Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3

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.

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).