NCT03181360.

Study name	Tenecteplase in Wake‐up Ischaemic Stroke Trial (TWIST)
Methods	PROBE; prospective, randomised, open, blinded‐endpoint
Participants	600 participants Inclusion criteria Stroke symptoms on awakening that were not present before sleep Clinical diagnosis of stroke with limb weakness with an NIHSS score ≥ 3, or dysphasia Treatment with tenecteplase is possible within 4.5 hours of awakening Written consent from the patient, non‐written consent from the patient (witnessed by non‐participating healthcare personnel), or written consent from the nearest family member (according to national/local ethics requirements) Exclusion criteria Age < 18 years NIHSS score > 25 or NIHSS consciousness score > 2, or seizures during stroke onset Findings on plain CT that indicate that the patient is unlikely to benefit from treatment: infarction comprising more than > 1/3 of the middle cerebral artery territory on plain CT or CT perfusion; intracranial haemorrhage, structural brain lesions that can mimic stroke (e.g. cerebral tumour). Active internal bleeding of high risk of bleeding, e.g. major surgery, trauma or gastrointestinal or urinary tract haemorrhage within the previous 21 days, or arterial puncture at a non‐compressible site within the previous 7 days; any known defect in coagulation, e.g. current use of vitamin K antagonist with an INR > 1.7 or prothrombin time > 15 seconds, or use of direct thrombin inhibitors or direct factor Xa inhibitors during the last 24 hours (unless reversal of effect can be achieved by agents such as idarucizumab) or with elevated sensitive laboratory tests (such as aPTT, INR, platelet count, eucarin clotting time, thrombin time, or appropriate factor Xa activity assays), or heparins during the last 24 hours or with an elevated aPTT greater than the upper limit of normal; known defect of clotting or platelet function or platelet count below 100,000/mm3 (but patients on antiplatelet agents may be included); ischaemic stroke or myocardial infarction in previous 3 months, previous intracranial haemorrhage, severe traumatic brain injury, or intracranial or intraspinal operation in previous 3 months, or known intracranial neoplasm, arteriovenous malformation, or aneurysm. Contraindications to tenecteplase, e.g. acute bacterial endocarditis or pericarditis; acute pancreatitis; severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension; active hepatitis; systemic cancer with increased bleeding risk; haemostatic defect including secondary to severe hepatic, renal disease; organ biopsy; prolonged cardiopulmonary resuscitation > 2 min (within 2 weeks) Persistent blood pressure elevation (systolic ≥ 185 mmHg or diastolic ≥ 110 mmHg), despite blood pressure‐lowering treatment Blood glucose < 2.7 or > 20.0 mmol/L (use of finger‐stick measurement devices is acceptable) Pregnancy, positive pregnancy test, childbirth during last 10 days, or breastfeeding. In any woman of childbearing potential, a pregnancy test must be performed and the result assessed before trial entry. Other serious or life‐threatening disease before the stroke: severe mental or physical disability (e.g. Mini Mental Status score < 20 or mRS score ≥ 3), or life expectancy less than 12 months Patient unavailable for follow‐up (e.g. no fixed address)
Interventions	Tenecteplase + best standard treatment or no tenecteplase + best standard treatment Tenecteplase (recombinant fibrin‐specific tissue plasminogen activator) is given as a single‐dose intravenous injection 0.25 mg (200 IU) per kg body weight up to a maximum of 25 mg (5000 IU), administered as a bolus over approximately 10 seconds
Outcomes	Primary outcome measures Functional outcome at 3 months assessed by the mRS on the ordinal scale 0 to 6 Secondary outcome measures Clinical events: Favourable functional outcome: mRS 0 to 1 Good functional outcome: mRS 0 to 2 Death from all cause during follow‐up Any intracranial haemorrhage during follow‐up Symptomatic intracranial haemorrhage by SITS‐MOST definition Symptomatic intracranial haemorrhage by IST‐3 definition Parenchymal haemorrhage type 2 Stroke progression during follow‐up Recurrent ischaemic stroke during follow‐up Major extra cranial bleeding NIHSS score at 24 hours and day 7 Change in NIHSS score from baseline to 24 hours and day 7 Other clinical outcomes at 3 months: NIHSS score Barthel Index score EuroQol score MMSE scores Health‐economic variables: Length of hospital stay Nursing home care after discharge Rehospitalisations during first 3 months
Starting date	June 2017
Contact information	Trial Manager: Melinda B Roaldsen; e‐mail: melinda.b.roaldsen@uit.no or twist@uit.no
Notes	ClinicalTrials.gov identifier: NCT03181360 Funding source: main source is the Norwegian Program for Clinical Research Therapy initiated by the Norwegian Ministry of Health and Care Services and financed through the Norwegian National Budget. Additional grants from the Swiss Heart Foundation, the British Heart Foundation, and the National Association for Public Health. The costs of tenecteplase are covered by an unconditional grant from Boehringer Ingelheim.