A Randomized Controlled Trial of TNK-tPA Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion

NCT ID: NCT02398656

Last Updated: 2025-01-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1274 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-04-01
• Study Completion Date: 2024-04-10

Brief Summary

This trial will enroll patients that have been diagnosed with a transient ischemic attack (TIA) or minor stroke that has occurred within the past 12 hours. Anyone diagnosed with a minor stroke faces the possibility of long-term disability and even death, regardless of treatment. Stroke symptoms such as weakness, difficulty speaking and paralysis may improve or worsen over the hours or days immediately following a stroke. TEMPO-2 is a minor stroke trial for patients presenting within 12 hours of their symptom onset. Patients will be randomized to TNK-tPA or standard of care. In the intervention group TNK-tPA is given as a single, intravenous bolus (0.25mg/Kg) immediately upon randomization. Maximum dose 50mg. The control group will receive antiplatelet agent(s) as decided by the treating physician. Antiplatelet agent(s) choice will be at the treating physician's discretion.

TEMPO-2 Coordinating Centre is located in Calgary, AB, Canada. There will be approximately 50 sites participating worldwide.

Dr. Shelagh Coutts is the Principal Investigator.

Detailed Description

TEMPO2 is an multicentre, prospective randomized open label, blinded-endpoint (PROBE) controlled trial of thrombolysis with low dose Tenecteplase (TNK-tPA) versus standard of care. A total of 1274 patients will be enrolled, at approximately 50 sites worldwide.

TEMPO-2 will enroll patients within a 12 hour time window with a NIHSS score of <6 and an ASPECTS >7. All patients will be evaluated clinically and then undergo brain imaging using CT followed immediately by a CT angiogram. Patients must have an intracranial occlusion on CTA or CTP.

Randomization will be 1:1 to TNK-tPA (experimental) or standard of care antiplatelet agents (control).

Experimental: TNK-tPA (0.25mg/kg) given as a single, intravenous bolus immediately upon randomization. Experimental treatment will be administered as a single intravenous bolus over 1-2 minutes.

Control: Patients will be treated with standard of care based antiplatelet treatment - choice at the discretion of the investigator. Low dose aspirin (single agent) will be the choice of most physicians, some will chose to use the combination of aspirin and clopidogrel. The local investigator to chose which antithrombotic regime should be used

All patients will be treated within 90 minutes of the first slice of the baseline CT. Patients will undergo a study CT angiogram of the intracranial circulation between 4-8 hours after treatment to determine whether the occluded artery has recanalized or not. In sites where MRI/MRA is routinely used this can be substituted for CT/CTA. Any patient who has neurological worsening should have standard of care brain imaging completed to rule out intracranial hemorrhage.

All patients will have standard of care medical management on an acute stroke unit and undergo follow-up imaging at 24 hours with CT or MR. Use of MR will be encouraged.

Patients will be assessed at 24 hours and at Days 5 and 90. The Day 90 Outcomes will be performed by a blinded assessor.

Conditions

Stroke, Acute

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Tenecteplase (tNK)

Experimental: TNK-tPA (0.25mg/kg) given as a single, intravenous bolus immediately upon randomization. Experimental treatment will be administered as a single intravenous bolus over 1-2 minutes as per the standard manufacturers' instructions for use. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, has a longer half-life, is more fibrin specific, produces less systemic depletion of circulating fibrinogen, and is more resistant to plasminogen activator inhibitor than alteplase.

Group Type: EXPERIMENTAL

Tenecteplase

Intervention Type: DRUG

TNK will be administered as a single intravenous bolus over 1-2 minutes within 90 minutes of the CT scan.

Control (Antiplatelet Agents)

Control: Patients will be treated with standard of care based antiplatelet treatment - choice at the discretion of the investigator. Low dose aspirin (single agent) will be the choice of most physicians, some will chose to use the combination of aspirin and clopidogrel. As this is a multi-centre, international trial where local practices will vary, rather than mandating a specific antiplatelet agent, we will allow the local investigator to chose which antithrombotic regime should be used. Standard of care medication(s) should be given immediately upon randomization.

