Background to the study: Data from over 5,000 patients are now available from trials of early thrombolysis for patients with acute ischaemic stroke. A systematic review of available evidence suggests that thrombolysis is very promising but the balance of risk and benefit remains unclear. The majority of data are from trials using recombinant tissue plasminogen activator (rt-PA), also known as alteplase. A further study, including at least 6,000 patients, is required to:

• establish the balance of risk and benefit more precisely for early thrombolytic therapy with rt-PA.

• determine which categories of patients are most likely to benefit (particularly the interaction between stroke severity, early brain imaging appearances and duration of the "therapeutic time window").

Trial design: This is a multi-centre, randomised controlled trial. Eligible patients will be randomly allocated to receive either rt-PA or control. rt-PA will be given in a dose of 0.9mg per kg, up to a maximum of 90mg, with 10% of the calculated dose given as an initial bolus, and the remaining infusion given over an hour. Patients are entered into the trial by means of a telephone call to a 24 hour central computerised randomisation service (Neurosciences Trials Unit, Edinburgh). Repeat brain imaging will be carried out 24-48 hours following treatment to identify early asymptomatic intracranial haemorrhage. Aspirin, other antiplatelet drugs and anticoagulation should not be used in the 24 hours following rt-PA treatment.

Inclusion: All patients with mild, moderate or severe stroke are eligible if, in the view of the responsible physician:

• there are symptoms and signs of acute stroke, with definite onset within the previous six hours;

• CT or MRI brain scanning has been performed and has excluded intracranial haemorrhage and structural lesions that can mimic stroke (e.g. intracranial tumour);

• treatment can be started within six hours of known symptom onset.

• symptoms are recovering rapidly and are considered likely to resolve completely within 24 hours (i.e. the patient will turn out to have had a transient ischaemic attack);

• recent trauma, especially at onset of stroke;

• the patient has other serious life-threatening illnesses (e.g. advanced cancer) likely to lead to death within the next few months;

• the patient is female of childbearing potential (unless she is certain that pregnancy is not possible) or is known to be breastfeeding;

• the patient is unable to be followed up

• there is significant potential for adverse events related to treatment, because the patient:

                        -has persistent, severe elevation of blood pressure;

                        -has undergone major surgery, or had a gastrointestinal or urinary tract
                         haemorrhage within previous 21 days;

                        -has had an arterial puncture at a non-compressible site within the previous 7 days;

                        -is currently anticoagulated e.g. warfarin or heparin;

                        -has a known defect of clotting or platelet function*.

NOTE: *Patients who have been taking aspirin (or other antiplatelet) before admission are eligible for the trial and this will be recorded at randomisation.

Uncertainty principle (absence of proof): Further inclusion and exclusion criteria are not specified precisely but are guided by the uncertainty principle (or absence of proof for that particular patient). If, for whatever reason, the clinician is convinced that a patient fulfilling the above criteria should be treated, that patient should be given open label rt-PA and not randomised. If the clinician is convinced that a patient should not be given rt-PA (for whatever reason), the patient should not be included in the trial. Only those patients who fulfil the eligibility criteria AND for whom the clinician is still substantially uncertain about the balance of risks and benefits of rt-PA should be randomised.

Follow-up: A discharge form must be completed for all patients at 7 days, death, hospital discharge or transfer, whichever occurs first. Six months after randomisation, all surviving patients will be mailed a questionnaire for self-completion to assess their disability and health related quality of life.

Analyses: All analyses will be intention-to-treat.

Primary analysis: A comparison of patients allocated rt-PA versus those allocated control, who are alive and independent at 6 months.

Secondary analyses: These will include exploration of the interaction between stroke severity, brain imaging appearances and time from onset of symptoms, to identify those patients who have the most the gain (or lose) from thrombolytic treatment; examination of the risks of intracranial haemorrhage identified by repeat brain imaging; and longer-term outcome to provide reliable estimates on the cost-effectiveness of trial treatment.