Study of Tenecteplase Versus Alteplase for Thrombolysis (Clot Dissolving) in Acute Ischemic Stroke

Study Overview
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Brief Summary
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BACKGROUND: Alteplase dissolves blood vessel clots in acute ischemic stroke and is the only approved acute drug treatment <4½ hours of stroke onset. The overall benefit from alteplase is substantial, but up to 2/3 of patients with large artery clots may not achieve reopening of the vessel and up to 40% of the patients may remain severely disabled or die, leaving substantial room for improvement. Tenecteplase, widely used in coronary heart disease, may be more effective and may have less bleeding complications than alteplase, and may be the drug of choice also in stroke. HYPOTHESIS: Tenecteplase may be given safely to patients with acute ischemic stroke at a dose that is associated with improved clinical outcome compared with existing treatment options. AIMS: To compare efficacy and safety of tenecteplase vs. alteplase given <4½ hours after symptom onset. STUDY ENDPOINTS: The primary study endpoint is excellent clinical outcome at 3 months (effect). Secondary study endpoints are major early clinical improvement (effect) and bleeding complications (safety).

Detailed Description
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HYPOTHESIS: 1) Tenecteplase 0.4 mg/kg may be given safely to patients with acute ischaemic stroke <4½ hours after stroke onset. 2) Tenecteplase 0,4 mg/kg (single bolus)has superior efficacy and safety compared with alteplase 0.9 mg/kg (10% bolus + 90% infusion/60 minutes) when given within 4 ½ hours after stroke onset. DESIGN: NOR-TEST is a multi-centre PROBE (prospective randomised, open-label, blinded endpoint) trial with randomisation tenecteplase:alteplase 1:1. POWER CALCULATION: NOR-TEST aims at detecting a 9 % higher percentage excellent outcome with tenecteplase vs. alteplase (r1=0.40; r2=0.49; OR 1.44; power 0.8), and will include 954 patients during 3 years. PATIENT RECRUITMENT: All patients found eligible for thrombolytic therapy are eligible for NOR-TEST, i.e. NOR-TEST changes neither inclusion nor exclusion criteria. The number of patients treated at a participating centre will therefore essentially remain unchanged. Estimated 400 patients are thrombolysed per year in participating centres. Allowing for 20% of patients not being included in NOR-TEST, the total number of patients (n=954) will still be met.

Official Title
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Randomised Trial of Tenecteplase vs. Alteplase for Recanalisation in Acute Ischemic Stroke

Conditions
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Ischemic Stroke

Intervention / Treatment
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* Drug: Tenecteplase
* Drug: Alteplase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older Ischaemic stroke with measurable deficit on NIH Stroke Scale All stroke sub-types, severities and vascular distributions,a visible arterial occlusion is not required for inclusion Treatment within 4 ½ hours of stroke onset Patients awakening with symptoms are defined by the time last observed normal and awake Informed written consent signed by the patient, verbal consent from the patients as witnessed by a non-participating health care person, or consent by the signature of the patient's family must be provided Exclusion Criteria: Patients with premorbid modified Rankin Scale (mRS) score ≥3 Patients for whom a complete NIH Stroke Score cannot be obtained Hemiplegic migraine with no arterial occlusion on CTA Seizure at stroke onset and no visible occlusion on baseline CTA Intracranial haemorrhage on baseline CT Clinical presentation suggesting subarachnoid haemorrhage even if baseline CT is normal Large areas of hypodense ischaemic changes on baseline CT Patients with systolic blood pressure >185 mm Hg or diastolic blood pressure >110 mm Hg Female, pregnant or breast feeding Known bleeding diathesis Use of oral anticoagulants and International Normalized Ratio (INR) ≥1,4 Use of new oral anticoagulants (NOAC) within the last 12 hours Heparin <48 hours and increased Activated partial thromboplastin tike (APTT) Low molecular weight heparin(oid) <24 hours Any other investigational drug <14 days Sepsis Patients with arterial puncture at a noncompressible site or lumbar puncture <7 days Major surgery or serious trauma <14 days Gastrointestinal or urinary tract hemorrhage <14 days Clinical stroke <2 months History of intracranial haemorrhage Brain neurosurgery <2 months Serious head trauma <2 months Pericarditis Any serious medical illness likely to interact with treatment Confounding pre-existent neurological or psychiatric disease Unlikely to complete follow-up Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tenecteplase<br>0.4 mg/kg single bolus intravenously | Drug: Tenecteplase<br>* 0.4 mg/kg single bolus intravenously<br>* Other names: Metalyse;|
| Active Comparator: Alteplase<br>0.9 mg/kg as 10% bolus + 90% infusion/60 minutes intravenously | Drug: Alteplase<br>* 0.9 mg/kg as 10% bolus + 90% infusion/60 minutes intravenously<br>* Other names: Actilyse;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical: Functional handicap | Excellent outcome defined as mRS 0-1 | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptomatic cerebral hemorrhage | Haemorrhagic transformation (haemorrhagic infarct / haematoma) as defined by CT (or MRI) | 24-36 hours | 
| Hemorrhagic transformation | Any hemorrhagic infarct or parenchymal hematoma | 24-36 hours | 
| Neurological improvement | NIHSS changes from baseline: NIHSS=0 or reduction of ≥4 NIHSS points | 24 hours | 
| Clinical: Functional handicap | Ordinal shift analysis of mRS | 90 days | 
| Safety | Death | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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treatment, intervention, thrombolysis