Regardless of vessel anatomic location, all vessel diameters should be within 1.5mm -2.5mm. (refer to the device labeling for recommended vessel diameters for each device model.)\*
- •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.
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 seen well.
Arms & Interventions
Standard of Care Treatment
Standard medical management in patients who suffer a distal medium vessel occlusion
Intervention: Standard medical management
Endovascular Thrombectomy
Endovascular thrombectomy in patients who suffer a distal medium vessel occlusion.
Intervention: Experimental: endovascular thrombectomy in patients who suffer a distal medium vessel occlusion
Outcomes
Primary Outcomes
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
Time Frame: 90-day follow-up
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
Secondary Outcomes
- Shift in distribution of the 90-day mRS (0;1;2;3;4;5;6) as assessed by structured assessment(90-day follow-up)
- Rates of Independent Outcome defined as mRS ≤2 and/ or equal to Baseline mRS at 90 days(90-day follow-up)
- Rates of Excellent Outcome defined as mRS ≤1 and/ or equal to Baseline mRS at 90 days(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:(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)(90-day follow-up)
- EVT arm only: Final reperfusion grades according to the rates of First Pass Effect (eTICI ≥2c)(90-Day follow up)
- EVT arm only: Final reperfusion grades according to the Modified First Pass Effect (eTICI ≥2b50)(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)(24 hours (-2hours /+12 hours))
- Final infarct growth (FIV - baseline infarct on CTP or DWI)(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)(3-5 days)
- Vessel patency evaluated by CTA or MRA perfusion at 24 hours in both treatment groups (if available)(24 hours)
- Patient reported outcomes (EQ-5D)(90-day follow-up)
- Mean score for disability on the utility-weighted modified Rankin scale (UW-mRS) at 90 days(90-day follow-up)
- Final infarct growth (FIV - baseline infarct on CTP or DWI) evaluated on CT or MRI at 3-5 days (if available)(3 to 5 days)
- Clinical improvement at 24 hours calculated as the difference between 24-hour and baseline NIHSS score(24 hours)
- Cost effectiveness analysis of endovascular thrombectomy vs standard medical therapy(90-day follow-up)
- Brain tissue reperfusion evaluated by CT or MRI perfusion at 24 hours in both treatment groups (if available)(24 hours)
- Patient reported outcomes (PROMIS Global-10)(90 day follow up)
- Patient reported outcomes (PROMIS Fatigue)(90 day follow up)
- Patient reported outcomes ( IADL)(90 day follow up)
- Patient reported outcomes ( MoCa)(90 day follow up)
- All cause mortality(90 day follow up)
- Mortality due to stroke(90 day follow up)
- Intracranial hemorrhage(24 hours (-2 hours /+12 hours))
- Procedure-related vessel perforation.(24 hours (-2 hours /+12 hours))
- Procedure-related vessel dissection(24 hours (-2 hours/+12 hours))
- Embolization to a new territory during mechanical thrombectomy (MT) procedure(24 hours (-2 hours/+12hours))
- Significant extracranial hemorrhage (e.g., access site, retroperitoneal hematoma) requiring blood transfusion and/or surgical intervention.(24 hours (-2 hours/+12 hours))
- Intracranial hemorrhage(90 day follow up)