Group Type: ACTIVE_COMPARATOR

Antiplatelet treatment

Intervention Type: DRUG

Low dose aspirin (single agent) will be the choice of most physicians, some Investigators will chose to use the combination of aspirin and clopidogrel.

Interventions

Tenecteplase

TNK will be administered as a single intravenous bolus over 1-2 minutes within 90 minutes of the CT scan.

Intervention Type: DRUG

Antiplatelet treatment

Low dose aspirin (single agent) will be the choice of most physicians, some Investigators will chose to use the combination of aspirin and clopidogrel.

Intervention Type: DRUG

Other Intervention Names

TNK-tPA; ASA, Clopidogrel

Eligibility Criteria

Inclusion Criteria

1. Acute ischemic stroke in an adult patient (18 years of age or older)

2. Onset (last-seen-well) time to treatment time ≤ 12 hours.

3. TIA or minor stroke defined as a baseline NIHSS ≤ 5 at the time of randomization. Patients do not have to have persistent demonstrable neurological deficit on physical neurological examination.

4. Any acute intracranial occlusion or near occlusion (TICI 0 or 1) (MCA, ACA, PCA, VB territories) defined by non-invasive acute imaging (CT angiography or MR angiography) that is neurologically relevant to the presenting symptoms and signs. Multiphase CTA or CT perfusion are required for this study. An acute occlusion is defined as TICI 0 or TICI 1 flow.1 Practically this can include a small amount of forward flow in the presence of a near occlusion AND, Delayed washout of contrast with pial vessels on multiphase CTA in a region of brain concordant with clinical symptoms and signs OR, Any area of focal perfusion abnormality identified using CT or MR perfusion - e.g. transit delay (TTP, MTT or T Max), in a region of brain concordant with clinical symptoms and signs.

5. Pre-stroke independent functional status - structured mRS ≤2.

6. Informed consent from the patient or surrogate.

7. Patients can be treated within 90 minutes of the first slice of CT or MRI. Scans can be repeated to meet this requirement; if there is no change neurologically then only a CT head need be repeated for assessment of extent and depth of ischemia.

Exclusion Criteria

1. Hyperdensity on NCCT consistent with intracranial hemorrhage.

2. Large acute stroke ASPECTS < 7 visible on baseline CT scan.

3. Core of established infarction. No large area (estimated > 10 cc) of grey matter hypodensity at a similar density to white matter or in the judgment of the enrolling neurologist is consistent with a subacute ischemic stroke > 12 hours of age.

4. Clinical history, past imaging or clinical judgment suggest that that intracranial occlusion is chronic.

5. Patient has a severe or fatal or disabling illness that will prevent improvement or follow-up or such that the treatment would not likely benefit the patient.

6. Pregnancy

7. Planned thrombolysis with IV tPA or endovascular thrombolysis/thrombectomy treatment.

8. In-hospital stroke unless these patients are at their baseline prior to their stroke. E.g. a patient who had a stroke during a diagnostic coronary angiogram.

9. Commonly accepted exclusions for medical thrombolytic treatment. These are commonly relative contraindications (i.e. the final decision is at the discretion of the treating physician) but for the purposes of TEMPO-2 include the following:

