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

Primary Purpose

Ischemic Stroke

Status
Completed
Phase
Phase 3
Locations
Norway
Study Type
Interventional
Intervention
Tenecteplase
Alteplase
Sponsored by
Lars Thomassen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ischemic Stroke focused on measuring treatment, intervention, thrombolysis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Haukeland University Hospital
  • Nordland Hospital
  • Drammen Hospital
  • Førde Central Hospital
  • Haugesund Hospital
  • Molde Hospital
  • Akershus University Hospital
  • Ullevål University Hospital
  • Baerum Hospital
  • Telemark Hospital
  • Stavanger University Hosital
  • St. Olav Hospital NTNU
  • Tønsberg Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Tenecteplase

Alteplase

Arm Description

0.4 mg/kg single bolus intravenously

0.9 mg/kg as 10% bolus + 90% infusion/60 minutes intravenously

Outcomes

Primary Outcome Measures

Clinical: Functional handicap
Excellent outcome defined as mRS 0-1

Secondary Outcome Measures

Symptomatic cerebral hemorrhage
Haemorrhagic transformation (haemorrhagic infarct / haematoma) as defined by CT (or MRI)
Hemorrhagic transformation
Any hemorrhagic infarct or parenchymal hematoma
Neurological improvement
NIHSS changes from baseline: NIHSS=0 or reduction of ≥4 NIHSS points
Clinical: Functional handicap
Ordinal shift analysis of mRS
Safety
Death

Full Information

First Posted
September 21, 2013
Last Updated
May 5, 2017
Sponsor
Lars Thomassen
Collaborators
The Research Council of Norway
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1. Study Identification

Unique Protocol Identification Number
NCT01949948
Brief Title
Study of Tenecteplase Versus Alteplase for Thrombolysis (Clot Dissolving) in Acute Ischemic Stroke
Acronym
NOR-TEST
Official Title
Randomised Trial of Tenecteplase vs. Alteplase for Recanalisation in Acute Ischemic Stroke
Study Type
Interventional

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Completed
Study Start Date
September 2012 (Actual)
Primary Completion Date
December 31, 2016 (Actual)
Study Completion Date
December 31, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Lars Thomassen
Collaborators
The Research Council of Norway

4. Oversight

Data Monitoring Committee
Yes

5. 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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ischemic Stroke
Keywords
treatment, intervention, thrombolysis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantOutcomes Assessor
Allocation
Randomized
Enrollment
1050 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tenecteplase
Arm Type
Active Comparator
Arm Description
0.4 mg/kg single bolus intravenously
Arm Title
Alteplase
Arm Type
Active Comparator
Arm Description
0.9 mg/kg as 10% bolus + 90% infusion/60 minutes intravenously
Intervention Type
Drug
Intervention Name(s)
Tenecteplase
Other Intervention Name(s)
Metalyse
Intervention Description
0.4 mg/kg single bolus intravenously
Intervention Type
Drug
Intervention Name(s)
Alteplase
Other Intervention Name(s)
Actilyse
Intervention Description
0.9 mg/kg as 10% bolus + 90% infusion/60 minutes intravenously
Primary Outcome Measure Information:
Title
Clinical: Functional handicap
Description
Excellent outcome defined as mRS 0-1
Time Frame
90 days
Secondary Outcome Measure Information:
Title
Symptomatic cerebral hemorrhage
Description
Haemorrhagic transformation (haemorrhagic infarct / haematoma) as defined by CT (or MRI)
Time Frame
24-36 hours
Title
Hemorrhagic transformation
Description
Any hemorrhagic infarct or parenchymal hematoma
Time Frame
24-36 hours
Title
Neurological improvement
Description
NIHSS changes from baseline: NIHSS=0 or reduction of ≥4 NIHSS points
Time Frame
24 hours
Title
Clinical: Functional handicap
Description
Ordinal shift analysis of mRS
Time Frame
90 days
Title
Safety
Description
Death
Time Frame
90 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Lars Thomassen, MD PhD Prof.
Organizational Affiliation
Dept. Neurology, Haukeland University HospitalBergen, Norway
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Ulrike Waje-Andreassen, MD PhD Prof.
Organizational Affiliation
Dept. Neurology, Haukeland University Hospital, Bergen
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Nicola Logallo, MD PhD
Organizational Affiliation
Dept. Neurology, Haukeland University Hospital, Bergen, Norway
Official's Role
Principal Investigator
Facility Information:
Facility Name
Haukeland University Hospital
City
Bergen
ZIP/Postal Code
5021
Country
Norway
Facility Name
Nordland Hospital
City
Bodø
ZIP/Postal Code
8092
Country
Norway
Facility Name
Drammen Hospital
City
Drammen
ZIP/Postal Code
3004
Country
Norway
Facility Name
Førde Central Hospital
City
Førde
ZIP/Postal Code
6800
Country
Norway
Facility Name
Haugesund Hospital
City
Haugesund
ZIP/Postal Code
5516
Country
Norway
Facility Name
Molde Hospital
City
Molde
ZIP/Postal Code
6400
Country
Norway
Facility Name
Akershus University Hospital
City
Nordbyhagen
ZIP/Postal Code
1474
Country
Norway
Facility Name
Ullevål University Hospital
City
Oslo
ZIP/Postal Code
0424
Country
Norway
Facility Name
Baerum Hospital
City
Rud
ZIP/Postal Code
1309
Country
Norway
Facility Name
Telemark Hospital
City
Skien
ZIP/Postal Code
3710
Country
Norway
Facility Name
Stavanger University Hosital
City
Stavanger
ZIP/Postal Code
4017
Country
Norway
Facility Name
St. Olav Hospital NTNU
City
Trondheim
ZIP/Postal Code
7006
Country
Norway
Facility Name
Tønsberg Hospital
City
Tønsberg
ZIP/Postal Code
3100
Country
Norway

12. IPD Sharing Statement

Citations:
PubMed Identifier
24886064
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.
Results Reference
background
PubMed Identifier
34564893
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.
Results Reference
derived
PubMed Identifier
32631157
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.
Results Reference
derived
PubMed Identifier
32511749
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.
Results Reference
derived
PubMed Identifier
31009339
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.
Results Reference
derived
PubMed Identifier
30602354
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.
Results Reference
derived
PubMed Identifier
28780236
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.
Results Reference
derived
PubMed Identifier
26387127
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.
Results Reference
derived

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

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