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

NCT02398656 | Completed Phase 3 Results DMC

• 1 other identifier: Version 3.3 , Mar 24,2017
• Study Type: interventional
• Target: 1,274
• Locations: 9 countries
• Sites: 59

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.

Conditions

Stroke, Acute

Keywords

Minor Ischemic Stroke

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Return to Baseline Neurological Functioning Measured by the Modified Rankin Scale (mRS)

  Analysis will be a responder analysis where return to baseline level of neurological functioning is defined as follows: If pre-morbid mRS is 0-1 then mRS 0-1 at 90 days is a good outcome. If pre-morbid mRS is 2 then mRS 0-2 is a good outcome. Pre-morbid mRS is assessed using the structured mRS prior to randomization. Outcomes at 90 days will be assessed by an individual blinded to the treatment assignment. The 90day mRS will be rated using the structured mRS questionnaire . The 90 day mRS will be completed in person where possible and by telephone otherwise. The structured questionnaire has been showed to improve reliability in assessing the mRS both in person and by telephone. This is a scale from 0-6. Higher scores mean a worse outcome.

  90 Days

Secondary Outcomes (1)

• Number of Participants With Modified Rankin Score (mRS) 0-1 at 90 Days

  90 days

Study Arms (2)

Tenecteplase (tNK)

EXPERIMENTAL

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.

Drug: Tenecteplase

Control (Antiplatelet Agents)

ACTIVE COMPARATOR

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.

Drug: Antiplatelet treatment

Interventions

Tenecteplase DRUG

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

Also known as: TNK-tPA

Tenecteplase (tNK)

Antiplatelet treatment 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.

Also known as: ASA, Clopidogrel

Control (Antiplatelet Agents)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Acute ischemic stroke in an adult patient (18 years of age or older)
• Onset (last-seen-well) time to treatment time ≤ 12 hours.
• 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.
• 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.
• Pre-stroke independent functional status - structured mRS ≤2.
• Informed consent from the patient or surrogate.
• 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.

You may not qualify if:

• Hyperdensity on NCCT consistent with intracranial hemorrhage.
• Large acute stroke ASPECTS \< 7 visible on baseline CT scan.
• 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.
• Clinical history, past imaging or clinical judgment suggest that that intracranial occlusion is chronic.
• 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.
• Pregnancy
• Planned thrombolysis with IV tPA or endovascular thrombolysis/thrombectomy treatment.
• 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.
• 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.

Sponsors & Collaborators

• University of Calgary: lead

Study Sites (61)

Calvary Public Hospital Bruce

Canberra, Australian Capital Territory, Australia

Location

John Hunter Hospital

Newcastle, New South Wales, Australia

Location

Gold Coast University Hospital

Gold Coast, Queensland, Australia

Location

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Location

Box Hill Hospital

Box Hill, Victoria, Australia

Location

Royal Melbourne Hospital

Melbourne, Victoria, Australia

Location

Fiona Stanley Hospital

Murdoch, Western Australia, Australia

Location

Medical University of Vienna (Coordinating Centre)

