Study Results
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Basic Information
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UNKNOWN
PHASE3
600 participants
INTERVENTIONAL
2017-06-12
2022-12-31
Brief Summary
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In this study, patients with wake-up stroke will be randomized to thrombolysis with tenecteplase and best standard treatment or to best standard treatment without thrombolysis. Tenecteplase has several potential advantages over alteplase, including very rapid action and that it can be given as a single injection. Prior to thrombolysis, a brain scan must be done to exclude bleeding or significant brain damage as a result from the stroke. We will use a CT scan to inform this decision. CT is used as a routine examination in all stroke patients. Other studies testing clot-busting treatment in wake-up stroke are using alteplase and more complex brain scans, which are not routinely available in the emergency situation in all hospitals.
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Detailed Description
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One in five strokes occur during sleep, but patients with "wake-up" stroke are not given thrombolytic therapy because time of stroke onset is unknown. On-going trials are testing alteplase, and use MRI techniques for selection of patients. Tenecteplase has many pharmacological advantages over alteplase: greater fibrin specificity, very rapid action, longer half-life, and single bolus administration. In addition, patient selection based on MRI findings risks excluding many patients that might otherwise benefit. TWIST will test tenecteplase and will not use MRI techniques for selection of patients. Plain CT and CT angiography (if possible) will be performed before randomisation, and CT perfusion will be performed at selected centres, as part of a sub-study.
Study design: TWIST is an international, multi-centre, randomised, open-label, blinded-endpoint trial of tenecteplase for acute ischaemic 'wake-up' stroke.
Study questions:
1. Can tenecteplase given \<4.5 hours of awakening improve functional outcome at 3 months?
2. Can findings on cerebral plain CT and CT angiography (and CT perfusion, at selected centres) identify patients who benefit from such treatment, compared to other patients?
Patients eligible for treatment who are able to receive tenecteplase within 4.5 hours of waking, will be randomly allocated to treatment with tenecteplase in addition to best standard treatment, versus best standard treatment.
Randomisation and treatment: Central randomisation (over the internet) to tenecteplase 0.25 mg/mg i.v. (maximum dose 25 mg) plus best medical treatment vs. best medical treatment alone.
Imaging: All patients will undergo CT and CT angiography (CTA, if possible) before randomisation and on day 2. CT perfusion (CTP) will be performed at selected centres, as part of a sub-study.
Follow-up and primary effect variable: Centralised follow-up via telephone or mail at 3 months. The primary effect variable is functional outcome (modified Rankin Scale score).
Study size and centers: 600 patients from centers in Norway, Sweden, Denmark, Finland, Estonia, Latvia, Lithuania, United Kingdom, Switzerland and New Zealand.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
SINGLE
Study Groups
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Tenecteplase
Tenecteplase + Best standard treatment
Tenecteplase
Single dose intravenous injection of recombinant fibrin-specific tissue plasminogen activator (tenecteplase) 0.25 mg (200 IU) per kg body weight up to a maximum of 25 mg (5000 IU), given as a bolus over approx. 10 seconds.
Control
No tenecteplase + Best standard treatment
Control
Best standard treatment
Interventions
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Tenecteplase
Single dose intravenous injection of recombinant fibrin-specific tissue plasminogen activator (tenecteplase) 0.25 mg (200 IU) per kg body weight up to a maximum of 25 mg (5000 IU), given as a bolus over approx. 10 seconds.
