Phase Ib/IIa Clinical Study of ApTOLL for the Treatment of Acute Ischemic Stroke

This is a prospective, multicenter, double-blind, randomized, placebo-controlled, Phase Ib/IIa clinical study to assess the administration of ApTOLL together with endovascular therapy in acute ischemic stroke patients who are candidates to receive reperfusion therapies.

This is a prospective, multicenter, double-blind, randomized, placebo-controlled, Phase Ib/IIa clinical study to assess the administration of ApTOLL together with endovascular therapy in acute ischemic stroke (AIS) patients with confirmed Large Vessel Occlusion (LVO) who are candidates to receive reperfusion therapies including endovascular treatment with or without i.v. rt-PA (recombinant tissue Plasminogen Activator).

The study will be a Phase Ib/IIa trial where 2 doses selected, based on safety criteria, on Phase Ib will be administered in the following Phase IIa.The objective of the study is to evaluate if administration of ApTOLL at different doses is safe and well tolerated compared to placebo when administered with endovascular therapy (EVT), with or without i.v. rt-PA, in the AIS target population.

Eligibility Criteria:
Inclusion Criteria:

1. Age ≥18 and ≤90 years.
2. Informed consent obtained from subject or acceptable subject surrogate (i.e. next of kin, or legal representative).
3. A new focal disabling neurologic deficit consistent with acute cerebral ischemia.
4. Baseline NIHSS obtained prior to randomization ≥ 8 points and ≤ 25 points.
5. Pre-stroke mRS score of 0 - 2.
6. Treatable as soon as possible and at least within 6 hours of symptom onset, defined as point in time when the subject was last seen well (at baseline).
7. Patients should be candidates to receive EVT treatment with or without i.v. rt-PA.
8. Occlusion (TICI 0 or TICI 1 flow), of the terminal internal carotid artery (TICA), M1 or M2 segments of the middle cerebral artery, suitable for mechanical embolectomy, confirmed on Computed Tomography Angiography.
9. The following imaging criteria should also be met on admission neuroimaging:

   1. MRI criterion: volume of DWI (Diffusion-weighted Imaging) restriction ≥5 mL and ≤70 mL OR
   2. CT criterion: Alberta Stroke program early CT score (ASPECTS) 6 to 10 on baseline CT AND infarct core determined on admission CTPerfusion by Cerebral Blood Flow\<30%: ≥5 mL and ≤70 mL.
10. The subject has an indication and is planned to receive endovascular treatment of stroke according to the European Stroke Organization Guidelines.

Exclusion Criteria:

1. Subject has suffered a stroke in the past 1 year.
2. Occlusion (TICI 0 or TICI 1 flow) of the basilar or vertebral or posterior or anterior cerebral arteries.
3. Clinical symptoms suggestive of bilateral stroke or stroke in multiple territories.
4. Known hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR (international normalized ratio)\>3.0.
5. Baseline platelet count \<50,000/μL.
6. Baseline blood glucose of \<50 mg/dL or \>400 mg/dL.
7. Severe, sustained hypertension (systolic blood pressure \>185 mmHg or diastolic blood pressure \>110 mmHg).
8. Serious, advanced, or terminal illness with anticipated life expectancy of less than 1 year.
9. Subjects with identifiable intracranial tumors.
10. History of life-threatening allergy (more than rash) to contrast medium.
11. Known renal insufficiency with creatinine ≥3 mg/dL or Glomerular Filtration Rate (GFR) \<30 mL/min.
12. Cerebral vasculitis.
13. Evidence of active systemic infection.
14. Known current use of cocaine at time of treatment.
15. Patient participating in a study involving an investigational drug or device that would impact this study.
16. Patients that are unlikely to be available for a 90-day follow-up (e.g. no fixed home address, visitor from overseas).
17. Female who is pregnant or lactating or has a positive pregnancy test at time of admission.
18. CT or MRI evidence of hemorrhage (the presence of microbleeds is allowed).
19. Significant mass effect with midline shift.
20. Suspicion of aortic dissection presumed septic embolus, or suspicion of bacterial endocarditis.