Status:
Completed. Trial completed recruitment in April 2007. Results published in 2008.
Purpose:
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.
Location(s):
Australia, New Zealand, Belgium, Scotland.
Year Started:
2001
Year Finished:
2007
Design:
Double-blind, randomized, multi-center, controlled trial.
Inclusion Criteria
Patients who present with acute hemispheric stroke within 3-6 hours of onset, who have at least moderate limb weakness, a National Institute of Health Stroke Scale (NIHSS) score > 4, who had a pre-stroke modified Rankin Scale (MRS) score of 0 or 1, and who are able to undergo CT and MRI, are eligible for this study.
Exclusion Criteria
Females who are pregnant or breast-feeding, and persons who have CT-verified hemorrhagic stroke, major ischemia ( > 33% of the middle cerebral artery (MCA) territory infarcted), subarachniod hemorrhage, arteriovenous malformation, aneurysm, intracranial neoplasm that is terminal or poses a risk of hemorrhage , who are comatose or severely obtunded with fixed eye deviation and complete hemiplegia, who have had another stroke within the past 6 weeks, who have had a seizure prior to the administration of the study drug, who 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, who have a presumed septic embolus or a myocardial infarction within the past 30 days, whose blood glucose values are < 2.8 or > 22.0 mmol/L, who have pacemakers, aneurysm clips, implanted devices, claustrophobia, or any other contraindications to MRI, who have decreased consciousness, rapid clinical improvement, a confounding neurological condition (e.g. dementia), or any other life-threatening illness, or who are participating in another clinical trial, will be excluded from this study.
Patient Involvement:
All 100 participants will have baseline MRI studies with gadolinium contrast, including DWI, perfusion-weighted imaging (PWI), and magnetic resonance angiography (MRA). All participants will be randomized into tPA or placebo groups within 3-6 hours after stroke onset. tPA for all patients will be dosed at 0.9 mg/kg, with a maximum dose of 90 mg, and will be delivered with 10% injected in a 1-minute bolus, and the remainder infused over 60 minutes. Placebo infusions will be delivered in an identical manner. Patients will be observed every 15 minutes for 2 hours, every hour for 4 hours, every 2 hours for 12 hours, and every 4 hours until reviewed by an investigator. All patients will receive repeat MRI studies (DWI, PWI, MRA) at 3-5 days, and at 90 days post-stroke.
Primary Outcome:
Change in the size of the ischemic lesion between baseline and follow-up studies, as visualized with diffusion-weighted imaging (T2 lesion volume - acute DWI volume).
Secondary Outcome:
Reperfusion defined as change between acute PWI volume(3-6 hours) and subacute PWI volume (3-5 days); symptomatic hemorrhagic transformation at day 3, as assessed by MRI; infarct volume, as measured with T2-weighted MRI; degree of recanalization of the MCA; proportion of patients making an 8-point improvement in their NIHSS score or outcome score of 0,1; percentage of patients reaching an MRS score of 0 - 2.
Results:
We randomly assigned 52 patients to alteplase and 49 patients to placebo. Mean age was 71.6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1.24 with alteplase and 1.78 with placebo (ratio 0.69, 95% CI 0.38-1.28; Student's t test p=0.239); the median relative infarct growth was 1.18 with alteplase and 1.79 with placebo (ratio 0.66, 0.36-0.92; Wilcoxon's test p=0.054). Reperfusion was more common with alteplase than with placebo and was associated with less infarct growth (p=0.001), better neurological outcome (p<0.0001), and better functional outcome (p=0.010) than was no reperfusion. Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted.
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Source of Information:
Presented at multiple international conferences [June 2004, February 2005, May 2005].
Correspondence with trial coordinator.
Presented at the 2006 International Stroke Conference [February 2006].
Correspondence with trial coordinators [June 2007].
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