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

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).

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.

Eligibility Criteria:
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