• International normalized ratio > 1.7 or known full anticoagulation with use of any standard or direct oral anticoagulant therapy with full anticoagulant dosing. [DVT prophylaxis dosing shall not prohibit enrolment]. For low molecular weight heparins (LMWH) more than 48 hours off drug will be considered sufficient to allow trial enrollment. For direct oral anticoagulants; in patients with normal renal function more than 48 hours off drug will be considered sufficient to allow trial enrollment. Patients on direct oral anticoagulants who have any degree of renal impairment should not be enrolled in the trial unless they have not taken a dose of the drug in the last 5 days. Dual antiplatelet therapy does not prohibit enrolment.
• Dual antiplatelet therapy does not prohibit enrolment. [For patients who are known not to be taking anticoagulant therapy it is not necessary to wait for coagulation lab results (e.g. PT, PTT) prior to treatment]
• Patients who have been acutely treated with GP2b3a inhibitors.
• Arterial puncture at a non-compressible site in the previous seven days
• Clinical stroke or serious head or spinal trauma in the preceding three months that would normally preclude use of a thrombolytic agent.
• History of intracranial hemorrhage, subarachnoid hemorrhage or other brain hemorrhage that would normally preclude use of a thrombolytic agent.
• Major surgery within the last 3 months at a bodily site where bleeding could result in serious harm or death.
• Known platelet count below 100,000 per cubic millimeter. Treatment should not be delayed to wait for platelet count unless thrombocytopenia is known or suspected.
• Gastrointestinal or genitourinary bleeding within the past 3 months that is unresolved or associated with persisting anemia such that thrombolytic treatment of any kind would result in serious bleeding or death.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Calgary

OTHER

Sponsor Role: lead

Responsible Party

Shelagh B Coutts

Stroke Neurologist, Co- Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Michael D Hill, MD

Role: STUDY_DIRECTOR

University of Calgary

Locations

Calvary Public Hospital Bruce

Canberra, Australian Capital Territory, Australia

John Hunter Hospital

Newcastle, New South Wales, Australia

Gold Coast University Hospital

Gold Coast, Queensland, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Box Hill Hospital

Box Hill, Victoria, Australia

Royal Melbourne Hospital

Melbourne, Victoria, Australia

Fiona Stanley Hospital

Murdoch, Western Australia, Australia

Medical University of Vienna (Coordinating Centre)

Vienna, , Austria

St. John's of God Hospital Vienna

Vienna, , Austria

Hospital de Clínicas de Botucatu

Botucatu, , Brazil

Instituto Hospital de Base do Distrito Federal

Brasília, , Brazil

Hospital Universitário Maria Aparecida Pedrossian

Campo Grande, , Brazil

Hospital Celso Ramos Florianopolos

Celso Ramos, , Brazil

Hospital Geral de Fortaleza

Fortaleza, , Brazil

Clinica Neurologica e Neurocirurgica de Joinville Ltda

Joinville, , Brazil

Porto Alegre Hospital

Porto Alegre, , Brazil

Santa Casa de Porto Alegre

Porto Alegre, , Brazil

Hospital de Clínicas de Ribeirão Preto

Ribeirão Preto, , Brazil

Americas Medical City

Rio de Janeiro, , Brazil

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

São Paulo, , Brazil

Hospital São Paulo UNIFESP

São Paulo, , Brazil

Irmandade Da Santa Casa de Misericordia de Sao Paulo

São Paulo, , Brazil

Hospital Estadual Central

Vitória, , Brazil

University of Calgary/Foothills Medical Centre

Calgary, Alberta, Canada

University of Alberta

Edmonton, Alberta, Canada

Royal Columbian Hospital

New Westminster, B.C., Canada

Vancouver General Hospital

Vancouver, British Columbia, Canada

Victoria General Hospital

Victoria, British Columbia, Canada

Hamilton Health Sciences Centre

Hamilton, Ontario, Canada

Kingston General Hospital

Kingston, Ontario, Canada

London Health Sciences Centre

London, Ontario, Canada

Ottawa General Hospital

Ottawa, Ontario, Canada

St. Michael's Hospital

Toronto, Ontario, Canada

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

Toronto Western

Toronto, Ontario, Canada

McGill University

Montreal, Quebec, Canada

CHU de Québec-Université Laval

Québec, Quebec, Canada

University of Saskatchewan/ Royal University Hospital

Saskatoon, Saskatchewan, Canada

University Central Hospital HUCH

Helsinki, , Finland

Beaumont Hospital

Dublin, Leinster, Ireland

Mater Misericordiae University Hospital Dublin

Dublin, Leinster, Ireland

Christchurch Hospital

Christchurch, , New Zealand

National Neuroscience Institute Tan Tock Seng Hospital

Singapore, , Singapore

Singapore General Hospital

Singapore, , Singapore

Complejo Jospitalario Universitario A Coruna

A Coruña, , Spain

Vall d'Hebron Institut de Recerca (VHIR)

