Clinical trial NCT02586415: Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3
Official title: Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Stroke, Acute
Cerebral Infarction
Keywords: endovascular
endovascular procedure
Mechanical Thrombectomy
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
name: University of Cincinnati
name: Medical University of South Carolina
name: NINDS Stroke Trials Network (StrokeNet)
First posted: 2015-10-26
Enrollment: 182
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a study to evaluate the hypothesis that FDA cleared thrombectomy devices plus medical management leads to superior clinical outcomes in acute ischemic stroke patients at 90 days when compared to medical management alone in appropriately selected subjects with the Target mismatch profile and an MCA (M1 segment) or ICA occlusion who can be randomized and have endovascular treatment initiated between 6-16 hours after last seen well.

Detailed description: DEFUSE 3 is a prospective randomized Phase III multicenter controlled trial of patients with acute ischemic anterior circulation strokes due to large artery occlusion treated between 6-16 hours of stroke onset with endovascular thrombectomy therapy vs. control.

The primary endpoint, the modified Rankin Score, will be assessed at 3 months. The patients' participation in the study concludes at that time (3 months from stroke onset). The study will randomize up to 476 patients over 4 years. The purpose of DEFUSE 3 is to assess the safety and efficacy of thrombectomy in carefully selected patients in an extended time window. Only the devices listed in this protocol will be used. Selection of the specific device (or devices) is determined by the individual endovascular therapist.

Patients who meet the inclusion criteria will undergo either CT Perfusion/CT Angiogram or MR DWI/PWI/MRA studies prior to randomization. Patients who have evidence of an ICA or MCA M1 occlusion and a Target Mismatch Profile will be randomized in a 1:1 ratio to treatment with one or more DEFUSE 3 approved thrombectomy devices (only the devices listed in this protocol are approved for use in DEFUSE 3) plus standard medical therapy versus standard medical therapy alone. Patients who are enrolled, but not randomized, will receive standard therapy according to local guidelines. Baseline data, and information about early stroke therapies, will be captured for this group of patients.

Randomization of a maximum of 476 patients is planned. A novel adaptive design will identify, at interim analyses, the group with the best prospect for showing benefit from endovascular treatment, based on baseline core lesion volumes and the times since stroke onset. Interim analyses will be conducted at 200 and 340 patients, at which time the study may stop for efficacy/futility, or the inclusion criteria may be adjusted in the case of futility.

Eligibility criteria: Clinical Inclusion Criteria:

1. Signs \& symptoms consistent w/ the diagnosis of acute anterior circulation ischemic stroke
2. Age 18-90 years
3. Baseline NIHSSS is ≥ 6 and remains ≥6 immediately prior to randomization
4. Endovascular treatment can be initiated (femoral puncture) between 6 and 16 hours of stroke onset. Stroke onset is defined as the time the patient was last known to be at their neurologic baseline (wake-up strokes are eligible if they meet the above time limits).
5. modified Rankin Scale less than or equal to 2 prior to qualifying stroke (functionally independent for all ADLs)
6. Patient/Legally Authorized Representative has signed the Informed Consent form.

Clinical Exclusion Criteria:

1. Other serious, advanced, or terminal illness (investigator judgment) or life expectancy is less than 6 months.
2. Pre-existing medical, neurological or psychiatric disease that would confound the neurological or functional evaluations
3. Pregnant
4. Unable to undergo a contrast brain perfusion scan with either MRI or CT
5. Known allergy to iodine that precludes an endovascular procedure
6. Treated with tPA \>4.5 hours after time last known well
7. Treated with tPA 3-4.5 hours after last known well AND any of the following; age \>80, current anticoagulant use, history of diabetes or prior stroke, NIHSS \>25
8. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; recent oral anticoagulant therapy with INR \> 3 (recent use of one of the new oral anticoagulants is not an exclusion if estimated GFR \> 30 ml/min).
9. Seizures at stroke onset if it precludes obtaining an accurate baseline NIHSS
10. Baseline blood glucose of \<50mg/dL (2.78 mmol) or \>400mg/dL (22.20 mmol)
11. Baseline platelet count \< 50,000/uL
12. Severe, sustained hypertension (Systolic BP \>185 mmHg or Diastolic BP \>110 mmHg)
13. Current participation in another investigational drug or device study
14. Presumed septic embolus; suspicion of bacterial endocarditis
15. Clot retrieval attempted using a neurothrombectomy device prior to 6 hrs from symptom onset
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.

