EXTEND.

Study characteristics
Methods	Randomised, double‐blind, placebo‐controlled trial
Participants	225 participants, of whom 146 had wake‐up stroke. The study authors contributed unpublished data on participants with wake‐up stroke. Inclusion criteria Patients presenting with acute ischaemic stroke Patient, family member, or legally responsible person depending on local ethics requirements has given informed consent Age ≥ 18 years Treatment onset can commence within ≥ 3 to 9 hours after stroke onset according to registered product information, or within 4.5 to 9 hours according to locally accepted guidelines (guidelines are currently under international review ‐ advisory statement issued by the Stroke Council, American Heart Association, and American Stroke Association). Patients who awoke with stroke may be included if neurological and other exclusion criteria are satisfied. 'Wake‐up' stroke defined as having no symptoms at sleep onset, but stroke symptoms on waking. The time of stroke onset is to be taken as the midpoint between sleep onset (or last known to be normal) and time of waking. The maximum time window for randomisation is then 9 hours from the midpoint as described. NIHSS score of ≥ 4 to 26 with clinical signs of hemispheric infarction Penumbral imaging, using a Tmax > 6‐second delay, a PWI lesion volume to DWI lesion volume ratio > 1.2, a DWI volume ≤ 70 mL, and a perfusion lesion volume‐diffusion lesion volume difference > 10 mL Patients may be consented before or after penumbral screening depending upon local practice. The entire cohort of patients consented into the study will be followed up with clinical assessments and biomarker studies regardless of eligibility for randomisation to treatment based on penumbral mismatch criteria. Exclusion criteria Intracranial haemorrhage identified by CT or MRI Rapidly improving symptoms, particularly if in the judgement of the managing clinician improvement is likely to result in the patient having an NIHSS score of < 4 at randomisation Pre‐stroke mRS score of ≥ 2 (indicating previous disability) Contraindication to imaging with magnetic resonance with contrast agents Infarct core > 1/3 MCA territory qualitatively Participation in any investigational study in the previous 30 days Any terminal illness such that the patient would not be expected to survive more than 1 year Any condition that could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study (this applies to patients with severe microangiopathy such as haemolytic uraemic syndrome or thrombotic thrombocytopenic purpura). Judgement is left to the discretion of the investigator. Pregnant women (clinically evident) Previous stroke within last 3 months Recent past history or clinical presentation of intracerebral haemorrhage, subarachnoid haemorrhage, arteriovenous malformation, aneurysm, or cerebral neoplasm. At the discretion of each investigator Current use of oral anticoagulants and a prolonged prothrombin time (INR > 1.6) Use of heparin, except for low‐dose subcutaneous heparin, in the previous 48 hours, and an activated prolonged partial thromboplastin time exceeding the upper limit of the local laboratory normal range Use of glycoprotein IIb‐IIIa inhibitors within the past 72 hours. Use of single‐ or dual‐agent oral platelet inhibitors (clopidogrel or low‐dose aspirin, or both) prior to study entry is permitted. Clinically significant hypoglycaemia Uncontrolled hypertension defined by a blood pressure > 185 mmHg systolic or > 110 mmHg diastolic on at least 2 separate occasions at least 10 minutes apart, or requiring aggressive treatment to reduce the blood pressure to within these limits. The definition of 'aggressive treatment' is left to the discretion of the responsible investigator. Hereditary or acquired haemorrhagic diathesis Gastrointestinal or urinary bleeding within the preceding 21 days Major surgery within the preceding 14 days that poses risk in the opinion of the investigator Exposure to a thrombolytic agent within the previous 72 hours
Interventions	Intravenous t‐PA (alteplase) 0.9 mg/kg body weight up to a maximum of 90 mg, 10% as bolus, 90% over 1 hour as infusion Matching placebo
Outcomes	mRS 0 to 1 at 90 days follow‐up
Notes	ClinicalTrials.gov identifier: NCT01580839 (Australian part) and NCT00887328 (international part) Funding source: supported by Australian National Health and Medical Research Council and the Commonwealth Scientific and Industrial Research Organization Flagship Program. In Taiwan: Ministry of Health and Welfare Grant and the Ministry of Science and Technology Taiwan Clinical Trial Consortium for Stroke. Terminated due to lack of equipoise after 225 of 310 planned participants
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated
Allocation concealment (selection bias)	Low risk	Web‐based randomisation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double‐blind and placebo controlled
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	No participants lost to follow‐up
Selective reporting (reporting bias)	Low risk	Intention‐to‐treat analysis was provided.
Other bias	Unclear risk	Terminated prematurely due to lack of equipoise