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The Norwegian Tenecteplase Stroke Trial 2 (NOR-TEST 2)

Primary Purpose

Stroke, Acute, Cerebrovascular Disorders, Ischemic Stroke

Status
Terminated
Phase
Phase 3
Locations
Norway
Study Type
Interventional
Intervention
Tenecteplase
Alteplase
Sponsored by
Haukeland University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Stroke, Acute focused on measuring Tenecteplase, Thrombolysis, Alteplase

Eligibility Criteria

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

General inclusion criteria

  • 18 years or older
  • Ischaemic stroke with clinical symptoms corresponding to National Institutes of Health Stroke Scale Score (NIHSS) of >5. All stroke sub-types and vascular distributions are eligible. A visible arterial occlusion is not required for inclusion.
  • Treatment <4½ hours after stroke onset or after awakening with symptoms.
  • Informed consent by patient or by patient's family

Specific sub-set inclusion criteria

  • Wake-Up Stroke: FLAIR-DWI mismatch on MRI as judged by the (neuro-) radiologist or neurologist.
  • Thrombectomy: Occlusion of intracerebral artery technically accessible for endovascular embolectomy as defined by local treatment protocols.

Exclusion criteria

  • Prestroke modified rankin scale of ≥3
  • Large areas of hypodense ischaemic changes on baseline CT;
  • Patients with systolic blood pressure >185 mm Hg or diastolic blood pressure >110 mm Hg in spite of acute antihypertensive treatment;
  • Pregnant women (are treated with alteplase);
  • Women with possible pregnancy (are treated with alteplase)
  • Beast feeding women, if a 24 hours stop of feeding is not feasible.
  • Clinical presentation suggesting subarachnoid haemorrhage even if baseline CT is normal;
  • Known bleeding diathesis; use of oral anticoagulants with no antidot, INR ≥1,4; heparin <48 hours and increased APTT; low molecular weight heparin(oid) <24 hours; another investigational drug <14 days;
  • 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; CNS neurosurgery <2 months; serious head trauma <2 months; pericarditis; sepsis; any serious medical illness likely to interact with treatment; confounding pre-existent neurological or psychiatric disease; unlikely to complete follow-up;
  • Any condition that, in the opinion of the investigator, puts a patient at risk if treated with thrombolysis.

Sites / Locations

  • Haukeland University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Tenecteplase

Alteplase

Arm Description

Tenecteplase

Alteplase

Outcomes

Primary Outcome Measures

Proportion of patients with favorable functional outcome
Modified Rankin Scale 0-1 (favorable= 0-1, unfavorable 2-6)

Secondary Outcome Measures

Symptomatic cerebral hemorrhage
Proportion of patients with haemorrhagic infarct/haematoma as defined by CT or MRI
Any cerebral haemorrhage
Proportion of patients haemorrhagic infarct/haematoma as defined by CT or MRI
Major neurological improvement
Proportion of patients >3 Points improvement by NIHSS score or NIHSS score 0 (NIHSS score range is 0-42)
Functional handicap
Ordinal shift analysis of modified Rankin scale (0-6)
Mortality
Proportion of patients who died

Full Information

First Posted
January 21, 2019
Last Updated
September 14, 2023
Sponsor
Haukeland University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT03854500
Brief Title
The Norwegian Tenecteplase Stroke Trial 2
Acronym
NOR-TEST 2
Official Title
A Randomised Trial of Tenecteplase vs. Alteplase in Acute Ischemic Stroke
Study Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Terminated
Why Stopped
Per protocol safety analysis 200 patients showed a significant difference in bleeding rates between the two drug groups.
Study Start Date
October 28, 2019 (Actual)
Primary Completion Date
September 30, 2021 (Actual)
Study Completion Date
December 31, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Haukeland University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Background: Alteplase is the only approved acute drug treatment in ischemic stroke and aims at dissolving arterial clots causing cerebral ischemia. The overall benefit of alteplase is substantial. However, there is considerable room for improvement as 2/3 of patients with large clots may not achieve reopening of the vessel and up to 40% of the patients remain severely disabled or die. Tenecteplase, a modified tissue plasminogen activator, has been shown to be a more efficient and safer thrombolytic drug than alteplase in pre-clinical studies. Tenecteplase has replaced alteplase as thrombolytic treatment in myocardial infarction and may also be the drug of choice in ischemic stroke. Tenecteplase and alteplase had a similar safety profile in the NOR-TEST trial and there were no differences in efficacy between the two treatment groups. However, a majority of patients had mild stroke which may be associated with a natural favorable prognosis. In spite of these neutral results, tenecteplase has the potential to replace alteplase as the drug of choice, based on a better pharmacological profile and a simpler practical administration. There is, however, need for a higher number of patients to prove the efficacy and safety of tenecteplase. Hypothesis: Tenecteplase 0.4 mg/kg is non-inferior compared with alteplase 0.9 mg/kg.
Detailed Description
Objectives: To compare efficacy and safety of tenecteplase 0.4 mg/kg (single bolus) vs. alteplase 0.9 mg/kg (10% bolus + 90% infusion/60 minutes) a) within 4½ hours after symptom onset; b) within 4½ hours after awakening with stroke symptoms, and c) as bridging therapy within 4½ hours before thrombectomy. Study design: NOR-TEST-2 is a multi-centre PROBE (prospective randomised, open-label, blinded endpoint) trial, designed to establish non-inferiority of tenecteplase as compared with alteplase for consecutively admitted patients with acute ischaemic stroke treated within 4½ hours after symptom onset. Randomisation tenecteplase:alteplase is 1:1. Endpoints: Primary endpoint is functional outcome (mRS 0-1) at 90 days (efficacy). Secondary endpoints include rates of cerebral hemorrhages on CT/MR at 24-48 hours and mortality (safety). Patient recruitment: All patients admitted to hospital with acute ischaemic stroke eligible for standard iv thrombolysis with alteplase and with pre-stroke mRS<3 and NIHSS score of >5 on admission are potentially eligible for NOR-TEST-2. Based on power calculations from NOR-TEST, NOR-TEST 2 aims at including 1036 patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Stroke, Acute, Cerebrovascular Disorders, Ischemic Stroke
Keywords
Tenecteplase, Thrombolysis, Alteplase