Control
Best standard treatment
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Clinical diagnosis of stroke with limb weakness with 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 health care personnel), or written consent from the nearest family member
Exclusion Criteria
* 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 which 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 activated partial thromboplastin time (aPTT), international normalized ratio (INR), platelet count, ecarin clotting time, thrombin time (TT), 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 can 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 unavailability for follow-up (e.g. no fixed address)
18 Years
ALL
Yes
Sponsors
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UiT The Arctic University of Norway
OTHER
The Royal Norwegian Ministry of Health
OTHER
Norwegian Health Association
OTHER
University Hospital of North Norway
OTHER
Responsible Party
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Principal Investigators
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Ellisiv B Mathiesen
Role: PRINCIPAL_INVESTIGATOR
University Hospital of North Norway
Locations
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University of Massachusetts Medical School
Worcester, Massachusetts, United States
Bispebjerg hospital
Copenhagen, , Denmark
Odense University Hospital
Odense, , Denmark
Pärnu Hospital
Pärnu, , Estonia
East Tallin Central Hospital
Tallinn, , Estonia
West Tallin Central Hospital
Tallinn, , Estonia
Tartu University Clinic
Tartu, , Estonia
Satakunta Central Hospital
Pori, Satakunta, Finland
Helsinki University Hospital
Helsinki, , Finland
Siun sote - Joint municipal authority for North Karelia social and health services
Joensuu, , Finland
Pohjois-Kymen sairaala
Kouvola, , Finland
Central Hospital in Vaasa
Vaasa, , Finland
Riga East University Hospital
Riga, , Latvia
Alytus S. Kudirkos Hospital
Alytus, , Lithuania
Lithuanian University of Health Sciences Kauno Klinikos
Kaunas, , Lithuania
Klaipeda Seamen's Hospital
Klaipėda, , Lithuania
Republican Vilnius University Hospital
Vilnius, , Lithuania
Vilnius University Hospital
Vilnius, , Lithuania
Christchurch Hospital
Christchurch, , New Zealand
Sørlandet sykehus HF Arendal
Arendal, , Norway
Ålesund sjukehus Helse Møre og Romsdal
Ålesund, , Norway
Drammen sykehus Vestre Viken HF
Drammen, , Norway
Sørlandet Sykehus HF Flekkefjord
Flekkefjord, , Norway
Helse Førde HF
Førde, , Norway
Nordlandssykehuset Lofoten Gravdal
Gravdal, , Norway
Helse Finnmark Hammerfest
Hammerfest, , Norway
University Hospital of North Norway, Harstad
Harstad, , Norway
Helse Finnmark HF Kirkenes
Kirkenes, , Norway
Sørlandet sykehus Kristiansand HF
Kristiansand, , Norway
Sykehuset Levanger
Levanger, , Norway
Akershus universitetssykehus (Ahus)
Lørenskog, , Norway
Helgelandssykehuset Mosjøen
Mosjøen, , Norway
University Hospital of North Norway, Narvik
Narvik, , Norway
Bærum sykehus Vestre Viken HF
Sandvika, , Norway
Sykehuset Telemark Skien
Skien, , Norway
Stavanger Universitetssjukehus
Stavanger, , Norway
University Hospital of North Norway, Tromsø
Tromsø, , Norway
St Olavs Hospital
Trondheim, , Norway
Ängelholm Hospital
Ängelholm, , Sweden
Sahlgrenska Universitetssjukhuset
Gothenburg, , Sweden
Hässleholm Sjukhus
Hässleholm, , Sweden
Central Hospital Karlstad
Karlstad, , Sweden
Skåne University Hospital Lund
Lund, , Sweden
Skåne University Hospital Malmö
Malmo, , Sweden
Skaraborg Hospital Skövde
Skövde, , Sweden
Karolinska sjukhuset
Solna, , Sweden
Saint Göran Hospital
Stockholm, , Sweden
Danderyd Hospital
Stockholm, , Sweden
Akademiska Sjukhuset
Uppsala, , Sweden
University Hospital Basel
Basel, , Switzerland
Groupement Hospitalier Ouest Lémanique
Nyon, , Switzerland
Pinderfields Hospital
Wakefield, Mid Yorkshire, United Kingdom
