Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo (DAWN)

Diffusion Weighted Imaging (DWI) or Computerized Tomography Perfusion (CTP) Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention (DAWN)

The purpose of the study is to evaluate the hypothesis that Trevo thrombectomy plus medical management leads to superior clinical outcomes at 90 days as compared to medical management alone in appropriately selected subjects experiencing an acute ischemic stroke when treatment is initiated within 6-24 hours after last seen well.

Study Overview

• Status: Completed
• Conditions: Ischemic Stroke
• Intervention / Treatment: Device: Trevo Thrombectomy Procedure; Other: Medical Management

Detailed Description

The study is a prospective, randomized, multi-center, Phase II/III (feasibility/pivotal), adaptive, controlled trial, designed to demonstrate that mechanical thrombectomy using the Trevo Retriever with medical management is superior to medical management alone in improving clinical outcomes at 90 days in appropriately selected wake up and late presenting acute ischemic stroke subjects.

The intent of this study is to support the use of the Trevo Retriever beyond the currently labeled 8 hour indicated time limit in wake up, unclear onset, and late presenting ischemic stroke subjects, who currently have no other option besides medical management of their symptoms.

Patients with wake-up strokes, strokes with unclear onset time, and witnessed late presenting strokes may potentially benefit from intra-arterial reperfusion therapy. However, an important indicator of whether subjects will benefit or not during this later time window is the confirmation of a large vessel occlusion (LVO), and assessment of the core infarct volume relative to the volume of salvageable penumbra. Therefore, standardized imaging selection of subjects is required for inclusion into the study.

This trial has been designed with subject safety in mind, as a seamless Phase II (feasibility) / Phase III (pivotal) adaptive design, in order to address the concerns around potential unknown harms to enrolled subjects. This study will help to answer the question of whether carefully selecting subjects by using Clinical Imaging Mismatch will allow acute ischemic stroke patients who present at or beyond 6 hours from Time Last Seen Well (TLSW) to be considered for intra-arterial intervention. If Trevo thrombectomy plus medical management leads to better clinical outcomes over medical management alone, more patients in the future could receive endovascular treatment (either in addition to or in lieu of IV tPA).

• Study Type: Interventional
• Enrollment (Actual): 206
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • Parkville, Australia, 3050
    • Royal Melbourne
• Canada
  • Ontario
    • Toronto, Ontario, Canada
      • Toronto Western Hospital - University Health Network
• France
  • Montpellier, France, 34295
    • Hopital Gui de Chauliac
  • Toulouse, France, 40031
    • Hôpital Purpan - Toulouse
• Spain
  • Barcelona, Spain
    • Hospital Universitari de Bellvitge
  • Barcelona, Spain, 08916
    • Hospital Germans Trias i Pujol
  • Barcelona, Spain, 08035
    • Vall d'Hebron Barcelona
  • Barcelona, Spain, 08036
    • Hospital Clinic - Barcelona
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles
    • Los Angeles, California, United States, 90027
      • Kaiser Permanente Los Angeles Medical Center
    • San Francisco, California, United States, 94114
      • California Pacific Medical Center
  • Delaware
    • Newark, Delaware, United States, 19718
      • Christiana Care
  • Florida
    • Hollywood, Florida, United States, 33021
      • Memorial Regional
    • Jacksonville, Florida, United States, 32207
      • Baptist Jacksonville
    • Miami, Florida, United States, 33136
      • Jackson Memorial/University of Miami
    • Orlando, Florida, United States, 32803
      • Florida Hospital; Neuroscience Research Center
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University at Grady Memorial Hospital
    • Marietta, Georgia, United States, 30060
      • Wellstar Kennestone Hospital
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Baptist Health Lexington
  • Michigan
    • Pontiac, Michigan, United States, 48341
      • St. Joseph Mercy - Oakland
  • New Jersey
    • Edison, New Jersey, United States, 08818
      • JFK Neuroscience Institute at JFK Medical Center
    • Trenton, New Jersey, United States, 08638
      • Capital Health System
  • New York
    • Buffalo, New York, United States, 14203
      • Buffalo General Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44026
      • University Hospitals Case Medical Center
    • Columbus, Ohio, United States, 43214
      • Riverside Methodist Hospital/ Ohio Health Research Institute
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Abington Memorial Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Stroke Institute
  • Tennessee
    • Chattanooga, Tennessee, United States, 37377
      • Erlanger Health System
  • Texas
    • Harlingen, Texas, United States, 78550
      • Valley Baptist Medical Center-Harlingen
    • Plano, Texas, United States, 75075
      • North Texas Stroke Center HCA (dba TSI)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