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Model Description
Randomized, controlled multicenter study
Masking
ParticipantOutcomes Assessor
Allocation
Randomized
Enrollment
201 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tenecteplase
Arm Type
Active Comparator
Arm Description
Tenecteplase
Arm Title
Alteplase
Arm Type
Active Comparator
Arm Description
Alteplase
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
Proportion of patients with favorable functional outcome
Description
Modified Rankin Scale 0-1 (favorable= 0-1, unfavorable 2-6)
Time Frame
90 days
Secondary Outcome Measure Information:
Title
Symptomatic cerebral hemorrhage
Description
Proportion of patients with haemorrhagic infarct/haematoma as defined by CT or MRI
Time Frame
24-48 hours
Title
Any cerebral haemorrhage
Description
Proportion of patients haemorrhagic infarct/haematoma as defined by CT or MRI
Time Frame
24-48 hours
Title
Major neurological improvement
Description
Proportion of patients >3 Points improvement by NIHSS score or NIHSS score 0 (NIHSS score range is 0-42)
Time Frame
24 hours
Title
Functional handicap
Description
Ordinal shift analysis of modified Rankin scale (0-6)
Time Frame
90 days
Title
Mortality
Description
Proportion of patients who died
Time Frame
90 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
General inclusion criteria 18 years or older Ischaemic stroke with clinical symptoms corresponding to National Institutes of Health Stroke Scale Score (NIHSS) of >5. All stroke sub-types and vascular distributions are eligible. A visible arterial occlusion is not required for inclusion. Treatment <4½ hours after stroke onset or after awakening with symptoms. Informed consent by patient or by patient's family Specific sub-set inclusion criteria Wake-Up Stroke: FLAIR-DWI mismatch on MRI as judged by the (neuro-) radiologist or neurologist. Thrombectomy: Occlusion of intracerebral artery technically accessible for endovascular embolectomy as defined by local treatment protocols. Exclusion criteria Prestroke modified rankin scale of ≥3 Large areas of hypodense ischaemic changes on baseline CT; Patients with systolic blood pressure >185 mm Hg or diastolic blood pressure >110 mm Hg in spite of acute antihypertensive treatment; Pregnant women (are treated with alteplase); Women with possible pregnancy (are treated with alteplase) Beast feeding women, if a 24 hours stop of feeding is not feasible. Clinical presentation suggesting subarachnoid haemorrhage even if baseline CT is normal; Known bleeding diathesis; use of oral anticoagulants with no antidot, INR ≥1,4; heparin <48 hours and increased APTT; low molecular weight heparin(oid) <24 hours; another investigational drug <14 days; 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; CNS neurosurgery <2 months; serious head trauma <2 months; pericarditis; sepsis; any serious medical illness likely to interact with treatment; confounding pre-existent neurological or psychiatric disease; unlikely to complete follow-up; Any condition that, in the opinion of the investigator, puts a patient at risk if treated with thrombolysis.
Facility Information:
Facility Name
Haukeland University Hospital
City
Bergen
ZIP/Postal Code
5021
Country
Norway

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
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
background
PubMed Identifier
35525250
Citation
Kvistad CE, Naess H, Helleberg BH, Idicula T, Hagberg G, Nordby LM, Jenssen KN, Tobro H, Rorholt DM, Kaur K, Eltoft A, Evensen K, Haasz J, Singaravel G, Fromm A, Thomassen L. Tenecteplase versus alteplase for the management of acute ischaemic stroke in Norway (NOR-TEST 2, part A): a phase 3, randomised, open-label, blinded endpoint, non-inferiority trial. Lancet Neurol. 2022 Jun;21(6):511-519. doi: 10.1016/S1474-4422(22)00124-7. Epub 2022 May 4.
Results Reference
derived

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The Norwegian Tenecteplase Stroke Trial 2

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