Vienna, Austria

Location

St. John's of God Hospital Vienna

Vienna, Austria

Location

Hospital de Clínicas de Botucatu

Botucatu, Brazil

Location

Instituto Hospital de Base do Distrito Federal

Brasília, Brazil

Location

Hospital Universitário Maria Aparecida Pedrossian

Campo Grande, Brazil

Location

Hospital Celso Ramos Florianopolos

Celso Ramos, Brazil

Location

Hospital Geral de Fortaleza

Fortaleza, Brazil

Location

Clinica Neurologica e Neurocirurgica de Joinville Ltda

Joinville, Brazil

Location

Porto Alegre Hospital

Porto Alegre, Brazil

Location

Santa Casa de Porto Alegre

Porto Alegre, Brazil

Location

Hospital de Clínicas de Ribeirão Preto

Ribeirão Preto, Brazil

Location

Americas Medical City

Rio de Janeiro, Brazil

Location

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

São Paulo, Brazil

Location

Hospital São Paulo UNIFESP

São Paulo, Brazil

Location

Irmandade Da Santa Casa de Misericordia de Sao Paulo

São Paulo, Brazil

Location

Hospital Estadual Central

Vitória, Brazil

Location

University of Calgary/Foothills Medical Centre

Calgary, Alberta, T2N 2T9, Canada

Location

University of Alberta

Edmonton, Alberta, Canada

Location

Royal Columbian Hospital

New Westminster, B.C., V3L 3W7, Canada

Location

Vancouver General Hospital

Vancouver, British Columbia, Canada

Location

Victoria General Hospital

Victoria, British Columbia, Canada

Location

Hamilton Health Sciences Centre

Hamilton, Ontario, Canada

Location

Kingston General Hospital

Kingston, Ontario, Canada

Location

London Health Sciences Centre

London, Ontario, Canada

Location

Ottawa General Hospital

Ottawa, Ontario, Canada

Location

St. Michael's Hospital

Toronto, Ontario, Canada

Location

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

Location

Toronto Western

Toronto, Ontario, Canada

Location

McGill University

Montreal, Quebec, Canada

Location

CHU de Québec-Université Laval

Québec, Quebec, Canada

Location

University of Saskatchewan/ Royal University Hospital

Saskatoon, Saskatchewan, Canada

Location

University Central Hospital HUCH

Helsinki, Finland

Location

Beaumont Hospital

Dublin, Leinster, Ireland

Location

Mater Misericordiae University Hospital Dublin

Dublin, Leinster, Ireland

Location

Christchurch Hospital

Christchurch, New Zealand

Location

National Neuroscience Institute Tan Tock Seng Hospital

Singapore, Singapore

Location

Singapore General Hospital

Singapore, Singapore

Location

Complejo Jospitalario Universitario A Coruna

A Coruña, Spain

Location

Vall d'Hebron Institut de Recerca (VHIR)

Barcelona, Spain

Location

Vall d'Hebron Institut de Recerca

Barcelona, Spain

Location

Hospital Universitari Doctor Josep Trueta

Girona, Spain

Location

Clinc University Hospital Valladolid

Valladolid, Spain

Location

Countess of Chester

London, England, United Kingdom

Location

St George's University Hospitals NHS Foundation trust

London, England, United Kingdom

Location

Stoke University of North Midlands

London, England, United Kingdom

Location

University College London Hospital

London, England, United Kingdom

Location

Royal Victoria Hospital

Belfast, Northern Ireland, United Kingdom

Location

Queen Elizabeth University Hospital

Glasgow, Scotland, United Kingdom

Location

Queen Elizabeth Hospital

Birmingham, United Kingdom

Location

Addenbrooke Hospital

Cambridge, United Kingdom

Location

Charring Cross Hospital

London, United Kingdom

Location

Kings College Hospital

London, United Kingdom

Location

Nottingham University Hospital

Nottingham, United Kingdom

Location

John Radcliffe Hospital

Oxford, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 38768626 RESULT

• 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 Dec 1;82(12):1243-1250. doi: 10.1001/jamaneurol.2025.4152.

  PMID: 41143808 DERIVED

• 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.

  PMID: 26387127 DERIVED

MeSH Terms

Conditions

Stroke

Interventions

Tenecteplase; TNK-tissue plasminogen activator; Clopidogrel

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Tissue Plasminogen Activator; Serine Endopeptidases; Endopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Serine Proteases; Plasminogen Activators; Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Ticlopidine; Thienopyridines; Thiophenes; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

The trial was ended based on a recommendation from the DSMB that to continue was futile.

Results Point of Contact

• Title: Dr. Shelagh Coutts
• Organization: University of Calgary

scoutts@ucalgary.ca

4039444286

Study Officials

• Michael D Hill, MD

  University of Calgary

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Stroke Neurologist, Co- Investigator

Study Record Dates

• First Submitted: March 20, 2015
• First Posted: March 25, 2015
• Study Start: April 1, 2015
• Primary Completion: January 19, 2024
• Study Completion: April 10, 2024
• Last Updated: January 31, 2025
• Results First Posted: January 31, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

ES (5); GB (12); BR (14); CA (15); AU (7); NZ (1); FI (1); IE (2); SG (2)