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Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST)

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ClinicalTrials.gov Identifier: NCT03181360
Recruitment Status : Recruiting
First Posted : June 8, 2017
Last Update Posted : April 2, 2019
Sponsor:
Collaborators:
UiT The Arctic University of Norway
The Royal Norwegian Ministry of Health
Norwegian Health Association
Information provided by (Responsible Party):
University Hospital of North Norway

Tracking Information
First Submitted Date  ICMJE June 6, 2017
First Posted Date  ICMJE June 8, 2017
Last Update Posted Date April 2, 2019
Actual Study Start Date  ICMJE June 12, 2017
Estimated Primary Completion Date December 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 6, 2017)
Functional outcome at 3 months. [ Time Frame: 3 months ]
Functional outcome will be assessed by the modified Rankin Scale (mRS), values 0-6
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03181360 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 8, 2017)
  • Symptomatic intracranial haemorrhage during the first 7 days. [ Time Frame: First 7 days ]
    1. Symptoms (neurological deterioration, new headache, new acute hypertension, new nausea or vomiting, or sudden decrease in conscious level).
    2. Intracranial haemorrhage on brain MRI or CT.
  • Asymptomatic intracranial haemorrhage during the first 7 days. [ Time Frame: 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.
  • Recurrent ischaemic stroke during the first 7 days [ Time Frame: 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.
  • Death from all cause [ Time Frame: First 7 days ]
    Death will be classified according to cause:
    1. Initial stroke
    2. Recurrent stroke
    3. Myocardial infarction
    4. Pneumonia
    5. Other
  • Death from all cause [ Time Frame: 3 months ]
    Death will be classified according to cause:
    1. Initial stroke
    2. Recurrent stroke
    3. Myocardial infarction
    4. Pneumonia
    5. Other
  • Barthel Index score [ Time Frame: 3 months ]
    Ordinal scale for measuring performance in activities of daily living
  • EuroQol Score (EQ-5D) [ Time Frame: 3 months ]
    Measure of health-related quality of life
  • Mini Mental State Examination [ Time Frame: 3 months ]
    30-point questionnaire for measurement of cognitive impairment
  • Health-economic variables [ Time Frame: 3 months ]
    Costs related to length of hospital stay, nursing home care after discharge, re-hospitalisations during first 3 months
  • Functional outcome at 3 months [ Time Frame: 3 months ]
    Functional outcome assessed by dichotomized mRS; values 0-1 vs 2-6.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2017)
  • Symptomatic intracranial haemorrhage during the first 7 days. [ Time Frame: First 7 days ]
    1. Symptoms (neurological deterioration, new headache, new acute hypertension, new nausea or vomiting, or sudden decrease in conscious level).
    2. Intracranial haemorrhage on brain MRI or CT.
  • Asymptomatic intracranial haemorrhage during the first 7 days. [ Time Frame: 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.
  • Recurrent ischaemic stroke during the first 7 days [ Time Frame: 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.
  • Death from all cause [ Time Frame: First 7 days ]
    Death will be classified according to cause:
    1. Initial stroke
    2. Recurrent stroke
    3. Myocardial infarction
    4. Pneumonia
    5. Other
  • Death from all cause [ Time Frame: 3 months ]
    Death will be classified according to cause:
    1. Initial stroke
    2. Recurrent stroke
    3. Myocardial infarction
    4. Pneumonia
    5. Other
  • Barthel Index score [ Time Frame: 3 months ]
    Ordinal scale for measuring performance in activities of daily living
  • EuroCol Score [ Time Frame: 3 months ]
    Measure of health-related quality of life
  • Mini Mental State Examination [ Time Frame: 3 months ]
    30-point questionnaire for measurement of cognitive impairment
  • Health-economic variables [ Time Frame: 3 months ]
    Costs related to length of hospital stay, nursing home care after discharge, re-hospitalisations during first 3 months
  • Functional outcome at 3 months [ Time Frame: 3 months ]
    Functional outcome assessed by dichotomized mRS; values 0-1 vs 2-6.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Tenecteplase in Wake-up Ischaemic Stroke Trial
Official Title  ICMJE Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST). A Randomised-controlled Trial of Thrombolytic Treatment With Tenecteplase for Acute Ischaemic Stroke Upon Awakening
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: 500 patients from centers in Norway, Sweden, Denmark, Finland, Estonia, Lithuania, United Kingdom and Switzerland.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Ischemic Stroke
  • Stroke, Acute
Intervention  ICMJE
  • 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 Name: Metalyse
  • Other: Control
    Best standard treatment
Study Arms  ICMJE
  • Active Comparator: Tenecteplase
    Tenecteplase + Best standard treatment
    Intervention: Drug: Tenecteplase
  • Control
    No tenecteplase + Best standard treatment
    Intervention: Other: Control
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 6, 2017)
500
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date December 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 andexanet) 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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Melinda B Roaldsen, MD +47 77627120 melinda.b.roaldsen@uit.no
Contact: Ellisiv B Mathiesen, MD, PhD +47 77646418 ellisiv.mathiesen@uit.no
Listed Location Countries  ICMJE Denmark,   Estonia,   Finland,   Lithuania,   Norway,   Sweden,   Switzerland,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03181360
Other Study ID Numbers  ICMJE 2015/1070/REC North
2014-000096-80 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party University Hospital of North Norway
Study Sponsor  ICMJE University Hospital of North Norway
Collaborators  ICMJE
  • UiT The Arctic University of Norway
  • The Royal Norwegian Ministry of Health
  • Norwegian Health Association
Investigators  ICMJE
Study Chair: Eivind Berge, MD, PhD UiT The Arctic University of Norway
Principal Investigator: Ellisiv B Mathiesen University Hospital of North Norway
PRS Account University Hospital of North Norway
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP