THAWS.

Study characteristics
Methods	Randomised, single‐blinded, controlled trial
Participants	131 participants, of whom 89 had wake‐up stroke. The study authors contributed unpublished data on participants with wake‐up stroke. Inclusion criteria Clinical diagnosis of acute ischaemic stroke with unknown symptom onset (e.g. acute wake‐up ischaemic stroke, acute ischaemic stroke with unknown time of symptom onset) Last known well without neurological symptoms > 4.5 hours and < 12 hours of treatment initiation Treatment can be started within 4.5 hours of symptom recognition (e.g. awaking) Acute stroke MRI including DWI and FLAIR completed ASPECTS on initial DWI is 5 or more No marked parenchymal hyperintensity visible on FLAIR Initial NIHSS ≥ 5 and ≤ 25 Written informed consent by patient or next of kin Exclusion criteria Pre‐stroke mRS > 1 (patients who are unable to carry out all daily activities and require some help or supervision) Contraindications in the Japanese guideline for the intravenous application of rt‐PA (alteplase) History of non‐traumatic intracranial haemorrhage History of stroke within the last 1 month (excluding transient ischaemic attack) History of significant head/spinal injury or surgery within the last 3 months History of gastrointestinal or urinary tract bleeding within the last 21 days History of major surgery or significant trauma other than head injury within the last 14 days Hypersensitivity to alteplase Suspected subarachnoid haemorrhage Concurrent acute aortic dissection Concurrent haemorrhage (e.g. intracranial, gastrointestinal, urinary tract, or retroperitoneal, haemoptysis) Systolic blood pressure ≥ 185 mmHg despite antihypertensive therapy Diastolic blood pressure ≥ 110 mmHg despite antihypertensive therapy Significant hepatic disorder Acute pancreatitis Blood glucose < 50 mg/dL or > 400 mg/dL Platelet count ≤ 100,000/mm3 INR of prothrombin time > 1.7 or prolonged aPTT > 1.5 times the baseline value (> approximately 40 seconds only as a guide) for patients on anticoagulation therapy or those with abnormal coagulation Any contraindication to MRI (e.g. cardiac pacemaker) Extensive early ischaemic change in brainstem or cerebellum (e.g. more than half of brainstem or more than 1 hemisphere of cerebellum) Planned or anticipated treatment with surgery or endovascular reperfusion strategies (e.g. intra‐arterial thrombolysis, mechanical recanalisation techniques) Pregnant, lactating, or potentially pregnant Life expectancy 6 months or less by judgement of the investigator Inappropriate for study enrolment by judgement of the investigator
Interventions	Intravenous t‐PA (alteplase) 0.6 mg/kg body weight up to a maximum of 60 mg, 10% as bolus, 90% over 1 hour as infusion Best medical care
Outcomes	Favourable outcome (mRS score 0 to 1) at 90 days follow‐up
Notes	ClinicalTrials.gov identifier: NCT02002325  Funding Source: Japan Agency for Medical Research and Development and the Ministry of Health, Labour, and Welfare, and partly by the Mihara Cerebrovascular Disorder Research Promotion Fund. Terminated due to lack of equipoise after 131 of 300 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	Unclear risk	Open‐label
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinded outcome assessment
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 because of lack of equipoise after the WAKE‐UP trial published their results