Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3

Stroke, Acute Clinical Trial

— DEFUSE 3  

Official title:

Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02586415
• Other study ID #: 116661
• Secondary ID: U10NS086487U01NS
• Status: Terminated
• Phase: N/A
• Start date: April 2016
• Est. completion date: August 23, 2017

Study information

• Verified date: May 2019
• Source: Stanford University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 182
• Est. completion date: August 23, 2017
• Est. primary completion date: August 23, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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).

Related Conditions & MeSH terms

• Cerebral Infarction
• Infarction
• Stroke
• Stroke, Acute

Intervention

Procedure:
• 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.

Device:
• 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.

Locations

Country	Name	City	State
United States	University of Michigan Hospital	Ann Arbor	Michigan
United States	Seton Medical Center/UT Southwestern	Austin	Texas
United States	University Medical Center Brackenridge	Austin	Texas
United States	University of Alabama	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	The Brigham and Women's Hospital	Boston	Massachusetts
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	University of Cincinnati	Cincinnati	Ohio
United States	Cleveland Clinic	Cleveland	Ohio
United States	Palmetto Health Richland	Columbia	South Carolina
United States	Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Community Regional Medical Center	Fresno	California
United States	Memorial Hermann Texas Medical Center	Houston	Texas
United States	University of Iowa Hospital and Clinics	Iowa City	Iowa
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	University of Wisconsin	Madison	Wisconsin
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	Vanderbilt University	Nashville	Tennessee
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	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Oregon Health & Science University Hospital	Portland	Oregon
United States	Providence St. Vincent Medical Center	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	The Valley Hospital	Ridgewood	New Jersey
United States	Intermountain Medical Center	Salt Lake City	Utah
United States	University of Utah Healthcare	Salt Lake City	Utah
United States	UCSF Medical Center, San Francisco, CA	San Francisco	California
United States	Harborview Medical Center	Seattle	Washington
United States	Stanford University	Stanford	California
United States	Mercy Health St. Vincent Medical Center	Toledo	Ohio
United States	John Muir Medical Center	Walnut Creek	California
United States	MedStar Washington Hospital Center	Washington	District of Columbia

Sponsors (5)

Lead Sponsor	Collaborator
Gregory W Albers	Medical University of South Carolina, National Institute of Neurological Disorders and Stroke (NINDS), NINDS Stroke Trials Network (StrokeNet), University of Cincinnati

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View 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, Demch — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Count of Participants With Symptomatic Intracranial Hemorrhage (Primary Safety Outcome)	Defined as NIHSS worsening of 4 or more points associated with brain hemorrhage within 36 hours of randomization	36 hours
Other	Parenchymal Hematoma Type 2 (Safety Outcome)	PH 2 rates on the 24 hour scan (±6)	24 (±6) hours
Other	Infarct Volume (Imaging Outcome)	Infarct volume on diffusion-weighted MRI (or CT if MRI not feasible) at 24 (±6) hours after randomization	24 (+/- 6) hours
Other	Lesion Growth (Imaging Outcome)	Lesion growth between the RAPID-identified ischemic core on baseline imaging and the infarct volume at 24 hours (±6)	24 hours (±6)
Other	Reperfusion (Imaging Outcome)	Successful reperfusion defined as a >90% reduction in Tmax>6sec lesion volume between baseline and 24 hours	between baseline and 24 hours (+/- 6 hours)
Other	Recanalization (Imaging Outcome)	Recanalization of the primary arterial occlusive lesion at 24-hours on CTA/MRA	24 hours (±6)
Primary	The Distribution of Scores on the Modified Rankin Scale (mRS) at Day 90	The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6 with "0" being perfect health without symptoms to "6" being death. 0 - No symptoms.; - No significant disability. Able to carry out all usual activities, despite some symptoms.; - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.; - Moderate disability. Requires some help, but able to walk unassisted.; - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.; - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.; - Dead.	Day 90
Secondary	Count of Patients With mRS 0-2 at Day 90 as a Measure of Functional Independence	The modified Rankin Scale (mRS) is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The scale runs from 0-6 with "0" being perfect health without symptoms to "6" being death. 0 - No symptoms.; No significant disability. Able to carry out all usual activities, despite some symptoms.; Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.; Moderate disability. Requires some help, but able to walk unassisted.; Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.; Severe disability. Requires constant nursing care and attention, bedridden, incontinent.; Dead.	day 90