The primary objective of the trial is to establish the effectiveness of IAT (versus medical management) in patients with moderate-large infarcts (NCCT ASPECTS 2-5) at baseline, with adaptive enrichment to better define the upper limit of infarct volume for treatment eligibility. Furthermore, the investigators aim to determine whether certain subgroups of patients with large baseline infarcts will have a greater treatment benefit. Finally, the investigators will assess the agreement of ASPECTS scores between site investigators, the core imaging lab, and automated software.

Prospective, randomized, open-label, blinded endpoint study. Patients presenting with symptoms of AIS who have evidence of a moderate-large infarct volume (Non-contrast CT Alberta Stroke Program Early CT score [NCCT ASPECTS] 2-5 in the anterior circulation will be assigned to either best medical management alone (including IV rtPA) or intra-arterial treatment (IAT) with mechanical thrombectomy added to best medical management. Each treated patient will be followed and assessed for 3 months after randomization.

Inclusion Criteria:

1. 18 to 85 years of age
2. Presenting with symptoms consistent with an acute ischemic stroke
3. Imaging evidence of an anterior circulation occlusion of the Internal Carotid Artery (ICA) terminus and/or Middle Cerebral Artery Main Stem (MCA M1) segment
4. NIHSS score >6 at the time of randomization
5. Ability to randomize within 24 hours of stroke onset
6. Pre-stroke mRS score 0-1
7. Ability to obtain signed informed consent

Imaging evidence of moderate-large infarct defined as:

1. NCCT ASPECTS 2-5

Exclusion Criteria:

1. Females who are pregnant, or those of child-bearing potential with positive urine or serum beta Human Chorionic Gonadotropin (HCG) test

2. Known severe allergy (more than a rash) to contrast media uncontrolled by medications

3. Refractory hypertension (defined as persistent systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg)

4. CT evidence of the following conditions:

   • Midline shift or herniation
   • Evidence of intracranial hemorrhage
   • Mass effect with effacement of the ventricles

5. Computed Tomography Angiography (CTA) evidence suggestive of difficult endovascular access per the treating interventionalist

6. Presence of cervical ICA occlusion (e.g., related to atherosclerotic disease or dissection)

7. Rapidly improving neurological status prior to randomization to NIHSS <6

8. Bilateral strokes or multiple intracranial occlusions

9. Intracranial tumors

10. Known hemorrhagic diathesis, coagulation factor deficiency, or on anticoagulant therapy with an International Normalized Ratio (INR) of >3.0 or Partial Thromboplastin Time (PTT) >3 times of normal

11. Baseline platelet count <30,000 per microliter (µl)

12. Life expectancy less than 90 days prior to stroke onset

13. Participation in another randomized clinical trial that could confound the evaluation of the study

14. Any other condition (in the opinion of the site investigator) that precludes an endovascular procedure or poses a significant hazard to the patient if an endovascular procedure was performed

All shared data will be aggregate.

The patient and the treating physician will be aware of the treatment assignment. Assessment of outcome on NIHSS and mRS will be performed by a certified rater blinded to the treatment allocation. Each site must designate one or more individual(s) to perform these blinded assessments at 24 (16-36) hours, 6 ± 1 days or discharge (whichever is earlier), 30 days ± 7 days, and 90 days ± 30 days from randomization.

Neuroimaging core lab evaluation will also be assessed in a blinded manner, except for angiographic revascularization grading which will only be performed for the intra-arterial treatment arm.

Information on treatment allocation will be stored separately from the main study database. An unblinded independent statistician will combine treatment allocation data with the clinical data in order to report to the DSMB. A second blinded statistician will be part of the steering committee.