Clinical trial NCT03181360: Tenecteplase in Wake-up Ischaemic Stroke Trial
Official title: Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST). A Randomised-controlled Trial of Thrombolytic Treatment With Tenecteplase for Acute Ischaemic Stroke Upon Awakening
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Ischemic Stroke
Stroke, Acute
Keywords: ischemic stroke
wake-up
thrombolysis
tenecteplase
computed tomography
Lead sponsor: University Hospital of North Norway
Sponsor class: OTHER
Collaborators: name: UiT The Arctic University of Norway
name: The Royal Norwegian Ministry of Health
name: Norwegian Health Association
First posted: 2017-06-08
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Stroke is a leading causes of death and disability. At least 20% of strokes occur during sleep, so- called 'wake up stroke'. Thrombolysis with the clot-busting drug alteplase is effective for acute ischaemic stroke, provided that it is given within 4.5 hours of symptom onset. Patients with wake-up stroke are currently ineligible for clot-busting therapy. Previous studies indicate that many wake-up strokes occur just before awakening.

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.

Detailed description: Background:

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.

Eligibility criteria: Inclusion Criteria:

* Stroke symptoms on awakening that were not present before sleep
* 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:

* 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 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)

Primary outcomes:
measure: Functional outcome at 3 months.
timeFrame: 3 months
Secondary outcomes:
measure: Symptomatic intracranial haemorrhage during the first 7 days.
timeFrame: First 7 days
measure: Asymptomatic intracranial haemorrhage during the first 7 days.
timeFrame: First 7 days
measure: Recurrent ischaemic stroke during the first 7 days
timeFrame: First 7 days
measure: Death from all cause
timeFrame: First 7 days
measure: Death from all cause
timeFrame: 3 months
measure: Barthel Index score
timeFrame: 3 months
measure: EuroQol Score (EQ-5D)
timeFrame: 3 months
measure: Mini Mental State Examination
timeFrame: 3 months
measure: Health-economic variables
timeFrame: 3 months
measure: Functional outcome at 3 months
timeFrame: 3 months
Other outcomes:
Locations:
city: Worcester
country: United States
facility: University of Massachusetts Medical School
state: Massachusetts
city: København
country: Denmark
facility: Bispebjerg hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Pärnu
country: Estonia
facility: Pärnu Hospital
city: Tallinn
country: Estonia
facility: East Tallin Central Hospital
city: Tallin
country: Estonia
facility: West Tallin Central Hospital
city: Tartu
country: Estonia
facility: Tartu University Clinic
city: Pori
country: Finland
facility: Satakunta Central Hospital
state: Satakunta
city: Helsinki
country: Finland
facility: Helsinki University Hospital
city: Joensuu
country: Finland
facility: Siun sote - Joint municipal authority for North Karelia social and health services
city: Kouvola
country: Finland
facility: Pohjois-Kymen sairaala
city: Vaasa
country: Finland
facility: Central Hospital in Vaasa
city: Riga
country: Latvia
facility: Riga East University Hospital
city: Alytus
country: Lithuania
facility: Alytus S. Kudirkos Hospital
city: Kaunas
country: Lithuania
facility: Lithuanian University of Health Sciences Kauno Klinikos
city: Klaipėda
country: Lithuania
facility: Klaipeda Seamen's Hospital
city: Vilnius
country: Lithuania
facility: Republican Vilnius University Hospital
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Arendal
country: Norway
facility: Sørlandet sykehus HF Arendal
city: Drammen
country: Norway
facility: Drammen sykehus Vestre Viken HF
city: Flekkefjord
country: Norway
facility: Sørlandet Sykehus HF Flekkefjord
city: Førde
country: Norway
facility: Helse Førde HF
city: Gravdal
country: Norway
facility: Nordlandssykehuset Lofoten Gravdal
city: Hammerfest
country: Norway
facility: Helse Finnmark Hammerfest
city: Harstad
country: Norway
facility: University Hospital of North Norway, Harstad
city: Kirkenes