Neuroimaging Inclusion Criteria:

1. ICA or MCA-M1 occlusion (carotid occlusions can be cervical or intracranial; with or without tandem MCA lesions) by MRA or CTA

   AND
2. Target Mismatch Profile on CT perfusion or MRI (ischemic core volume is \< 70 ml, mismatch ratio is \>/= 1.8 and mismatch volume\* is \>/= 15 ml)

Alternative neuroimaging inclusion criteria (if perfusion imaging or CTA/MRA is technically inadequate):

A) If CTA (or MRA) is technically inadequate:

Tmax\>6s perfusion deficit consistent with an ICA or MCA-M1 occlusion AND Target Mismatch Profile (ischemic core volume is \< 70 ml, mismatch ratio is \>1.8 and mismatch volume is \>15 ml as determined by RAPID software)

B) If MRP is technically inadequate:

ICA or MCA-M1 occlusion (carotid occlusions can be cervical or intracranial; with or without tandem MCA lesions) by MRA (or CTA, if MRA is technically inadequate and a CTA was performed within 60 minutes prior to the MRI) AND DWI lesion volume \< 25 ml

C) If CTP is technically inadequate:

Patient can be screened with MRI and randomized if neuroimaging criteria are met.

Neuroimaging Exclusion Criteria:

1. ASPECTS score \<6 on non-contrast CT (if patient is enrolled based on CT perfusion criteria)
2. Evidence of intracranial tumor (except small meningioma) acute intracranial hemorrhage, neoplasm, or arteriovenous malformation
3. Significant mass effect with midline shift
4. Evidence of internal carotid artery dissection that is flow limiting or aortic dissection
5. Intracranial stent implanted in the same vascular territory that precludes the safe deployment/removal of the neurothrombectomy device
6. Acute symptomatic arterial occlusions in more than one vascular territory confirmed on CTA/MRA (e.g., bilateral MCA occlusions, or an MCA and a basilar artery occlusion).

