Optimizing Reperfusion to Improve Outcomes and Neurologic Function (ORION)

Prior treatment

• Major trauma, surgery, or invasive procedures: a. Severe head trauma within 3 months of screening or acute head trauma. b. Major trauma not involving the head within 14 days of screening. c. Major surgery with 14 days of screening. d. Intracranial or intraspinal surgery within 90 days of screening. e. Dural puncture (e.g., lumbar puncture) or arterial puncture of a noncompressible blood vessel within 7 days of screening.
• Prior thrombolytic administration within 90 days of screening or planned thrombolytic administration for the AIS. (Co-administration with any other thrombolytic agent(s) within 48 hours is prohibited).
• Known or suspected use of any oral anticoagulant therapy, including but not limited to vitamin K antagonists, thrombin inhibitors, or factor Xa inhibitors, within 48 hours of screening unless blood testing confirms absence of drug substance in the system.
• Use of nephrotoxic medications or agents within 7 days of screening that would (in the investigator’s opinion) pose significant risk of acute kidney injury (e.g. aminoglycosides, cyclosporins, lactams, amphotericin B, cisplatin, indomethacin, etc.).

Other illness

• Radiographic findings pre-randomization of any of the following: a. Large core infarction, evidenced by a core infarct volume > 70 mL, assessed on DWI or CTP; or extensive early ischemic change (hypodensity) on non-contrast CT estimated to be > 1 3 MCA territory, or significant hypodensity outside the Tmax > 6 seconds perfusion lesion that invalidates mismatch criteria, or b. Occlusion in more than 1 vascular territory confirmed on CTA MRA, or c. Significant mass effect or clinically significant cerebral edema per Investigator’s judgement, or d. Evidence of acute intracranial or extracranial hemorrhage, intracranial tumor (except small meningioma), neoplasm, or arteriovenous malformation, or e. Clinical history, past imaging, or clinical judgement suggests that the intracranial occlusion is chronic.
• Pre-existing medical, neurological, or psychiatric disease that would confound the neurological or functional evaluations of this study.
• Life expectancy less than 6 months due to comorbid condition.
• Non-ischemic or non-thrombotic etiology of current stroke symptoms such as suspected cerebral vasospasm, infectious source (e.g., bacterial endocarditis, septic shock), complications from acute drug abuse (e.g., cocaine intoxication).
• Medical history or active clinically significant bleeding, lesions, or conditions (at the investigator’s judgement) considered to be of significant risk for major bleeding; (this may include but not limited to any history of intracranial hemorrhage or vascular aneurysm of the large arteries of major intraspinal or intracerebral abnormalities).
• Arterial dissection involving any intracranial artery or the aortic arch. Confirmed acute coronary syndrome within 90 days of screening.
• Severe hepatic impairment as defined by decompensated liver disease (e.g., Child-Pugh Class C) or clinically significant hepatic condition associated with coagulopathy or bleeding risk.
• Medical history of chronic renal failure, any condition requiring dialysis or renal replacement therapy or evidence of acute kidney injury at the time of screening, an estimated glomerular filtration rate < 30 mLmin1.73m2.
• Severe, uncontrolled hypertension (systolic blood pressure ≥ 185 mmHg or diastolic blood pressure ≥ 110 mmHg) that cannot be controlled with antihypertensive therapy.

Lab values

• Pre-treatment blood glucose > 400 mgdL (22.20 mmolL) or Pre-treatment blood glucose < 50 mgdL (2.78 mmolL) unless it is corrected prior to study treatment administration. Participants with subsequently normalized blood glucose levels may be considered for inclusion, per Investigator judgement.
• Known hereditary or acquired abnormality of UGT1A1 metabolism or deficiency such as Gilbert's syndrome (hereditary liver condition with elevated bilirubin), Crigler-Najjar syndrome (UGT1A1 gene defect associated with congenital non-hemolytic jaundice).
• Prolonged QT with QTc of > 450 ms for males and > 460 ms for females
• Use of dual anti-platelet therapy, IV aspirin, or glycoprotein IIb/IIIa inhibitors within 24 hours of screening. Pre-screening use of oral antiplatelet monotherapy with aspirin at doses less than or equal to 325 mg daily OR clopidogrel 75 mg daily is permitted.
• Use of heparin or low molecular weight heparin at a therapeutic dose, excluding prescreening prophylactic dose low molecular weight heparin with a normal aPTT.
• Known bleeding diathesis (hereditary or acquired) or any significant coagulopathy. Specifically, platelet count < 100,000 microliter, international normalized ratio > 1.7, aPTT > 40 seconds, or prothrombin time > 15 seconds.

Other

• Cerebral infarction within 90 days of screening.

• Age ≥ 18 and ≤ 90 years old (Age > 85 must be mRS 0 at baseline (premorbid) to be eligible).
• Written informed consent by patient, his her legally authorized representative, or independent physician where local regulation allows (in accordance with all local and national regulations or according to the local ethics committee's guidelines or by another process compliant with applicable national laws and regulations and ethics committee requirements).
• Acute ischemic stroke with compatible clinical presentation and either symptomatic high-grade stenosis or complete intracranial internal carotid, M1, M2 or distal branches of the middle cerebral artery (MCA), anterior cerebral artery (ACA), or posterior cerebral artery (PCA), demonstrated by: a. Computer Tomography Angiography (CTA) or Magnetic Resonance Angiography (MRA) with high grade stenosis or occlusion of an eligible artery, or b. Computer Tomography or Magnetic Resonance Perfusion (CTP/MRP) with focal deficit in an eligible artery, or c. Non-contrast Computer Tomography (NCCT) with hyperdense artery sign in an eligible artery or Magnetic Resonance Imaging (MRI) with susceptibility vessel sign (defined as a hypointense signal exceeding the diameter of the contralateral artery at the thrombus site) in an eligible artery.
• Radiographic evidence of salvageable tissue* is present based on: a. A mismatch ratio (perfusion lesion (Tmax > 6 seconds) volume core estimate) > 1.2, b. Estimated core infarct volume < 70 mL, and c. Total mismatch volume ≥ 10 mL on CTP or magnetic resonance (MR) perfusion weighted imaging (PWI) MRI diffusion imaging. The perfusion criteria apply to all participants, including those who present within 4.5 to 6 hours of LKW, if perfusion imaging is obtained. Perfusion is mandatory for patients presenting beyond 6 hours, optional for patients < 6 hours. *The quantitative assessment of penumbra may include alternative methods (e.g., if the software uses different parameters in place of Tmax).
• Presentation with intended study treatment within 4.5 to 6 hours of Last Know Well (LKW) in the absence of radiographic assessment of perfusion or within 4.5 to 24 hours of LKW with radiographic evidence of penumbra meeting criterion
• Pre-treatment score of NIHSS ≥ 5.
• Functionally independent prior to stroke onset as evidenced by premorbid mRS < 2 (< 1 if age 86-90).
• All women of childbearing potential and all men must practice contraception as described in Section 8.3.5. For women of childbearing potential, a negative pregnancy test at screening is required. All women of childbearing potential must practice effective contraception for at least 30 days after their last dose of study treatment. All men must practice effective contraception during the study and for 90 days after their last dose of study treatment. In addition, participants should not donate sperm or eggs during the study and for at least 90 days after their dose of study treatment.