Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET)

Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) in Acute Stroke

To determine whether the extent of the ischemic penumbra apparent on perfusion-diffusion MRI can be used to identify patients who would respond positively and safely to tissue plasminogen activator (tPA) beyond 3 hours post-stroke.

Study Overview

• Status: Completed
• Conditions: Stroke
• Intervention / Treatment: Drug: Alteplase t-PA

• Study Type: Interventional
• Enrollment: 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Newcastle, New South Wales, Australia, 2310
      • Hunter New England Area Health Service
  • Queensland
    • Brisbane, Queensland, Australia, 4072
      • Royal Brisbane Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
    • Adelaide, South Australia, Australia, 5042
      • Flinders Medical Center
  • Victoria
    • Melbourne, Victoria, Australia, 3050
      • Royal Melbourne Hospital
    • Melbourne, Victoria, Australia, 3128
      • Box Hill Hospital
    • Melbourne, Victoria, Australia, 3065
      • St Vincents Hospital
    • Melbourne, Victoria, Australia, 3081
      • Austin Hospital
    • Melbourne, Victoria, Australia, 3144
      • Alfred Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6001
      • Royal Perth Hospital
• Belgium
  • Brussels, Belgium, B-1200
    • Cliniques Universitaires St Luc
• New Zealand
  • Auckland, New Zealand, 92024
    • Auckland City Hospital
  • Christchurch, New Zealand, 4710
    • Christchurch Hospital
• United Kingdom
  • Scotland
    • Glasgow, Scotland, United Kingdom
      • Southern General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients who present:
• with acute hemispheric stroke within 3-6 hours of onset,
• have at least moderate limb weakness,
• a National Institute of Health Stroke Scale (NIHSS) score > 4,
• had a pre-stroke modified Rankin Scale (MRS) score of 0 - 2
• and who are able to undergo CT and MRI, are eligible for this study.

Exclusion Criteria:

• Females who are pregnant or breast-feeding,
• persons who have CT-verified hemorrhagic stroke, major ischemia ( > 33% of the middle cerebral artery (MCA) territory infarcted), subarachnoid hemorrhage, arteriovenous malformation, aneurysm, intracranial neoplasm that is terminal or poses a risk of hemorrhage ,
• are comatose or severely obtunded with fixed eye deviation and complete hemiplegia,
• have had another stroke within the past 6 weeks,
• have had a seizure prior to the administration of the study drug,
• have active peptic ulceration, bleeding diatheses, previous intracerebral hemorrhage,
• blood pressure > 185/110,
• major surgery or trauma within the past 30 days, or any other contraindications to tPA
• have a presumed septic embolus or a myocardial infarction within the past 30 days
• blood glucose values are < 2.8 or > 22.0 mmol/L,
• pacemakers, aneurysm clips, implanted devices, claustrophobia, or any other contraindications to MRI,
• decreased consciousness,
• rapid clinical improvement,
• confounding neurological condition (e.g. dementia),
• any other life-threatening illness, or who are participating in another clinical trial, will be excluded from this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Primary Hypothesis - lesion growth
In patients with penumbra, there will be attenuation of lesion growth (outcome T2 lesion volume - acute DWI volume ) with tPA.

Secondary Outcome Measures

Outcome Measure
Secondary Hypotheses
In the non-penumbral group, lesion growth will be lower and will not be attenuated by tPA.
Favourable functional outcome (mRS 0-2) will be more likely in patients with penumbra receiving tPA.
That the proportion of patients achieving good neurological outcome (an 8 point improvement in NIH-SS or outcome NIH-SS of 0, 1) will be greater in those patients with a penumbra receiving tPA.
Symptomatic hemorrhagic transformation (sICH) will be predicted by the size of the baseline DWI volume in those patients receiving tPA.
Reperfusion (greater than 90% PWI lesion reduction, or recanalisation on MRA, between the acute and sub-acute interval), will be increased (in patients with penumbra) receiving tPA.
In patients with malignant mismatch (Definition DWI 100ml or more and / or PWI 100ml or more) there will be unfavourable clinical outcome (even if there is attenuation of growth).

Collaborators and Investigators

• Sponsor: Melbourne Health
• Collaborators: Boehringer Ingelheim
• Investigators: Study Chair: Stephen M Davis, MD FRCP FRACP, Melbourne Health; Study Chair: Geoffrey Donnan, MD FRACP, National Stroke Research Institute, Australia

Publications and helpful links

General Publications

• Ogata T, Christensen S, Nagakane Y, Ma H, Campbell BC, Churilov L, Lansberg MG, Straka M, De Silva DA, Mlynash M, Bammer R, Olivot JM, Desmond PM, Albers GW, Davis SM, Donnan GA; EPITHET and DEFUSE Investigators. The effects of alteplase 3 to 6 hours after stroke in the EPITHET-DEFUSE combined dataset: post hoc case-control study. Stroke. 2013 Jan;44(1):87-93. doi: 10.1161/STROKEAHA.112.668301. Epub 2012 Dec 18.
• Mlynash M, Lansberg MG, De Silva DA, Lee J, Christensen S, Straka M, Campbell BC, Bammer R, Olivot JM, Desmond P, Donnan GA, Davis SM, Albers GW; DEFUSE-EPITHET Investigators. Refining the definition of the malignant profile: insights from the DEFUSE-EPITHET pooled data set. Stroke. 2011 May;42(5):1270-5. doi: 10.1161/STROKEAHA.110.601609. Epub 2011 Apr 7.
• Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A, Barber PA, Bladin C, De Silva DA, Byrnes G, Chalk JB, Fink JN, Kimber TE, Schultz D, Hand PJ, Frayne J, Hankey G, Muir K, Gerraty R, Tress BM, Desmond PM; EPITHET investigators. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol. 2008 Apr;7(4):299-309. doi: 10.1016/S1474-4422(08)70044-9. Epub 2008 Feb 28.

Helpful Links

• Click here for more information about this study. Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET)

Study record dates

Study Major Dates

• Study Start: August 1, 2001
• Study Completion: April 1, 2007

Study Registration Dates

• First Submitted: October 11, 2005
• First Submitted That Met QC Criteria: October 11, 2005
• First Posted (Estimate): October 13, 2005

Study Record Updates

• Last Update Posted (Estimate): May 30, 2013
• Last Update Submitted That Met QC Criteria: May 28, 2013
• Last Verified: May 1, 2009

More Information

Terms related to this study

• Keywords: MRI; Stroke; Thrombolysis; Penumbra; Echoplanar
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tissue Plasminogen Activator
• Other Study ID Numbers: 145671; TGA Trial Number: 1999/271; Enterprise ID: 15314