General Inclusion Criteria:

1. Clinical signs and symptoms consistent with the diagnosis of an acute ischemic stroke, and subject belongs to one of the following subgroups:

   1. Subject has failed IV t-PA therapy (defined as a confirmed persistent occlusion 60 min after administration)
   2. Subject is contraindicated for IV t-PA administration
2. Age ≥18
3. Baseline NIHSS ≥10 (assessed within one hour of measuring core infarct volume)
4. Subject can be randomized between with 6 to 24 hours after time last known well
5. No significant pre-stroke disability (pre-stroke mRS must be 0 or 1)
6. Anticipated life expectancy of at least 6 months
7. Subject willing/able to return for protocol required follow up visits

8. Subject or subject's Legally Authorized Representative (LAR) has signed the study Informed Consent form*

   • If approved by local ethics committee and country regulations, the investigator is allowed to enroll a patient utilizing emergency informed consent procedures if neither the patient nor the representative or person of trust is available to sign the informed consent form. However, as soon as possible, the patient is informed and his/her consent is requested for the possible continuation of this research. (Not applicable to U.S. Sites.)

Imaging Inclusion Criteria:

1. < 1/3 MCA territory involved, as evidenced by CT or MRI
2. Occlusion of the intracranial ICA and/or MCA-M1 as evidenced by MRA or CTA

3. Clinical Imaging Mismatch (CIM) defined as one of the following on MR-DWI or CTP-rCBF maps:

   1. 0-<21 cc core infarct and NIHSS ≥ 10 (and age ≥ 80 years old)
   2. 0-<31 cc core infarct and NIHSS ≥ 10 (and age < 80 years old)
   3. 31 cc to <51 cc core infarct and NIHSS ≥ 20 (and age < 80 years old)

General Exclusion Criteria:

1. History of severe head injury within past 90 days with residual neurological deficit, as determined by medical history
2. Rapid improvement in neurological status to an NIHSS <10 or evidence of vessel recanalization prior to randomization
3. Pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations, e.g. dementia with prescribed anti-cholinesterase inhibitor (e.g. Aricept)
4. Seizures at stroke onset if it makes the diagnosis of stroke doubtful and precludes obtaining an accurate baseline NIHSS assessment
5. Baseline blood glucose of <50mg/dL (2.78 mmol) or >400mg/dL (22.20 mmol)
6. Baseline hemoglobin counts of <7 mmol/L
7. Baseline platelet count < 50,000/uL
8. Abnormal baseline electrolyte parameters as defined by sodium concentration <130 mmol/L, potassium concentration <3 mEq/L or >6 mEq/L
9. Renal failure as defined by a serum creatinine >3.0 mg/dL (264 µmol/L) NOTE: subjects on renal dialysis may be treated regardless of serum creatinine levels
10. Known hemorrhagic diathesis, coagulation factor deficiency, or on anticoagulant therapy with INR > 3.0 or PTT > 3 times normal. Patients on factor Xa inhibitor for 24-48 hours ago must have a normal PTT.
11. Any active or recent hemorrhage within the past 30 days
12. History of severe allergy (more than rash) to contrast medium
13. Severe, sustained hypertension (Systolic Blood Pressure >185 mmHg or Diastolic Blood Pressure >110 mmHg) NOTE: If the blood pressure can be successfully reduced and maintained at the acceptable level using medication the subject can be enrolled
14. Female who is pregnant or lactating at time of admission
15. Current participation in another investigational drug or device study
16. Presumed septic embolus, or suspicion of bacterial endocarditis
17. Treatment with any cleared thrombectomy devices or other intra-arterial (neurovascular) therapies prior to randomization

Imaging Exclusion Criteria:

