Clinical trial NCT01949948: Study of Tenecteplase Versus Alteplase for Thrombolysis (Clot Dissolving) in Acute Ischemic Stroke
Official title: Randomised Trial of Tenecteplase vs. Alteplase for Recanalisation in Acute Ischemic Stroke
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Ischemic Stroke
Keywords: treatment, intervention, thrombolysis
Lead sponsor: Haukeland University Hospital
Sponsor class: OTHER
Collaborators: name: The Research Council of Norway
First posted: 2013-09-25
Enrollment: 1050
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

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

Primary outcomes:
measure: Clinical: Functional handicap
timeFrame: 90 days
Secondary outcomes:
measure: Symptomatic cerebral hemorrhage
timeFrame: 24-36 hours
measure: Hemorrhagic transformation
timeFrame: 24-36 hours
measure: Neurological improvement
timeFrame: 24 hours
measure: Clinical: Functional handicap
timeFrame: 90 days
measure: Safety
timeFrame: 90 days
Other outcomes:
Locations:
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Bodø
country: Norway
facility: Nordland Hospital
city: Drammen
country: Norway
facility: Drammen Hospital
city: Førde
country: Norway
facility: Førde Central Hospital
city: Haugesund
country: Norway
facility: Haugesund Hospital
city: Molde
country: Norway
facility: Molde Hospital
city: Nordbyhagen
country: Norway
facility: Akershus University Hospital
city: Oslo
country: Norway
facility: Ullevål University Hospital
city: Rud
country: Norway
facility: Baerum Hospital
city: Skien
country: Norway
facility: Telemark Hospital
city: Stavanger
country: Norway
facility: Stavanger University Hosital
city: Trondheim
country: Norway
facility: St. Olav Hospital NTNU
city: Tønsberg
country: Norway
facility: Tønsberg Hospital
Study officials:
affiliation: Dept. Neurology, Haukeland University HospitalBergen, Norway
name: Lars Thomassen, MD PhD Prof.
role: STUDY_CHAIR
affiliation: Dept. Neurology, Haukeland University Hospital, Bergen
name: Ulrike Waje-Andreassen, MD PhD Prof.
role: STUDY_DIRECTOR
affiliation: Dept. Neurology, Haukeland University Hospital, Bergen, Norway
name: Nicola Logallo, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Logallo N, Kvistad CE, Nacu A, Naess H, Waje-Andreassen U, Asmuss J, Aamodt AH, Lund C, Kurz MW, Ronning 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.
citation: Ihle-Hansen H, Sandset EC, Ihle-Hansen H, Hagberg G, Thommessen B, Ronning OM, Kvistad CE, Novotny V, Naess H, Waje-Andreassen U, Thomassen L, Logallo N. Sex differences in the Norwegian Tenecteplase Trial (NOR-TEST). Eur J Neurol. 2022 Feb;29(2):609-614. doi: 10.1111/ene.15126. Epub 2021 Oct 4.
citation: Thommessen B, Naess H, Logallo N, Kvistad CE, Waje-Andreassen U, Ihle-Hansen H, Ihle-Hansen H, Thomassen L, Morten Ronning O. Tenecteplase versus alteplase after acute ischemic stroke at high age. Int J Stroke. 2021 Apr;16(3):295-299. doi: 10.1177/1747493020938306. Epub 2020 Jul 6.
citation: 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.
citation: Kvistad CE, Novotny V, Kurz MW, Ronning OM, Thommessen B, Carlsson M, Waje-Andreassen U, Naess 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.
citation: Ronning OM, Logallo N, Thommessen B, Tobro H, Novotny V, Kvistad CE, Aamodt AH, Naess 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.
citation: Logallo N, Novotny V, Assmus J, Kvistad CE, Alteheld L, Ronning OM, Thommessen B, Amthor KF, Ihle-Hansen H, Kurz M, Tobro H, Kaur K, Stankiewicz M, Carlsson M, Morsund A, Idicula T, Aamodt AH, Lund C, Naess 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.
citation: 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.