Loss of equipoise in the 0-4.5h population which comprised the majority of ETERNAL-LVO trial recruitment due to publication of other trials demonstrating efficacy of tenecteplase vs alteplase in the 0-4.5h time window.

Patients presenting to the emergency department with an acute ischemic stroke due to a large vessel occlusion eligible for thrombectomy and target mismatch on computed tomography perfusion imaging within 24 hours of onset will be assessed determine their eligibility for randomization into the trial. If the patient gives informed consent they will be randomised using a central computerised allocation process to either standard of care (no intravenous thrombolytic treatment or intravenous alteplase 0.9mg/kg) or tenecteplase before undergoing intra-arterial clot retrieval. The trial is prospective, randomised, open-label, blinded endpoint (PROBE) design.

Inclusion Criteria:

• Patients presenting with acute hemispheric ischemic stroke with onset (or the time they last known to be well) within 24 hours.
• Patient's age is ≥18 years.
• Premorbid mRS <3, with a concurrent assessment of whether the patient was able, immediately prior to the stroke, to: 1) Drive, or (if never drives) perform own Domestic duties, and 2) Shop for themselves, and 3) Bank/do their own finances (i.e. Drive/Domestic, Bank, Shop = DBS +ve). Need to be DBS +ve to be study eligible.
• Presence of a vessel occlusion on CTA or MRA. LVO will be defined as 'potentially retrievable' thrombus at one or more of the following sites: intracranial internal carotid (ICA), middle cerebral artery (MCA) first segment (M1), proximal middle cerebral artery second segment (M2) or isolated/tandem occlusion of the extracranial ICA. Patients with an extracranial ICA stenosis and occlusion are also eligible.
• Presence of 'target mismatch' on automated perfusion CT (CTP) or diffusion-perfusion MRI software defined as an ischemic core of <70mL, penumbra of >20mL and an ischemic core to perfusion lesion ratio of >1.8

Exclusion Criteria:

• Intracranial hemorrhage (ICH) or other diagnosis (e.g. tumor).
• Basilar Artery occlusion.
• Extensive early ischemic change (hypodensity on NCCT or high signal on DWI-MRI) or early ischemic change outside the perfusion lesion that invalidates mismatch criteria.
• Pre-stroke mRS score of > 2 (indicating significant previous disability) or DBS -ve.
• Any terminal illness such that patient would not be expected to survive more than 1 year
• Any condition that, in the judgment of the investigator could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study.
• Pregnant women.
• Other standard contraindications to thrombolysis.
• Minor stroke symptoms, or major stroke symptoms rapidly improving
• Clinical presentation suggesting subarachnoid haemorrhage
• Known bleeding diasthesis and/or platelet count <100,000 or taking warfarin with INR > 1.7.
• Patients who have received heparin within 48 hours must have normal aPTT.
• Major surgery or serious trauma within 14 days, serious head trauma within 3 months.
• GI or urinary tract haemorrhage within last 21 days
• Arterial puncture at a non-compressible site or lumbar puncture within 7 days
• Systolic BP > 185, diastolic BP > 110mmHg
• Clinical stroke within 3 months or history of ICH
• Unable to gain consent from patient or person responsible
• Known severe renal impairment (GFR < 15mls/min)