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Thrombolysis plus neuroprotection in acute ischemic stroke: a four-arm safety and efficacy European trial


- To design, organize and perform a therapeutic trial combining t-PA with a neuroprotector (NP) in the treatment of acute ischemic stroke patients - To evaluate whether the combination of the two drugs can make pharmacological reperfusion effective and safe for a larger population that at present is treatable with thrombolysis alone, by:
- prolonging the interval time available between stroke onset and thrombolysis (so called "therapeutic window")
- protecting brain tissue from eventual reperfusional damage.

Approximately one million Europeans suffer from stroke each year. About 1/3 die within the first 6-month, and more than one third of them never regain functional independence, a tragedy for patients and their families and a huge economic burden for public health services. Stroke prevention is useful but insufficient. Acute ischemic stroke treatment can influence both mortality and disability. A significant reduction in disability in patients given rt-PA has recently been demonstrated by the European Cooperative Acute Stroke Study(ECASS) and by the National Institute for Neurological Disorders and Stroke(NINDS) study. However, the high incidence of life threatening hemorrhagic transformation in the ECASS led the European Ad Hoc Consensus Group to recommend limitation of rt-PA to the very selected subgroup of patients with limited ischemic damage at the baseline CT scan. The Food and Drug Administration suggests further limitation only to patients' treatable within3 hours as in the NINDS study. Both limitations reduce the cost effectiveness of rt-PA, making it a cure for at most 5% of stroke patients.

In order to makert-PA available for a larger stroke population therapeutic strategies in the acute phase of stroke could resort to neuroprotectors aimed at:
1) antagonizing the events induced by ischemia as to widen the therapeutic window;
2) protecting tissue from possible reper fusional injury.

Our hypothesis is that more patients might benefit by rt-PA if they are treated in advance with a neuroprotector.

Proposal content: a Reinforced Concerted Action aimed at organizing and performing a Four-arm Safety and Efficacy Multicenter Clinical Trial in acuteischemic stroke.

Objective of the Trial: To evaluate whether thrombolysis and a neuroprotector(NP) in combination, administered within 6 hours of stroke, improve the clinical outcome of acute ischemic stroke patients, as compared with thosereceiving each of the single drugs or placebo.

Drugs to be tested: rt-PA and a NP shown to be safe by the ongoing clinical trials.L
%End/points: a. quality of life (by using the Modified Rankin Scale- RS); b. fatality; c. residual neurological deficit (by using the Scandinavian Stroke Scale- SSS) and; d. disability (by using the Barthel Index-BI score).

Primary Efficacy hypothesis: rt-PA plus a NP significantly improve the RSafter 3 months of stroke as compared to each of the single drugs and to placebo. Deceased patients are included and scored 6.Secondary Efficacy hypotheses: rt-PA plus a NP are able to significantly reduce mortality at 1 week and at 1 and 3 months as compared to each of the single drugs and to placebo. The hospitalisation length, the residual SSS deficit at 1 week, the BI score at 1 month, the RS at 3 months of survivors, the infarct volume at repeat CT, will also be evaluated.

Safety Hypothesis: the combination of rt-PA and a NP results in an incidenceof petechial hemorragic infarction (HI), parenchymal hemorrhage (PH) withclinical deterioration or CT evidence of mass effect lower than that reportedwith rt-PA alone.

Patients' characteristics and Randomization: Each patient affected by a presumptive ischemic hemispheric stroke, observed and treatable within 6 hours of stroke onset, will be randomised for either NP or placebo. After a cerebral CT scan, all patients with a negative CT or with early signs of the infarctin less than 1/3 of the MCA territory who can undergo thrombolysis within 3 hours will ralsoeceive rt-PA, whereas those treatable between 3 and 6 hours will be randomised for either rt-PA or placebo. This scheme will result in four groups of treatment: placebo, rt-PA, NP, rt-PA+NP. All randomised patients will be followed and treated with the assigned treatment, including patients not receiving rt-PA. On the basis of previous experience, we estimate that it will be possible to recruit a total of 42 patients/month throughout Europe. The collaboration of 75 experienced European centers will thus guarantee the inclusion in the Trial of 1000 patients over a 24-monthperiod.

Keywords: Acute Ischemic Stroke / Clinical Trials / rt-PA / Neuro protection. 04


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