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. 2018 Aug 21;2018(8):CD010995. doi: 10.1002/14651858.CD010995.pub2

NCT01525290.

Trial name or title Efficacy and safety of magnetic resonance imaging‐based thrombolysis in wake‐up stroke (WAKE‐UP)
Methods Randomised, double‐blinded, placebo‐controlled trial
Participants 800 participants
Clinical inclusion criteria
  • Clinical diagnosis of acute ischaemic stroke with unknown symptom onset (e.g. stroke symptoms recognised on awakening)

  • Last known well (without neurological symptoms) > 4.5 hours of treatment initiation

  • Measurable disabling neurological deficit (defined as an impairment of 1 or more of the following: language, motor function, cognition, gaze, vision, neglect)

  • Age 18 to 80 years

  • Treatment can be started within 4.5 hours of symptom recognition (e.g. awakening)

  • Written informed consent by patient or proxy


Imaging inclusion criteria
  • Acute stroke MRI including DWI and FLAIR completed

  • MRI showing a pattern of "diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) ‐mismatch," i.e. acute ischaemic lesion visibly on DWI ("positive DWI") but no marked parenchymal hyperintensity visible on FLAIR ("negative FLAIR") indicative of an acute ischaemic lesion ≤ 4.5 hours of age


Clinical exclusion criteria
  • Planned or anticipated treatment with endovascular reperfusion strategies (e.g. intra‐arterial thrombolysis, mechanical recanalisation techniques)

  • Pre‐stroke disability (inability to carry out all daily activities, requiring some help or supervision, i.e. slight disability corresponding to an mRS score > 1)

  • Participation in any investigational study in the previous 30 days

  • Severe stroke by clinical assessment (e.g. NIHSS > 25)

  • Hypersensitivity to alteplase or any of the excipients

  • Pregnancy or lactating (formal testing needed in woman of childbearing potential; childbearing potential is assumed in women up to 55 years of age)

  • Significant bleeding disorder at present or within past 6 months

  • Known haemorrhagic diathesis

  • Manifest or recent severe or dangerous bleeding

  • Known history of or suspected intracranial haemorrhage

  • Suspected subarachnoid haemorrhage (even if CT is negative) or condition after subarachnoid haemorrhage from aneurysm

  • History of central nervous system damage (e.g. neoplasm, aneurysm, intracranial or spinal surgery)

  • Recent (within 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a non‐compressible blood vessel

  • Current use of anticoagulants (e.g. phenprocoumon, warfarin, new anticoagulants such as dabigatran) or current use of heparin and elevated thromboplastin time (low‐dose subcutaneous heparin is allowed)

  • Platelet count < 100,000/mm3

  • Blood glucose < 50 or > 400 mg/dL (< 2.8 or 22.2 mmol/L)

  • Severe uncontrolled hypertension, i.e. systolic blood pressure > 185 mmHg or diastolic blood pressure > 110 mmHg or requiring aggressive medication to maintain blood pressure within these limits (routine medical treatment is allowed to lower the blood pressure below these limits)

  • Manifest or recent bacterial endocarditis, pericarditis

  • Manifest or recent acute pancreatitis

  • Documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial aneurysm, arterial/venous malformations

  • Neoplasm with increased bleeding risk

  • Manifest severe liver disease including hepatic failure, cirrhosis, portal hypertension, and active hepatitis

  • Major surgery or significant trauma in past 3 months

  • Stroke within 30 days

  • Life expectancy 6 months or less by judgement of the investigator

  • Any condition associated with a significantly increased risk of severe bleeding not mentioned above

  • Any contraindication to MRI (e.g. cardiac pacemaker)


Imaging exclusion criteria
  • Poor MRI quality precluding interpretation according to the study protocol

  • Any sign of intracranial haemorrhage on baseline MRI

  • FLAIR showing a marked parenchymal hyperintensity in a region corresponding to the acute DWI lesion indicative of an acute ischaemic lesion with a high likelihood of being > 4.5 hours old

  • Large DWI lesion volume > 1/3 of the middle cerebral artery or > 50% of the anterior cerebral artery or posterior cerebral artery territory (visual inspection) or > 100 mL

  • Any MRI findings indicative of a high risk of symptomatic intracranial haemorrhage related to potential IV alteplase treatment in the judgement of the investigator

Interventions
  • IV tissue plasminogen activator (alteplase) 0.9 mg/kg body weight up to a maximum of 90 mg, 10% as bolus, 90% over 1 hour as infusion

  • Matching placebo

Outcomes
  • Favourable outcome (mRS 0 to 1) at 90 days' follow‐up

  • Mortality at 90 days' follow‐up

  • Death or dependency (mRS 4 to 6) at 90 days' follow‐up

Starting date September 2012
Contact information Principal Investigator: Goetz Thomalla, Universitätsklinikum Hamburg‐Eppendorf, Germany
E‐mail: thomalla@uke.uni‐hamburg.de
Notes ClinicalTrials.gov identifier: NCT01525290