Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3
NCT ID: NCT02586415
Last Updated: 2019-05-21
Study Results
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View full resultsBasic Information
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TERMINATED
NA
182 participants
INTERVENTIONAL
2016-04-30
2017-08-23
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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endovascular thrombectomy therapy
Treatment with one or more thrombectomy devices (only the devices listed in this protocol are approved for use in DEFUSE 3) plus standard medical therapy for patients who have evidence of an ICA or MCA M1 occlusion and a Target Mismatch Profile.
Devices approved for use in DEFUSE 3:
* Trevo Retriever
* Solitaire™ FR Revascularization Device
* Penumbra thrombectomy system
* Covidien MindFrame Capture Revascularization Device
Endovascular Thrombectomy
Patients will be treated with thrombectomy devices (stent-retrievers) and/or suction thrombectomy systems currently cleared by the FDA for thrombus removal in patients experiencing an acute stroke following the published instructions for use for these devices. These devices will be used between 6 and 16 hours following symptom onset in DEFUSE 3 based on an FDA IDE. The devices which will be used are the Trevo Retriever, the Solitaire Revascularization Device and the Penumbra system thrombectomy system.
Trevo Retriever
Trevo Retriever is one of the interventional devices that is approved for use in DEFUSE 3 during the endovascular thrombectomy procedure. The device choice is at the discretion of the physician performing the procedure.
Solitaire™ FR Revascularization Device
Solitaire™ FR Revascularization Device is one of the interventional devices that is approved for use in DEFUSE 3 during the endovascular thrombectomy procedure. The device choice is at the discretion of the physician performing the procedure.
Penumbra thrombectomy system
Penumbra thrombectomy system is one of the interventional devices that is approved for use in DEFUSE 3 during the endovascular thrombectomy procedure. The device choice is at the discretion of the physician performing the procedure. The Penumbra System includes:
• Penumbra Aspiration Pump (1115V) Penumbra System 054 Penumbra System MAX Penumbra System 110 Aspiration Tubing Penumbra System \[026, 032, 041\] Penumbra System Separator Flex \[026, 032, 041, 054\] Penumbra Pump MAX Penumbra System Reperfusion Catheter ACE64 \& ACE68
Covidien MindFrame Capture Revascularization Device
Covidien MindFrame Capture Revascularization Device is one of the interventional devices that is approved for use in DEFUSE 3 during the endovascular thrombectomy procedure. The device choice is at the discretion of the physician performing the procedure.
Medical Management
standard medical therapy alone
No interventions assigned to this group
Interventions
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Endovascular Thrombectomy
Patients will be treated with thrombectomy devices (stent-retrievers) and/or suction thrombectomy systems currently cleared by the FDA for thrombus removal in patients experiencing an acute stroke following the published instructions for use for these devices. These devices will be used between 6 and 16 hours following symptom onset in DEFUSE 3 based on an FDA IDE. The devices which will be used are the Trevo Retriever, the Solitaire Revascularization Device and the Penumbra system thrombectomy system.
Trevo Retriever
Trevo Retriever is one of the interventional devices that is approved for use in DEFUSE 3 during the endovascular thrombectomy procedure. The device choice is at the discretion of the physician performing the procedure.
Solitaire™ FR Revascularization Device
Solitaire™ FR Revascularization Device is one of the interventional devices that is approved for use in DEFUSE 3 during the endovascular thrombectomy procedure. The device choice is at the discretion of the physician performing the procedure.
Penumbra thrombectomy system
Penumbra thrombectomy system is one of the interventional devices that is approved for use in DEFUSE 3 during the endovascular thrombectomy procedure. The device choice is at the discretion of the physician performing the procedure. The Penumbra System includes:
• Penumbra Aspiration Pump (1115V) Penumbra System 054 Penumbra System MAX Penumbra System 110 Aspiration Tubing Penumbra System \[026, 032, 041\] Penumbra System Separator Flex \[026, 032, 041, 054\] Penumbra Pump MAX Penumbra System Reperfusion Catheter ACE64 \& ACE68
Covidien MindFrame Capture Revascularization Device
Covidien MindFrame Capture Revascularization Device is one of the interventional devices that is approved for use in DEFUSE 3 during the endovascular thrombectomy procedure. The device choice is at the discretion of the physician performing the procedure.
Eligibility Criteria
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Inclusion Criteria
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.
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)
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.
Exclusion Criteria
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.
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).
18 Years
90 Years
ALL
No
Sponsors
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National Institute of Neurological Disorders and Stroke (NINDS)
NIH
University of Cincinnati
OTHER
Medical University of South Carolina
OTHER
NINDS Stroke Trials Network (StrokeNet)
OTHER
Gregory W Albers
OTHER
Responsible Party
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Gregory W Albers
Professor of Neurology
Principal Investigators
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Gregory Albers, MD
Role: PRINCIPAL_INVESTIGATOR
Stanford University
Michael Marks, MD
Role: PRINCIPAL_INVESTIGATOR
Stanford University
Maarten Lansberg, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Stanford University
Locations
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University of Alabama
Birmingham, Alabama, United States
Community Regional Medical Center
Fresno, California, United States
Scripps Memorial Hospital
La Jolla, California, United States
UCSD Medical Center/Hillcrest Hospital
La Jolla, California, United States
Keck Hospital of University of Southern California
Los Angeles, California, United States
UCSF Medical Center, San Francisco, CA
San Francisco, California, United States
Stanford University
Stanford, California, United States
John Muir Medical Center
Walnut Creek, California, United States
MedStar Washington Hospital Center
Washington D.C., District of Columbia, United States
Northwestern Memorial Hospital
Chicago, Illinois, United States
University of Iowa Hospital and Clinics
Iowa City, Iowa, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
The Brigham and Women's Hospital
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
University of Michigan Hospital
Ann Arbor, Michigan, United States
Abbott Northwestern Hospital
Minneapolis, Minnesota, United States
Hennepin County Medical Center
Minneapolis, Minnesota, United States
University of Minnesota Medical Center, Fairview
Minneapolis, Minnesota, United States
The Valley Hospital
Ridgewood, New Jersey, United States
Mount Sinai Hospital
New York, New York, United States
New York Presbyterian Hospital at Columbia
New York, New York, United States
NYP Weill Cornell Medical Center
New York, New York, United States
University of Cincinnati
Cincinnati, Ohio, United States
Cleveland Clinic
Cleveland, Ohio, United States
Ohio State University Wexner Medical Center
Columbus, Ohio, United States
Mercy Health St. Vincent Medical Center
Toledo, Ohio, United States
Providence St. Vincent Medical Center
Portland, Oregon, United States
Oregon Health & Science University Hospital
Portland, Oregon, United States
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States
Temple University Hospital
Philadelphia, Pennsylvania, United States
Rhode Island Hospital
Providence, Rhode Island, United States
Palmetto Health Richland
Columbia, South Carolina, United States
Vanderbilt University
Nashville, Tennessee, United States
University Medical Center Brackenridge
Austin, Texas, United States
Seton Medical Center/UT Southwestern
Austin, Texas, United States
Memorial Hermann Texas Medical Center
Houston, Texas, United States
Intermountain Medical Center
Salt Lake City, Utah, United States
University of Utah Healthcare
Salt Lake City, Utah, United States
Harborview Medical Center
Seattle, Washington, United States
University of Wisconsin
Madison, Wisconsin, United States
Countries
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References
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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.
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.
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.
Yu Y, Christensen S, Ouyang J, Scalzo F, Liebeskind DS, Lansberg MG, Albers GW, Zaharchuk G. Predicting Hypoperfusion Lesion and Target Mismatch in Stroke from Diffusion-weighted MRI Using Deep Learning. Radiology. 2023 Apr;307(1):e220882. doi: 10.1148/radiol.220882. Epub 2022 Dec 6.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Provided Documents
Download supplemental materials such as informed consent forms, study protocols, or participant manuals.
Document Type: Statistical Analysis Plan
Document Type: Study Protocol
Other Identifiers
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