Primary outcomes:
measure: The Distribution of Scores on the Modified Rankin Scale (mRS) at Day 90
timeFrame: Day 90
Secondary outcomes:
measure: Count of Patients With mRS 0-2 at Day 90 as a Measure of Functional Independence
timeFrame: day 90
Other outcomes:
measure: Count of Participants With Symptomatic Intracranial Hemorrhage (Primary Safety Outcome)
timeFrame: 36 hours
measure: Parenchymal Hematoma Type 2 (Safety Outcome)
timeFrame: 24 (±6) hours
measure: Infarct Volume (Imaging Outcome)
timeFrame: 24 (+/- 6) hours
measure: Lesion Growth (Imaging Outcome)
timeFrame: 24 hours (±6)
measure: Reperfusion (Imaging Outcome)
timeFrame: between baseline and 24 hours (+/- 6 hours)
measure: Recanalization (Imaging Outcome)
timeFrame: 24 hours (±6)
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Fresno
country: United States
facility: Community Regional Medical Center
state: California
city: La Jolla
country: United States
facility: Scripps Memorial Hospital
state: California
city: La Jolla
country: United States
facility: UCSD Medical Center/Hillcrest Hospital
state: California
city: Los Angeles
country: United States
facility: Keck Hospital of University of Southern California
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center, San Francisco, CA
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Walnut Creek
country: United States
facility: John Muir Medical Center
state: California
city: Washington
country: United States
facility: MedStar Washington Hospital Center
state: District of Columbia
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospital and Clinics
state: Iowa
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: The Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Abbott Northwestern Hospital
state: Minnesota
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center, Fairview
state: Minnesota
city: Ridgewood
country: United States
facility: The Valley Hospital
state: New Jersey
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital at Columbia
state: New York
city: New York
country: United States
facility: NYP Weill Cornell Medical Center
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Wexner Medical Center
state: Ohio
city: Toledo
country: United States
facility: Mercy Health St. Vincent Medical Center
state: Ohio
city: Portland
country: United States
facility: Providence St. Vincent Medical Center
state: Oregon
city: Portland
country: United States
facility: Oregon Health & Science University Hospital
state: Oregon
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Columbia
country: United States
facility: Palmetto Health Richland
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Austin
country: United States
facility: University Medical Center Brackenridge
state: Texas
city: Austin
country: United States
facility: Seton Medical Center/UT Southwestern
state: Texas
city: Houston
country: United States
facility: Memorial Hermann Texas Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: Intermountain Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah Healthcare
state: Utah
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: Stanford University
name: Gregory Albers, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Michael Marks, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Maarten Lansberg, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Albers GW, Lansberg MG, Kemp S, Tsai JP, Lavori P, Christensen S, Mlynash M, Kim S, Hamilton S, Yeatts SD, Palesch Y, Bammer R, Broderick J, Marks MP. A multicenter randomized controlled trial of endovascular therapy following imaging evaluation for ischemic stroke (DEFUSE 3). Int J Stroke. 2017 Oct;12(8):896-905. doi: 10.1177/1747493017701147. Epub 2017 Mar 24.
citation: Albers GW, Marks MP, Kemp S, Christensen S, Tsai JP, Ortega-Gutierrez S, McTaggart RA, Torbey MT, Kim-Tenser M, Leslie-Mazwi T, Sarraj A, Kasner SE, Ansari SA, Yeatts SD, Hamilton S, Mlynash M, Heit JJ, Zaharchuk G, Kim S, Carrozzella J, Palesch YY, Demchuk AM, Bammer R, Lavori PW, Broderick JP, Lansberg MG; DEFUSE 3 Investigators. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018 Feb 22;378(8):708-718. doi: 10.1056/NEJMoa1713973. Epub 2018 Jan 24.
citation: Marks MP, Heit JJ, Lansberg MG, Kemp S, Christensen S, Derdeyn CP, Rasmussen PA, Zaidat OO, Broderick JP, Yeatts SD, Hamilton S, Mlynash M, Albers GW; DEFUSE 3 Investigators. Endovascular Treatment in the DEFUSE 3 Study. Stroke. 2018 Aug;49(8):2000-2003. doi: 10.1161/STROKEAHA.118.022147.