1. Evidence of intracranial hemorrhage on CT/MRI
2. CTA or MRA evidence of flow limiting carotid dissection, high-grade stenosis, or complete cervical carotid occlusion requiring stenting at the time of the index procedure (i.e., mechanical thrombectomy).
3. Excessive tortuosity of cervical vessels on CTA/MRA that would likely preclude device delivery/deployment
4. Suspected cerebral vasculitis based on medical history and CTA/MRA
5. Suspected aortic dissection based on medical history and CTA/MRA
6. Intracranial stent implanted in the same vascular territory that would preclude the safe deployment/removal of the Trevo device
7. Occlusions in multiple vascular territories (e.g., bilateral anterior circulation, or anterior circulation/vertebrobasilar system) as confirmed on CTA/MRA, or clinical evidence of bilateral strokes or strokes in multiple territories
8. Significant mass effect with midline shift as confirmed on CT/MRI
9. Evidence of intracranial tumor (except small meningioma) as confirmed on CT/MRI

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Trevo Thrombectomy Procedure; Trevo Thrombectomy Procedure and Medical Management	Device: Trevo Thrombectomy Procedure; stent retriever; intended to restore blood flow in the neurovasculature by removing thrombus (clot); Other Names: Trevo ProVue Retriever; Trevo XP ProVue Retriever; Other: Medical Management; Standard of Care not including mechanical thrombectomy, no intra arterial treatment, may include aspirin, therapy etc; Other Names: Standard of Care
ACTIVE_COMPARATOR: Medical Management	Other: Medical Management; Standard of Care not including mechanical thrombectomy, no intra arterial treatment, may include aspirin, therapy etc; Other Names: Standard of Care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Weighted Modified Rankin Scale (mRS) Score, Lead Co-Primary Efficacy Outcome	mRS is a scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes neurological disability. Functional Independence: 0 - no symptoms at all; - no significant disability despite symptoms; able to carry out all usual duties and activities; - slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance; - moderate disability; requiring some help, but able to walk without assistance; - moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; - severe disability; bedridden, incontinent and requiring constant nursing care and attention; - dead	90 days
Functional Independence (mRS 0-2), Nested Co-Primary Efficacy Outcome	Number of participants with functional independence mRS is a scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes neurological disability. Functional Independence: 0 - no symptoms at all; - no significant disability despite symptoms; able to carry out all usual duties and activities; - slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance	90 days
Stroke-related Mortality, Primary Safety Outcome		90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All Cause Mortality		90 days
Good Functional Outcome	Proportion of participants with functional independence mRS is a scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes neurological disability. Functional Independence: 0 - no symptoms at all; - no significant disability despite symptoms; able to carry out all usual duties and activities; - slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance	90 days
Early Response	The proportion of subjects with "early response" at Day 5-7/Discharge (whichever is earlier), defined as a National Institutes of Health Stroke Scale (NIHSS) drop of ≥10 from baseline or NIHSS score 0 or 1. The NIHSS is an assessment which objectively quantifies the impairment caused by a stroke. It is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a total NIHSS score. The maximum possible score is 42, with the minimum score being a 0.	5-7 Days
Revascularization Rates	Revascularization rates at 24 hours from randomization are based on the assessment of vessel patency utilizing CTA/MRA and processed by the CT-MR core laboratory. Revascularization at 24 hours was defined as the presence of partial or complete recanalization. CTA/MRA images utilized ionizing radiation exposure.	24 hours
Neurological Deterioration From Baseline NIHSS Score	Neurological deterioration from baseline NIHSS score through Day 5-7/discharge (whichever is earlier) post randomization. Neurological deterioration is defined as ≥ 4 point increase in the NIHSS score from the baseline score. The calculated difference in NIHSS scores was assessed at baseline and Day 5-7/discharge (two time points). The NIHSS is an assessment which objectively quantifies the impairment caused by a stroke. It is composed of 11 items, each of which scores a specific ability between a 0 and 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores from each item are summed in order to calculate a total NIHSS score. The maximum possible score is 42, with the minimum score being a 0.	5-7 days

Collaborators and Investigators

• Sponsor: Stryker Neurovascular
• Investigators: Principal Investigator: Tudor G Jovin, MD, University of Pittsburg Medical Center Stroke Institute; Principal Investigator: Raul Nogueira, MD, Marcus Stroke & Neuroscience Center, Grady Memorial Hospital

