Tenecteplase in Wake-up Ischaemic Stroke Trial

Ischemic Stroke Clinical Trial

— TWIST  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03181360
• Other study ID #: 2015/1070/REC North
• Secondary ID: 2014-000096-80
• Status: Recruiting
• Phase: Phase 3
• Start date: June 12, 2017
• Est. completion date: December 31, 2022

Study information

• Verified date: May 2021
• Source: University Hospital of North Norway
• Contact: Melinda B Roaldsen, MD
• Phone: +47 77627120
• Email: melinda.b.roaldsen[@]uit.no
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 600
• Est. completion date: December 31, 2022
• Est. primary completion date: December 31, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Cerebral Infarction
• Ischemia
• Ischemic Stroke
• Stroke
• Stroke, Acute

Intervention

Drug:
• 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.

Other:
• Control
Best standard treatment

Locations

Country	Name	City	State
Denmark	Bispebjerg hospital	København
Denmark	Odense University Hospital	Odense
Estonia	Pärnu Hospital	Pärnu
Estonia	West Tallin Central Hospital	Tallin
Estonia	East Tallin Central Hospital	Tallinn
Estonia	Tartu University Clinic	Tartu
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	Satakunta Central Hospital	Pori	Satakunta
Finland	Central Hospital in Vaasa	Vaasa
Latvia	Riga East University Hospital	Riga
Lithuania	Alytus S. Kudirkos Hospital	Alytus
Lithuania	Lithuanian University of Health Sciences Kauno Klinikos	Kaunas
Lithuania	Klaipeda Seamen's Hospital	Klaipeda
Lithuania	Republican Vilnius University Hospital	Vilnius
Lithuania	Vilnius University Hospital	Vilnius
New Zealand	Christchurch Hospital	Christchurch
Norway	Ålesund sjukehus Helse Møre og Romsdal	Ålesund
Norway	Sørlandet sykehus HF Arendal	Arendal
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
Sweden	Ängelholm Hospital	Ängelholm
Sweden	Sahlgrenska Universitetssjukhuset	Göteborg
Sweden	Hässleholm Sjukhus	Hässleholm
Sweden	Central Hospital Karlstad	Karlstad
Sweden	Skåne University Hospital Lund	Lund
Sweden	Skåne University Hospital Malmö	Malmö
Sweden	Skaraborg Hospital Skövde	Skövde
Sweden	Karolinska sjukhuset	Solna
Sweden	Danderyd Hospital	Stockholm
Sweden	Saint Göran Hospital	Stockholm
Sweden	Akademiska Sjukhuset	Uppsala
Switzerland	University Hospital Basel	Basel
Switzerland	Groupement Hospitalier Ouest Lémanique	Nyon
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	Northumbria Specialist Emergency Care Hospital	Cramlington	Northumberland
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	Kingston upon Hull
United Kingdom	Leeds General Infirmary	Leeds
United Kingdom	Leicester Royal Infirmary	Leicester
United Kingdom	Royal Liverpool University Hospital	Liverpool
United Kingdom	Charing Cross Hospital	London
United Kingdom	King´s College Hospital	London
United Kingdom	Royal London Hospital	London
United Kingdom	St Georges Hospital	London
United Kingdom	University College London	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	Pinderfields Hospital	Wakefield	Mid Yorkshire
United Kingdom	Yeovil District Hospital	Yeovil
United States	University of Massachusetts Medical School	Worcester	Massachusetts

Sponsors (4)

Lead Sponsor	Collaborator
University Hospital of North Norway	Norwegian Health Association, The Royal Norwegian Ministry of Health, UiT The Arctic University of Norway

Countries where clinical trial is conducted

United States,  Denmark,  Estonia,  Finland,  Latvia,  Lithuania,  New Zealand,  Norway,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Functional outcome at 3 months.	Functional outcome will be assessed by the modified Rankin Scale (mRS), values 0-6	3 months
Secondary	Symptomatic intracranial haemorrhage during the first 7 days.	Symptoms (neurological deterioration, new headache, new acute hypertension, new nausea or vomiting, or sudden decrease in conscious level).; Intracranial haemorrhage on brain MRI or CT.	First 7 days
Secondary	Asymptomatic intracranial haemorrhage during the first 7 days.	Intracranial haemorrhage on brain MRI or CT without: neurological deterioration, new headache, new acute hypertension, new nausea or vomiting or sudden decrease in consciousness level.	First 7 days
Secondary	Recurrent ischaemic stroke during the first 7 days	Neurological deterioration (increase of =2 on NIHSS, after exclusion of other causes for neurological deterioration) occurring after 72 hours will be considered as a recurrent stroke. A recurrent stroke will be classified as ischaemic if imaging has excluded haemorrhage.	First 7 days
Secondary	Death from all cause	Death will be classified according to cause: Initial stroke; Recurrent stroke; Myocardial infarction; Pneumonia; Other	First 7 days
Secondary	Death from all cause	Death will be classified according to cause: Initial stroke; Recurrent stroke; Myocardial infarction; Pneumonia; Other	3 months
Secondary	Barthel Index score	Ordinal scale for measuring performance in activities of daily living	3 months
Secondary	EuroQol Score (EQ-5D)	Measure of health-related quality of life	3 months
Secondary	Mini Mental State Examination	30-point questionnaire for measurement of cognitive impairment	3 months
Secondary	Health-economic variables	Costs related to length of hospital stay, nursing home care after discharge, re-hospitalisations during first 3 months	3 months
Secondary	Functional outcome at 3 months	Functional outcome assessed by dichotomized mRS; values 0-1 vs 2-6.	3 months