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

Tracking Information

• First Submitted Date: September 21, 2013
• First Posted Date: September 25, 2013
• Last Update Posted Date: May 9, 2017
• Actual Study Start Date: September 2012
• Actual Primary Completion Date: December 31, 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 5, 2017)

Clinical: Functional handicap [ Time Frame: 90 days ]

Excellent outcome defined as mRS 0-1

Original Primary Outcome Measures (submitted: September 21, 2013)

Functional handicap [ Time Frame: 90 days ]

modified Rankin Scale score (mRS) 0-1

Current Secondary Outcome Measures (submitted: May 5, 2017)

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

Original Secondary Outcome Measures (submitted: September 21, 2013)

• Symptomatic cerebral hemorrhage [ Time Frame: 24-36 hours ]
  Haemorrhagic transformation (haemorrhagic infarct / haematoma) as defined by CT (or MRI)
• Hemorrhagic transformation [ Time Frame: 24-36 hours ]
  Any hemorrhagic infarct or parenchymal hematoma
• Major neurological improvement [ Time Frame: 24 hours ]
  Reduction of ≥4 NIHSS (National Institutes of Health Stroke Scale) points compared with baseline (for patients with NIHSS ≥4 on admission)

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: September 21, 2013)

Major neurological improvement [ Time Frame: 7 days ]

Sliding dichotomy/responder analysis: Excellent outcome is defined as mRS 0 with baseline NIHSS ≤7, as mRS 0-1 with baseline NIHSS 8-14, as mRS 0-2 with baseline NIHSS ≥15

Descriptive Information

• Brief Title: 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

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Ischemic Stroke

Intervention

• Drug: Tenecteplase
  0.4 mg/kg single bolus intravenously
  Other Name: Metalyse
• Drug: Alteplase
  0.9 mg/kg as 10% bolus + 90% infusion/60 minutes intravenously
  Other Name: Actilyse

Study Arms

• Active Comparator: Tenecteplase
  0.4 mg/kg single bolus intravenously
  Intervention: Drug: Tenecteplase
• Active Comparator: Alteplase
  0.9 mg/kg as 10% bolus + 90% infusion/60 minutes intravenously
  Intervention: Drug: Alteplase

Publications *

• 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.
• 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.
• 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.
• 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, 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 27, 2017): 1050
• Original Estimated Enrollment (submitted: September 21, 2013): 954
• Actual Study Completion Date: December 31, 2016
• Actual Primary Completion Date: December 31, 2016 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Norway

Administrative Information

• NCT Number: NCT01949948
• Other Study ID Numbers: REK 2011/2435
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Lars Thomassen, Haukeland University Hospital
• Original Responsible Party: Haukeland University Hospital
• Current Study Sponsor: Lars Thomassen
• Original Study Sponsor: Haukeland University Hospital
• Collaborators: 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

• PRS Account: Haukeland University Hospital
• Verification Date: May 2017