Northumbria Specialist Emergency Care Hospital
Cramlington, Northumberland, United Kingdom
Aberdeen Royal Infirmary
Aberdeen, , United Kingdom
Arrowe Park
Birkenhead, , United Kingdom
University Hospital Birmingham
Birmingham, , United Kingdom
Royal Bournemoth and Christchurch Hospital
Bournemouth, , United Kingdom
Addenbrookes Hospital
Cambridge, , United Kingdom
Countess of Chester Hospital NHS Foundation Trust
Chester, , United Kingdom
University Hospitals Coventry & Warwickshire
Coventry, , United Kingdom
Royal Derby Hospital
Derby, , United Kingdom
Royal Infirmary of Edinburgh Hospital
Edinburgh, , United Kingdom
Royal Devon and Exeter Hospital
Exeter, , United Kingdom
Gloucestershire Royal Hospital
Gloucester, , United Kingdom
Calderdale Royal Infirmary
Halifax, , United Kingdom
Hull University Teaching Hospital
Hull, , United Kingdom
Leeds General Infirmary
Leeds, , United Kingdom
Leicester Royal Infirmary
Leicester, , United Kingdom
Royal Liverpool University Hospital
Liverpool, , United Kingdom
University College London
London, , United Kingdom
King´s College Hospital
London, , United Kingdom
St Georges Hospital
London, , United Kingdom
Charing Cross Hospital
London, , United Kingdom
Royal London Hospital
London, , United Kingdom
Luton and Dunstable University Hospital
Luton, , United Kingdom
Morriston Hospital
Morriston, , United Kingdom
Royal Victoria Infirmary
Newcastle upon Tyne, , United Kingdom
Nottingham City Hospital
Nottingham, , United Kingdom
Salford Royal Hospital
Salford, , United Kingdom
Southhampton General Hospital
Southampton, , United Kingdom
Royal Stoke University Hospital
Stoke-on-Trent, , United Kingdom
Musgrove Park Hospital
Taunton, , United Kingdom
Yeovil District Hospital
Yeovil, , United Kingdom
Countries
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Central Contacts
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Facility Contacts
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Sirpa Kaipiainen, MD
Role: primary
Aleksejs Višņakovs
Role: primary
Gunnar Andsberg, MD
Role: primary
References
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Roaldsen MB, Eltoft A, Wilsgaard T, Christensen H, Engelter ST, Indredavik B, Jatuzis D, Karelis G, Korv J, Lundstrom E, Petersson J, Putaala J, Soyland MH, Tveiten A, Bivard A, Johnsen SH, Mazya MV, Werring DJ, Wu TY, De Marchis GM, Robinson TG, Mathiesen EB; TWIST Investigators. Safety and efficacy of tenecteplase in patients with wake-up stroke assessed by non-contrast CT (TWIST): a multicentre, open-label, randomised controlled trial. Lancet Neurol. 2023 Feb;22(2):117-126. doi: 10.1016/S1474-4422(22)00484-7. Epub 2022 Dec 19.
Eltoft A, Wilsgaard T, Roaldsen MB, Soyland MH, Lundstrom E, Petersson J, Indredavik B, Putaala J, Christensen H, Korv J, Jatuzis D, Engelter ST, De Marchis GM, Werring DJ, Robinson T, Tveiten A, Mathiesen EB. Statistical analysis plan for the randomized controlled trial Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST). Trials. 2022 May 19;23(1):421. doi: 10.1186/s13063-022-06301-0.
Roaldsen MB, Lindekleiv H, Eltoft A, Jusufovic M, Soyland MH, Petersson J, Indredavik B, Tveiten A, Putaala J, Christensen H, Korv J, Jatuzis D, Engelter ST, Marco De Marchis G, Wilsgaard T, Werring DJ, Robinson T, Mathiesen EB, Berge E. Tenecteplase in wake-up ischemic stroke trial: Protocol for a randomized-controlled trial. Int J Stroke. 2021 Oct;16(8):990-994. doi: 10.1177/1747493020984073. Epub 2021 Jan 14.
Provided Documents
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Document Type: Study Protocol
Other Identifiers
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2014-000096-80
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
2015/1070/REC North
Identifier Type: -
Identifier Source: org_study_id
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