Mild Acute Ischemic Stroke With Large Vessel Occlusion (MISTWAVE)

Patients who present with mild stroke symptoms (mAIS), and are also found to have an
intracranial large vessel occlusion (LVO) pose an exceptionally difficult therapeutic
dilemma. The need for any acute treatment is often debated since these patients "only" have
mild deficits, and any therapy has associated risks. However, it has been shown that acute
ischemic stroke (AIS) can lead to considerable morbidity and mortality even in patients
presenting with mild symptoms (mAIS) in the presence of LVO. Despite reports that such
patients have less favorable outcomes, these patients are often excluded from acute stroke
therapy. Recent studies demonstrated that, despite mild and rapidly improving symptoms, many
patients end up with unfavorable outcome. While the most recent AHA/ASA guidelines no longer
recommend excluding patients with milder improving symptoms from intravenous tissue
plasminogen activator administration, the role of endovascular intervention has not been
clarified for these patients.

Prior data has shown high morbidity and mortality in mAIS patients (without specified large
vessel status), who did not receive IV tPA, demonstrating that as high as 32% of patients was
dependent during discharge or died in one study. A common reason for foregoing treatment in
this patient group was that mild symptoms or rapid improvement were a contraindication to
IV-tPA administration according to previous ASA/AHA guidelines. Higher morbidity was
specifically noted in patients with concurrent large vessel occlusion as a cause of the
symptom in another study. Mokin et al showed that for LVO patients excluded from
thrombolysis, only 2/3rd could walk independently at discharge.

When assessing predictors of poor outcome, LVO seems to correlate with poor outcome despite
mild symptoms. Nedeltchev et al published a study with 162 patients with either mild stroke
symptoms (NIHSS of 3 or less) or rapidly improving symptoms (NIHSS improvement of 4 points or
more), in which 25% of the patients had an unfavorable outcome. NIHSS of 10 or more and
proximal vessel occlusion were independent predictors of poor outcome. LVO in patients with
rapidly improving /mild symptoms conferred an 18-fold increased risk of early neurological
deficit with infarct expansion. Patients with LVO were also more likely to have increased
modified ranking scale (mRS), and LVO was an independent predictor of decline in functional
status and a borderline significant predictor of poor outcome when adjusting for age, gender
and presenting NIHSS.

NIH Stroke Scale Score Threshold The ideal NIHSS cutoff value for "mild" stroke remains
unclear, and varies across studies. The investigators specifically chose the NIHSS 5 cut-off
value for the cohort after careful consideration of the results of several earlier reports,
which were available at the initiation of our research project. These studies, albeit with
limited sensitivity and specificity, have concluded that an NIHSS cut-off of 7-10 and higher
might be a reliable predictor of LVO. Since the investigators were trying to capture a
controversial stroke population that was unlikely to have LVO because of mild symptoms, the
investigators decided to include patients with NIHSS 5 or less.

Currently approved treatment and limitations At present, the American Heart Association and
American Stroke Association guidelines recommend that eligible ischemic strokes be treated
with IV tissue plasminogen activator (tPA) and/or mechanical thrombectomy. Severity of the
stroke is based on the National institute of health stroke scale (NIHSS), and the guidelines
do not specify any thrombolysis treatment for mild strokes.

Mechanical thrombectomy using stent retrievers for LVO stroke has become the standard of
care; however, current guidelines exclude patients with mild or improving symptoms. These
recommendations were made based on the 2015 randomized control trials, most of which did not
include patients with NIHSS <6.

Despite the MR-CLEAN trial's inclusion of patients with NIHSS as low as 2, which showed
efficacy of IAT for LVO, it is unclear what proportion of successfully treated patients were
actually in the mAIS category. The PRISMS study investigated the efficacy IV-tPA in mAIS
patients, although establishment of large vessel status was not specifically required
(NCT02072226). The TEMPO -1 trial showed safety and feasibility of tenecteplase in patients
with LVO and mAIS, and the TEMPO - 2 trial (NCT02398656) comparing tenecteplase to standard
therapy is currently ongoing.

