Clinical trial NCT05983757: Combined Thrombectomy for Distal MediUm Vessel Occlusion StroKe
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.
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: NA
Conditions: Ischemic Stroke
Keywords: Stroke
Ischemic
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Stryker Neurovascular
name: Brainstorme Imaging Core Lab Inc
name: Berry Consultants
First posted: 2023-08-09
Enrollment: 564
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Age ≥18 years (no upper age limit)
2. 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.
3. 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.
4. No significant pre-stroke functional disability (mRS ≤2)
5. Evidence of a disabling stroke defined as follows:

   1. Baseline National Institutes of Health Stroke Scale (NIHSS) score \>5 at the time of randomization.
   2. 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.
6. The presence of a Target Mismatch defined as:

   1. 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.
   2. Mismatch Volume (TMax \>6sec lesion - Core volume lesion) \>10cc
   3. Mismatch Ratio \>1.4
7. 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.
8. Informed consent obtained from patient or acceptable patient surrogate

Exclusion Criteria:

1. Any sign of intracranial hemorrhage on baseline CT/MR (SDH/SAH/ICH).
2. 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.
3. 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.
4. Contra indication to imaging with MR or CT with contrast agents.
5. Infarct core \>1/3 occluded territory (MCA, ACA, or PCA) qualitatively or \>50 mL quantitatively (determined by NCCT, CTP or DWI).
6. Any terminal illness such that patient would not be expected to survive more than 1 year.
7. Recent past history or clinical presentation of ICH, subarachnoid hemorrhage (SAH), arterio-venous (AV) malformation, aneurysm, or cerebral neoplasm other than meningioma.
8. Any imaging findings suggestive of futile recanalization in the judgment of the local investigator.
9. Premorbid disability (mRS ≥3).
10. Inability to initiate endovascular treatment within 12 hours of last known well.
11. Seizures at stroke onset if it precludes obtaining an accurate baseline NIHSS.
12. Baseline blood glucose of \<50 mg/dL (2.78 mmol) or \>400 mg/dL (22.20 mmol).
13. Known history of hereditary or acquired hemorrhagic diathesis and/or platelet count \<100,000/uL.
14. Known renal failure as defined as serum creatinine levels \> 3.0 mg/dL.
15. Presumed septic embolus or suspicion of bacterial endocarditis.
16. 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.
17. History of drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
18. Subjects with occlusions in multiple vascular territories (e.g., bilateral or multi-territorial anterior circulation, or anterior/posterior circulation)
19. Subject participating in a study involving an investigational drug or device that would impact this study
20. Known pregnancy
21. Prisoner or incarceration
22. Known acute symptomatic COVID-19 infection

Primary outcomes:
measure: 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
timeFrame: 90-day follow-up
Secondary outcomes:
measure: Shift in distribution of the 90-day mRS (0;1;2;3;4;5;6) as assessed by structured assessment
timeFrame: 90-day follow-up
measure: Rates of Independent Outcome defined as mRS ≤2 and/ or equal to Baseline mRS at 90 days
timeFrame: 90-day follow-up
measure: Rates of Excellent Outcome defined as mRS ≤1 and/ or equal to Baseline mRS at 90 days
timeFrame: 90-day follow-up
measure: 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:
timeFrame: 90-day follow-up
measure: 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)
timeFrame: 90-day follow-up
measure: EVT arm only: Final reperfusion grades according to the rates of First Pass Effect (eTICI ≥2c)
timeFrame: 90-Day follow up
measure: EVT arm only: Final reperfusion grades according to the Modified First Pass Effect (eTICI ≥2b50)
timeFrame: 90 day follow up
measure: Mean score for disability on the utility-weighted modified Rankin scale (UW-mRS) at 90 days
timeFrame: 90-day follow-up
measure: Final infarct volume (FIV) (FIV - baseline infarct on CTP or DWI) evaluated on CT or MRI at 24 hours (-2/+12 hours)
timeFrame: 24 hours (-2hours /+12 hours)
measure: Final infarct growth (FIV - baseline infarct on CTP or DWI)
timeFrame: 24 hours (-2 hours/+12 hours)
measure: 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)
timeFrame: 3-5 days
measure: Final infarct growth (FIV - baseline infarct on CTP or DWI) evaluated on CT or MRI at 3-5 days (if available)
timeFrame: 3 to 5 days
measure: Clinical improvement at 24 hours calculated as the difference between 24-hour and baseline NIHSS score
timeFrame: 24 hours
measure: Cost effectiveness analysis of endovascular thrombectomy vs standard medical therapy
timeFrame: 90-day follow-up
measure: Brain tissue reperfusion evaluated by CT or MRI perfusion at 24 hours in both treatment groups (if available)
timeFrame: 24 hours
measure: Vessel patency evaluated by CTA or MRA perfusion at 24 hours in both treatment groups (if available)
timeFrame: 24 hours
measure: Patient reported outcomes (EQ-5D)
timeFrame: 90-day follow-up
measure: Patient reported outcomes (PROMIS Global-10)
timeFrame: 90 day follow up
measure: Patient reported outcomes (PROMIS Fatigue)
timeFrame: 90 day follow up
measure: Patient reported outcomes ( IADL)
timeFrame: 90 day follow up
measure: Patient reported outcomes ( MoCa)
timeFrame: 90 day follow up
measure: All cause mortality
timeFrame: 90 day follow up
measure: Mortality due to stroke
timeFrame: 90 day follow up
measure: Intracranial hemorrhage
timeFrame: 90 day follow up
measure: Intracranial hemorrhage
timeFrame: 24 hours (-2 hours /+12 hours)
measure: Procedure-related vessel perforation.
timeFrame: 24 hours (-2 hours /+12 hours)
measure: Procedure-related vessel dissection
timeFrame: 24 hours (-2 hours/+12 hours)
measure: Embolization to a new territory during mechanical thrombectomy (MT) procedure
timeFrame: 24 hours (-2 hours/+12hours)
measure: Significant extracranial hemorrhage (e.g., access site, retroperitoneal hematoma) requiring blood transfusion and/or surgical intervention.
timeFrame: 24 hours (-2 hours/+12 hours)
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Raul G Nogueira, MD
role: PRINCIPAL_INVESTIGATOR
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