Barcelona, , Spain

Vall d'Hebron Institut de Recerca

Barcelona, , Spain

Hospital Universitari Doctor Josep Trueta

Girona, , Spain

Clinc University Hospital Valladolid

Valladolid, , Spain

Countess of Chester

London, England, United Kingdom

St George's University Hospitals NHS Foundation trust

London, England, United Kingdom

Stoke University of North Midlands

London, England, United Kingdom

University College London Hospital

London, England, United Kingdom

Royal Victoria Hospital

Belfast, Northern Ireland, United Kingdom

Queen Elizabeth University Hospital

Glasgow, Scotland, United Kingdom

Queen Elizabeth Hospital

Birmingham, , United Kingdom

Addenbrooke Hospital

Cambridge, , United Kingdom

Charring Cross Hospital

London, , United Kingdom

Kings College Hospital

London, , United Kingdom

Nottingham University Hospital

Nottingham, , United Kingdom

John Radcliffe Hospital

Oxford, , United Kingdom

Countries

Australia; Austria; Brazil; Canada; Finland; Ireland; New Zealand; Singapore; Spain; United Kingdom

References

Coutts SB, Ankolekar S, Appireddy R, Arenillas JF, Assis Z, Bailey P, Barber PA, Bazan R, Buck BH, Butcher KS, Camden MC, Campbell BCV, Casaubon LK, Catanese L, Chatterjee K, Choi PMC, Clarke B, Dowlatshahi D, Ferrari J, Field TS, Ganesh A, Ghia D, Goyal M, Greisenegger S, Halse O, Horn M, Hunter G, Imoukhuede O, Kelly PJ, Kennedy J, Kenney C, Kleinig TJ, Krishnan K, Lima F, Mandzia JL, Marko M, Martins SO, Medvedev G, Menon BK, Mishra SM, Molina C, Moussaddy A, Muir KW, Parsons MW, Penn AMW, Pille A, Pontes-Neto OM, Roffe C, Serena J, Simister R, Singh N, Spratt N, Strbian D, Tham CH, Wiggam MI, Williams DJ, Willmot MR, Wu T, Yu AYX, Zachariah G, Zafar A, Zerna C, Hill MD; TEMPO-2 investigators. Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial. Lancet. 2024 Jun 15;403(10444):2597-2605. doi: 10.1016/S0140-6736(24)00921-8. Epub 2024 May 17.

Reference Type: RESULT

PMID: 38768626 (View on PubMed)

Zhang Y, Buck BH, Barber PA, Chatterjee K, Clarke B, Choi PMC, Hunter G, Ganesh A, Mishra SM, Williams D, Campbell BCV, Dowlatshahi D, Butcher KS, Krishnan K, Wiggam MI, Kleinig TJ, Muir KW, Zerna C, Field TS, Goyal M, Yu AYX, Roffe C, Demchuck AM, Parsons MW, Bazan R, Ankolekar S, Kennedy J, Menon BK, Mandzia JL, Pille A, Kelly PJ, Marko M, Singh N, Vatanpour S, Lima FO, Catanese L, Horn M, Ghia D, Ferrari J, Greisenegger S, Hill MD, Coutts SB; TEMPO-2 Investigators. Thrombolysis With Tenecteplase for Minor Disabling Stroke: Secondary Analysis of the TEMPO-2 Randomized Clinical Trial. JAMA Neurol. 2025 Oct 27. doi: 10.1001/jamaneurol.2025.4152. Online ahead of print.

Reference Type: DERIVED

PMID: 41143808 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26387127 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

Version 3.3 , Mar 24,2017

Identifier Type: -

Identifier Source: org_study_id