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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
A Double-Blind, Placebo-Controlled, Randomized, Phase Ib/IIa Clinical Study of ApTOLL for the Treatment of Acute Ischemic Stroke

Conditions
-----------------
Stroke, Acute Stroke, Ischemic Stroke

Intervention / Treatment
-----------------
* Drug: ApTOLL
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥18 and ≤90 years. Informed consent obtained from subject or acceptable subject surrogate (i.e. next of kin, or legal representative). A new focal disabling neurologic deficit consistent with acute cerebral ischemia. Baseline NIHSS obtained prior to randomization ≥ 8 points and ≤ 25 points. Pre-stroke mRS score of 0 - 2. 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). Patients should be candidates to receive EVT treatment with or without i.v. rt-PA. 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. The following imaging criteria should also be met on admission neuroimaging: MRI criterion: volume of DWI (Diffusion-weighted Imaging) restriction ≥5 mL and ≤70 mL OR 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. The subject has an indication and is planned to receive endovascular treatment of stroke according to the European Stroke Organization Guidelines. Exclusion Criteria: Subject has suffered a stroke in the past 1 year. Occlusion (TICI 0 or TICI 1 flow) of the basilar or vertebral or posterior or anterior cerebral arteries. Clinical symptoms suggestive of bilateral stroke or stroke in multiple territories. Known hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR (international normalized ratio)>3.0. Baseline platelet count <50,000/μL. Baseline blood glucose of <50 mg/dL or >400 mg/dL. Severe, sustained hypertension (systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg). Serious, advanced, or terminal illness with anticipated life expectancy of less than 1 year. Subjects with identifiable intracranial tumors. History of life-threatening allergy (more than rash) to contrast medium. Known renal insufficiency with creatinine ≥3 mg/dL or Glomerular Filtration Rate (GFR) <30 mL/min. Cerebral vasculitis. Evidence of active systemic infection. Known current use of cocaine at time of treatment. Patient participating in a study involving an investigational drug or device that would impact this study. Patients that are unlikely to be available for a 90-day follow-up (e.g. no fixed home address, visitor from overseas). Female who is pregnant or lactating or has a positive pregnancy test at time of admission. CT or MRI evidence of hemorrhage (the presence of microbleeds is allowed). Significant mass effect with midline shift. Suspicion of aortic dissection presumed septic embolus, or suspicion of bacterial endocarditis.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Phase Ib ApTOLL<br>ApTOLL is administered intravenously in a single ascending dose pattern in four dose levels (0.025mg/kg - 0.2mg/kg). All levels include six patients. | Drug: ApTOLL<br>* ApTOLL is a Toll-like receptor 4 (TLR4) antagonist, a receptor that is involved in innate immune responses but also responds to tissue damage, and therefore it is directly involved in a large number of diseases where the inflammatory response is involved. ApTOLL has demonstrated specific binding to human TLR4 as well as a TLR4 antagonistic effect, reducing inflammation and improving outcome after different disease models.<br>|
| Placebo Comparator: Phase Ib Placebo<br>Placebo is administered intravenously in a single ascending dose pattern in four dose levels (0.025mg/kg - 0.2mg/kg). All levels include two patients. | Other: Placebo<br>* White freeze-dried powder which is indistinguishable to ApTOLL for taste, color, texture and size.<br>|
| Active Comparator: Phase IIa ApTOLL<br>ApTOLL is administered intravenously (two doses selected in Phase Ib). The two dose levels include 35 patients each one. | Drug: ApTOLL<br>* ApTOLL is a Toll-like receptor 4 (TLR4) antagonist, a receptor that is involved in innate immune responses but also responds to tissue damage, and therefore it is directly involved in a large number of diseases where the inflammatory response is involved. ApTOLL has demonstrated specific binding to human TLR4 as well as a TLR4 antagonistic effect, reducing inflammation and improving outcome after different disease models.<br>|
| Placebo Comparator: Phase IIa Placebo<br>Placebo is administered intravenously in one arm which includes 49 patients. | Other: Placebo<br>* White freeze-dried powder which is indistinguishable to ApTOLL for taste, color, texture and size.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of ApTOLL | To assess if ApTOLL is safe when combined with EVT therapy as determined by: Death. Adverse events that occur during the study. Physical examination. Laboratory tests. Recurrent stroke. Symptomatic intracranial hemorrhage (sICH). | From dosing to follow-up (day 90 after dosing) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean infarct volume | Magnetic Resonance Image | 72 hours | 
| Effect in inflammatory response | Proinflammatory markers in blood between study groups | Predose and up to 72 hours post-dose | 
| Early clinical course | NIHSS (National institute of Health Stroke Scale). The maximum possible score is 42, with the minimum score being a 0 (the higher the score, the more impaired a stroke patient is) | 72 hours post-dose | 
| Long-term outcome | mRS (modified Ranking Score). Coded from 0 (no symptoms at all) through 5 (severe disability) 6 (death). | Day 90 post-dose |