The recently completed DAWN trial is an international multi-center randomized trial study of
patients with acute ischemic anterior stroke due to large vessel occlusions between 6 -24
hours of stroke with endovascular therapy. The results from 206 patients enrolled in the
trial demonstrated treatment with use of stentriver significantly decreased post-stroke
disability and improved functional independence at 90 days when compared to medical
management alone (48.6% vs 13.1%, p<0.001), a relative reduction in disability of 73%
percent. The study showed that one in 2.8 patients treated with the stentriever within 24
hours of a stroke is saved from severe disability. Another large trial, the Diffusion and
Perfusion Imaging Evaluation for Understanding Stroke Evolution 3 (DEFUSE 3), was halted
after the DAWN trial results were presented. This study enrolled patients with large vessel
occlusion presenting within 6 and 16 hours of stroke onset based on advanced imaging
criteria. Patients who underwent endovascular therapy had 2.77 times greater odds of
regaining functional independence at 90 days, versus medical management alone (45% vs 17%,
p<0.001), showing benefit for the endovascular group.

Acute vertebrobasilar occlusion The efficacy of mechanical thrombectomy in the anterior
circulation raised the question of its potential applicability in the posterior circulation.
Acute basilar occlusion accounts for approximately 1% of all acute ischemic strokes, and is
disproportionately associated with a mortality rate of approximately 70%. Given these
statistics, procedural risks in acute basilar occlusion syndromes have long been regarded
much lower than the risk of unfavorable outcome without intervention. Therefore these
patients have largely been omitted from clinical trials resulting in a paucity of clinical
evidence, in contrast with anterior circulation strokes. Patients with mild-to-moderate
posterior circulation AIS pose a unique challenge, as retrospective data correlate the
patients' clinical outcome with severity at presentation, giving them up to 67% chance of
achieving a favorable outcome.

Inclusion Criteria:

1. Age 18 - 85.

2. Clinical signs consistent with acute ischemic stroke.

3. No prestroke functional dependence (prestroke Modified Rankin Score ≤ 1).

4. NIHSS <6 at the time of enrollment.

5. Consent obtained within 24 hours from last known well.

6. Thrombolysis in Cerebral Infarction (TICI) 0-1 flow in

1. The M1 or M2 segment of the MCA, or carotid terminus confirmed by CT or MR
angiography; or

2. The basilar artery.

7. Subject can be treated within 1 hours (60 minutes) from pre-procedure CT or MRI to
groin puncture.

8. CT or MRI-DWI ASPECT Score of > 6 in the anterior circulation, or posterior
circulation ASPECT Score (pc-ASPECTS) of > 7.36

9. Subject is willing to conduct protocol‐required follow‐up visits.

10. Subject or subject's legally authorized representative has signed and dated an
Informed Consent Form.

NB: Patient can be enrolled regardless of whether the patient received IV t-PA. However,
the decision for administration of IV t-PA must be made before enrolling into the study.

Exclusion Criteria:

1. Female who is pregnant or lactating or has a positive pregnancy test at time of
admission.

2. Known serious sensitivity to radiographic contrast agents.

3. Subject with a pre‐existing neurological or psychiatric disease that would confound
the neurological and functional evaluations. Computed tomography (CT) or Magnetic
Resonance Imaging (MRI) evidence of hemorrhage on presentation.

4. CT or MRI ASPECT score of ≤6 in the anterior circulation, or pc-ASPECTS of ≤7.

5. CT or MRI evidence of mass effect or intra‐cranial tumor (except small meningioma).

6. Current participation in another investigation drug or device treatment study.

7. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency.

8. Warfarin therapy with INR greater than 1.7.

9. Low molecular Weight Heparins, Heparin, Factor Xa inhibitors or direct thrombin
inhibitors as full dose within the last 48 hours from screening and must have a normal
partial thromboplastin time (PTT) to be eligible.

10. Baseline lab values: glucose < 50 mg/dL or > 400 mg/dL, platelets < 100,000 or Hct <
25.

11. Renal Failure as defined by a serum creatinine > 2.0 or Glomerular Filtration Rate
[GFR]< 30.

12. Life expectancy of less than 90 days.

13. Clinical presentation suggests a subarachnoid hemorrhage, even if initial CT or MRI
scan is normal.

14. Presumed septic embolus, or suspicion of bacterial endocarditis.

15. Preprocedural or intraprocedural diagnosis of an unexpected vascular lesion or
condition that may require additional, non-standard thrombectomy endovascular
procedure(s), such as stenting, angioplasty or other treatment, and pose an additional
or elevated risk. Such conditions, listed below, exclude or invalidate enrollment in
the study:

1. Previous intracranial hemorrhage, neoplasm, subarachnoid hemorrhage, cerebral
aneurysm, or arteriovenous malformation

2. Previously unknown dissection, vasculitis, vasculopathy, severe hemodynamically
significant vascular stenosis, or other atypical vascular lesion

3. Tandem lesions, defined as an occlusion involving both the cervical and
intracranial segment of the same vascular distribution

4. Stroke or vascular occlusions in multiple vascular territories