country: Norway
facility: Helse Finnmark HF Kirkenes
city: Kristiansand
country: Norway
facility: Sørlandet sykehus Kristiansand HF
city: Levanger
country: Norway
facility: Sykehuset Levanger
city: Lørenskog
country: Norway
facility: Akershus universitetssykehus (Ahus)
city: Mosjøen
country: Norway
facility: Helgelandssykehuset Mosjøen
city: Narvik
country: Norway
facility: University Hospital of North Norway, Narvik
city: Sandvika
country: Norway
facility: Bærum sykehus Vestre Viken HF
city: Skien
country: Norway
facility: Sykehuset Telemark Skien
city: Stavanger
country: Norway
facility: Stavanger Universitetssjukehus
city: Tromsø
country: Norway
facility: University Hospital of North Norway, Tromsø
city: Trondheim
country: Norway
facility: St Olavs Hospital
city: Ålesund
country: Norway
facility: Ålesund sjukehus Helse Møre og Romsdal
city: Göteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset
city: Hässleholm
country: Sweden
facility: Hässleholm Sjukhus
city: Karlstad
country: Sweden
facility: Central Hospital Karlstad
city: Lund
country: Sweden
facility: Skåne University Hospital Lund
city: Malmö
country: Sweden
facility: Skåne University Hospital Malmö
city: Skövde
country: Sweden
facility: Skaraborg Hospital Skövde
city: Solna
country: Sweden
facility: Karolinska sjukhuset
city: Stockholm
country: Sweden
facility: Saint Göran Hospital
city: Stockholm
country: Sweden
facility: Danderyd Hospital
city: Uppsala
country: Sweden
facility: Akademiska Sjukhuset
city: Ängelholm
country: Sweden
facility: Ängelholm Hospital
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Nyon
country: Switzerland
facility: Groupement Hospitalier Ouest Lémanique
city: Wakefield
country: United Kingdom
facility: Pinderfields Hospital
state: Mid Yorkshire
city: Cramlington
country: United Kingdom
facility: Northumbria Specialist Emergency Care Hospital
state: Northumberland
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Birkenhead
country: United Kingdom
facility: Arrowe Park
city: Birmingham
country: United Kingdom
facility: University Hospital Birmingham
city: Bournemouth
country: United Kingdom
facility: Royal Bournemoth and Christchurch Hospital
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital
city: Chester
country: United Kingdom
facility: Countess of Chester Hospital NHS Foundation Trust
city: Coventry
country: United Kingdom
facility: University Hospitals Coventry & Warwickshire
city: Derby
country: United Kingdom
facility: Royal Derby Hospital
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary of Edinburgh Hospital
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
city: Gloucester
country: United Kingdom
facility: Gloucestershire Royal Hospital
city: Halifax
country: United Kingdom
facility: Calderdale Royal Infirmary
city: Kingston upon Hull
country: United Kingdom
facility: Hull University Teaching Hospital
city: Leeds
country: United Kingdom
facility: Leeds General Infirmary
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
city: London
country: United Kingdom
facility: University College London
city: London
country: United Kingdom
facility: King´s College Hospital
city: London
country: United Kingdom
facility: St Georges Hospital
city: London
country: United Kingdom
facility: Charing Cross Hospital
city: London
country: United Kingdom
facility: Royal London Hospital
city: Luton
country: United Kingdom
facility: Luton and Dunstable University Hospital
city: Morriston
country: United Kingdom
facility: Morriston Hospital
city: Newcastle Upon Tyne
country: United Kingdom
facility: Royal Victoria Infirmary
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Salford
country: United Kingdom
facility: Salford Royal Hospital
city: Southampton
country: United Kingdom
facility: Southhampton General Hospital
city: Stoke-on-Trent
country: United Kingdom
facility: Royal Stoke University Hospital
city: Taunton
country: United Kingdom
facility: Musgrove Park Hospital
city: Yeovil
country: United Kingdom
facility: Yeovil District Hospital
Study officials:
affiliation: University Hospital of North Norway
name: Ellisiv B Mathiesen
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.