Publications and helpful links

General Publications

• Roaldsen MB, Lindekleiv H, Mathiesen EB. Intravenous thrombolytic treatment and endovascular thrombectomy for ischaemic wake-up stroke. Cochrane Database Syst Rev. 2021 Dec 1;12(12):CD010995. doi: 10.1002/14651858.CD010995.pub3.
• Liebeskind DS, Saber H, Xiang B, Jadhav AP, Jovin TG, Haussen DC, Budzik RF, Bonafe A, Bhuva P, Yavagal DR, Hanel RA, Ribo M, Cognard C, Sila C, Hassan AE, Smith WS, Saver JL, Nogueira RG; DAWN Investigators. Collateral Circulation in Thrombectomy for Stroke After 6 to 24 Hours in the DAWN Trial. Stroke. 2022 Mar;53(3):742-748. doi: 10.1161/STROKEAHA.121.034471. Epub 2021 Nov 3.
• Liebeskind DS, Saber H, Bhuva P, Xiang B, Yoo AJ, Jadhav AP, Haussen DC, Budzik RF, Bonafe A, Yavagal DR, Hanel RA, Ribo M, Cognard C, Sila C, Hassan AE, Smith WS, Saver JL, Nogueira RG, Jovin TG. Serial ASPECTS in the DAWN Trial: Infarct Evolution and Clinical Impact. Stroke. 2021 Oct;52(10):3318-3324. doi: 10.1161/STROKEAHA.120.033477. Epub 2021 Jul 20.
• Tekle WG, Hassan AE, Jadhav AP, Haussen DC, Budzik RF, Bonafe A, Bhuva P, Yavagal DR, Hanel RA, Ribo M, Cognard C, Sila CA, Smith WS, Saver JL, Liebeskind DS, Shields R, Nogueira RG, Jovin TG; DAWN Trial Investigators. Impact of Periprocedural and Technical Factors and Patient Characteristics on Revascularization and Outcome in the DAWN Trial. Stroke. 2020 Jan;51(1):247-253. doi: 10.1161/STROKEAHA.119.026437. Epub 2019 Nov 20.
• Aghaebrahim A, Jadhav AP, Hanel R, Sauvageau E, Granja MF, Zhang Y, Haussen DC, Budzik RF, Bonafe A, Bhuva P, Ribo M, Cognard C, Sila C, Yavagal D, Hassan AE, Smith WS, Saver J, Liebeskind DS, Nogueira RG, Jovin TG; DAWN Investigators. Outcome in Direct Versus Transfer Patients in the DAWN Controlled Trial. Stroke. 2019 Aug;50(8):2163-2167. doi: 10.1161/STROKEAHA.119.025710. Epub 2019 Jul 15.
• Nogueira RG, Jadhav AP, Haussen DC, Bonafe A, Budzik RF, Bhuva P, Yavagal DR, Ribo M, Cognard C, Hanel RA, Sila CA, Hassan AE, Millan M, Levy EI, Mitchell P, Chen M, English JD, Shah QA, Silver FL, Pereira VM, Mehta BP, Baxter BW, Abraham MG, Cardona P, Veznedaroglu E, Hellinger FR, Feng L, Kirmani JF, Lopes DK, Jankowitz BT, Frankel MR, Costalat V, Vora NA, Yoo AJ, Malik AM, Furlan AJ, Rubiera M, Aghaebrahim A, Olivot JM, Tekle WG, Shields R, Graves T, Lewis RJ, Smith WS, Liebeskind DS, Saver JL, Jovin TG; DAWN Trial Investigators. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med. 2018 Jan 4;378(1):11-21. doi: 10.1056/NEJMoa1706442. Epub 2017 Nov 11.

Study record dates

Study Major Dates

• Study Start: July 1, 2014
• Primary Completion (ACTUAL): May 15, 2017
• Study Completion (ACTUAL): May 15, 2017

Study Registration Dates

• First Submitted: May 15, 2014
• First Submitted That Met QC Criteria: May 19, 2014
• First Posted (ESTIMATE): May 20, 2014

Study Record Updates

• Last Update Posted (ACTUAL): July 20, 2018
• Last Update Submitted That Met QC Criteria: July 18, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Acute ischemic stroke; Mechanical thrombectomy; Wake up stroke; Late presenting stroke
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke
• Other Study ID Numbers: T4024