Study of Tenecteplase Versus Alteplase for Thrombolysis (Clot Dissolving) in Acute Ischemic Stroke (NOR-TEST)

• ClinicalTrials.gov Identifier: NCT01949948
• Recruitment Status: Completed
• First Posted: September 25, 2013
• Last Update Posted: May 9, 2017
• Sponsor: Lars Thomassen
• Collaborator: The Research Council of Norway
• Information provided by (Responsible Party): Lars Thomassen, Haukeland University Hospital

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Ischemic Stroke	Drug: Tenecteplase; Drug: Alteplase	Phase 3

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1050 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomised Trial of Tenecteplase vs. Alteplase for Recanalisation in Acute Ischemic Stroke
• Actual Study Start Date: September 2012
• Actual Primary Completion Date: December 31, 2016
• Actual Study Completion Date: December 31, 2016

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Tenecteplase; 0.4 mg/kg single bolus intravenously	Drug: Tenecteplase; 0.4 mg/kg single bolus intravenously; Other Name: Metalyse
Active Comparator: Alteplase; 0.9 mg/kg as 10% bolus + 90% infusion/60 minutes intravenously	Drug: Alteplase; 0.9 mg/kg as 10% bolus + 90% infusion/60 minutes intravenously; Other Name: Actilyse

Outcome Measures

Primary Outcome Measures :

1. Clinical: Functional handicap [ Time Frame: 90 days ]
   Excellent outcome defined as mRS 0-1

Secondary Outcome Measures :

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

Eligibility Criteria

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

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

Contacts and Locations

Locations

Norway

Haukeland University Hospital

Bergen, Norway, 5021

Nordland Hospital

Bodø, Norway, 8092

Drammen Hospital

Drammen, Norway, 3004

Førde Central Hospital

Førde, Norway, 6800

Haugesund Hospital

Haugesund, Norway, 5516

Molde Hospital

Molde, Norway, 6400

Akershus University Hospital

Nordbyhagen, Norway, 1474

Ullevål University Hospital

Oslo, Norway, 0424

Baerum Hospital

Rud, Norway, 1309

Telemark Hospital

Skien, Norway, 3710

Stavanger University Hosital

Stavanger, Norway, 4017

St. Olav Hospital NTNU

Trondheim, Norway, 7006

Tønsberg Hospital

Tønsberg, Norway, 3100

Sponsors and Collaborators

Lars Thomassen

The Research Council of Norway

Investigators

• Study Chair: Lars Thomassen, MD PhD Prof.; Dept. Neurology, Haukeland University HospitalBergen, Norway
• Study Director: Ulrike Waje-Andreassen, MD PhD Prof.; Dept. Neurology, Haukeland University Hospital, Bergen
• Principal Investigator: Nicola Logallo, MD PhD; Dept. Neurology, Haukeland University Hospital, Bergen, Norway

More Information

Publications:

Logallo N, Kvistad CE, Nacu A, Naess H, Waje-Andreassen U, Asmuss J, Aamodt AH, Lund C, Kurz MW, Rønning OM, Salvesen R, Idicula TT, Thomassen L. The Norwegian tenecteplase stroke trial (NOR-TEST): randomised controlled trial of tenecteplase vs. alteplase in acute ischaemic stroke. BMC Neurol. 2014 May 15;14:106. doi: 10.1186/1471-2377-14-106.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Thommessen B, Næss H, Logallo N, Kvistad CE, Waje-Andreassen U, Ihle-Hansen H, Ihle-Hansen H, Thomassen L, Rønning OM. Tenecteplase versus alteplase after acute ischemic stroke at high age. Int J Stroke. 2020 Jul 6:1747493020938306. doi: 10.1177/1747493020938306. [Epub ahead of print]

Ahmed HK, Logallo N, Thomassen L, Novotny V, Mathisen SM, Kurz MW. Clinical outcomes and safety profile of Tenecteplase in wake-up stroke. Acta Neurol Scand. 2020 Nov;142(5):475-479. doi: 10.1111/ane.13296. Epub 2020 Jun 23.

Kvistad CE, Novotny V, Kurz MW, Rønning OM, Thommessen B, Carlsson M, Waje-Andreassen U, Næss H, Thomassen L, Logallo N. Safety and Outcomes of Tenecteplase in Moderate and Severe Ischemic Stroke. Stroke. 2019 May;50(5):1279-1281. doi: 10.1161/STROKEAHA.119.025041.

Rønning OM, Logallo N, Thommessen B, Tobro H, Novotny V, Kvistad CE, Aamodt AH, Næss H, Waje-Andreassen U, Thomassen L. Tenecteplase Versus Alteplase Between 3 and 4.5 Hours in Low National Institutes of Health Stroke Scale. Stroke. 2019 Feb;50(2):498-500. doi: 10.1161/STROKEAHA.118.024223.

Logallo N, Novotny V, Assmus J, Kvistad CE, Alteheld L, Rønning OM, Thommessen B, Amthor KF, Ihle-Hansen H, Kurz M, Tobro H, Kaur K, Stankiewicz M, Carlsson M, Morsund Å, Idicula T, Aamodt AH, Lund C, Næss H, Waje-Andreassen U, Thomassen L. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol. 2017 Oct;16(10):781-788. doi: 10.1016/S1474-4422(17)30253-3. Epub 2017 Aug 2.

Logallo N, Kvistad CE, Thomassen L. Therapeutic Potential of Tenecteplase in the Management of Acute Ischemic Stroke. CNS Drugs. 2015;29(10):811-8. doi: 10.1007/s40263-015-0280-9. Review.

• Responsible Party: Lars Thomassen, Senior Consultant neurologist; Professor, Haukeland University Hospital
• ClinicalTrials.gov Identifier: NCT01949948
• Other Study ID Numbers: REK 2011/2435
• First Posted: September 25, 2013
• Last Update Posted: May 9, 2017
• Last Verified: May 2017

Keywords provided by Lars Thomassen, Haukeland University Hospital:

treatment, intervention, thrombolysis

Additional relevant MeSH terms:

Stroke; Cerebral Infarction; Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Brain Infarction; Brain Ischemia; Tissue Plasminogen Activator; Tenecteplase; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action