citation: Tate WJ, Polding LC, Christensen S, Mlynash M, Kemp S, Heit JJ, Marks MP, Albers GW, Lansberg MG. Predictors of Early and Late Infarct Growth in DEFUSE 3. Front Neurol. 2021 Jul 1;12:699153. doi: 10.3389/fneur.2021.699153. eCollection 2021.
citation: Polding LC, Tate WJ, Mlynash M, Marks MP, Heit JJ, Christensen S, Kemp S, Albers GW, Lansberg MG; DEFUSE 3 Investigators. Quality of Life in Physical, Social, and Cognitive Domains Improves With Endovascular Therapy in the DEFUSE 3 Trial. Stroke. 2021 Apr;52(4):1185-1191. doi: 10.1161/STROKEAHA.120.031490. Epub 2021 Feb 18.
citation: Sarraj A, Mlynash M, Heit J, Pujara D, Lansberg M, Marks M, Albers GW. Clinical Outcomes and Identification of Patients With Persistent Penumbral Profiles Beyond 24 Hours From Last Known Well: Analysis From DEFUSE 3. Stroke. 2021 Mar;52(3):838-849. doi: 10.1161/STROKEAHA.120.031147. Epub 2021 Feb 10.
citation: Cereda CW, Mlynash M, Cippa PE, Kemp S, Heit JJ, Marks MP, Lansberg MG, Albers GW. Renal Safety of Multimodal Brain Imaging Followed by Endovascular Therapy. Stroke. 2021 Jan;52(1):313-316. doi: 10.1161/STROKEAHA.120.030816. Epub 2020 Nov 30.
citation: Heit JJ, Mlynash M, Christensen S, Kemp SM, Lansberg MG, Marks MP, Olivot JM, Gregory AW. What predicts poor outcome after successful thrombectomy in late time windows? J Neurointerv Surg. 2021 May;13(5):421-425. doi: 10.1136/neurintsurg-2020-016125. Epub 2020 Jun 17.
citation: Kim-Tenser M, Mlynash M, Lansberg MG, Tenser M, Bulic S, Jagadeesan B, Christensen S, Simpkins A, Albers GW, Marks MP, Heit JJ. CT perfusion core and ASPECT score prediction of outcomes in DEFUSE 3. Int J Stroke. 2021 Apr;16(3):288-294. doi: 10.1177/1747493020915141. Epub 2020 Mar 31.
citation: Dula AN, Mlynash M, Zuck ND, Albers GW, Warach SJ; DEFUSE 3 Investigators. Neuroimaging in Ischemic Stroke Is Different Between Men and Women in the DEFUSE 3 Cohort. Stroke. 2020 Feb;51(2):481-488. doi: 10.1161/STROKEAHA.119.028205. Epub 2019 Dec 12.
citation: Amukotuwa SA, Fischbein NJ, Albers GW, Davis S, Donnan GA, Andre JB, Bammer R. Comparison of T2*GRE and DSC-PWI for hemorrhage detection in acute ischemic stroke patients: Pooled analysis of the EPITHET, DEFUSE 2, and SENSE 3 stroke studies. Int J Stroke. 2020 Feb;15(2):216-225. doi: 10.1177/1747493019858781. Epub 2019 Jul 10.
citation: Tate WJ, Polding LC, Kemp S, Mlynash M, Heit JJ, Marks MP, Albers GW, Lansberg MG. Thrombectomy Results in Reduced Hospital Stay, More Home-Time, and More Favorable Living Situations in DEFUSE 3. Stroke. 2019 Sep;50(9):2578-2581. doi: 10.1161/STROKEAHA.119.025165. Epub 2019 Jul 10.
citation: Heit JJ, Mlynash M, Kemp SM, Lansberg MG, Christensen S, Marks MP, Ortega-Gutierrez S, Albers GW. Rapid Neurologic Improvement Predicts Favorable Outcome 90 Days After Thrombectomy in the DEFUSE 3 Study. Stroke. 2019 May;50(5):1172-1177. doi: 10.1161/STROKEAHA.119.024928.
citation: Christensen S, Mlynash M, Kemp S, Yennu A, Heit JJ, Marks MP, Lansberg MG, Albers GW. Persistent Target Mismatch Profile >24 Hours After Stroke Onset in DEFUSE 3. Stroke. 2019 Mar;50(3):754-757. doi: 10.1161/STROKEAHA.118.023392.
citation: Sarraj A, Mlynash M, Savitz SI, Heit JJ, Lansberg MG, Marks MP, Albers GW. Outcomes of Thrombectomy in Transferred Patients With Ischemic Stroke in the Late Window: A Subanalysis From the DEFUSE 3 Trial. JAMA Neurol. 2019 Jun 1;76(6):682-689. doi: 10.1001/jamaneurol.2019.0118.
citation: Rao V, Christensen S, Yennu A, Mlynash M, Zaharchuk G, Heit J, Marks MP, Lansberg MG, Albers GW. Ischemic Core and Hypoperfusion Volumes Correlate With Infarct Size 24 Hours After Randomization in DEFUSE 3. Stroke. 2019 Mar;50(3):626-631. doi: 10.1161/STROKEAHA.118.023177.
citation: de Havenon A, Mlynash M, Kim-Tenser MA, Lansberg MG, Leslie-Mazwi T, Christensen S, McTaggart RA, Alexander M, Albers G, Broderick J, Marks MP, Heit JJ; DEFUSE 3 Investigators. Results From DEFUSE 3: Good Collaterals Are Associated With Reduced Ischemic Core Growth but Not Neurologic Outcome. Stroke. 2019 Mar;50(3):632-638. doi: 10.1161/STROKEAHA.118.023407.
citation: Lansberg MG, Mlynash M, Hamilton S, Yeatts SD, Christensen S, Kemp S, Lavori PW, Ortega-Gutierrez S, Broderick J, Heit J, Marks MP, Albers GW; DEFUSE 3 Investigators. Association of Thrombectomy With Stroke Outcomes Among Patient Subgroups: Secondary Analyses of the DEFUSE 3 Randomized Clinical Trial. JAMA Neurol. 2019 Apr 1;76(4):447-453. doi: 10.1001/jamaneurol.2018.4587.