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

Stroke, Acute Clinical Trial

— TEMPO-2  

Official title:

Multicentre, Prospective Randomized Open Label, Blinded-endpoint (PROBE) Controlled Trial of Thrombolysis With Low Dose Tenecteplase (TNK-tPA) Versus Standard of Care in Minor Ischemic Stroke With Proven Acute Symptomatic Occlusion

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02398656
• Other study ID #: Version 3.3 , Mar 24,2017
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: April 2015
• Est. completion date: April 10, 2024

Study information

• Verified date: March 2024
• Source: University of Calgary
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1274
• Est. completion date: April 10, 2024
• Est. primary completion date: January 19, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Ischemic Stroke
• Stroke
• Stroke, Acute

Intervention

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

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Box Hill Hospital	Box Hill	Victoria
Australia	Calvary Public Hospital Bruce	Canberra	Australian Capital Territory
Australia	Gold Coast University Hospital	Gold Coast	Queensland
Australia	Royal Melbourne Hospital	Melbourne	Victoria
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	John Hunter Hospital	Newcastle	New South Wales
Austria	Medical University of Vienna (Coordinating Centre)	Vienna
Austria	St. John's of God Hospital Vienna	Vienna
Brazil	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
Canada	University of Calgary/Foothills Medical Centre	Calgary	Alberta
Canada	University of Alberta	Edmonton	Alberta
Canada	Hamilton Health Sciences Centre	Hamilton	Ontario
Canada	Kingston General Hospital	Kingston	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	McGill University	Montreal	Quebec
Canada	Royal Columbian Hospital	New Westminster	B.C.
Canada	Ottawa General Hospital	Ottawa	Ontario
Canada	CHU de Québec-Université Laval	Quebec City	Quebec
Canada	University of Saskatchewan/ Royal University Hospital	Saskatoon	Saskatchewan
Canada	St. Michael's Hospital	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	Toronto Western	Toronto	Ontario
Canada	Vancouver General Hospital	Vancouver	British Columbia
Canada	Victoria General Hospital	Victoria	British Columbia
Finland	University Central Hospital HUCH	Helsinki
Ireland	Beaumont Hospital	Dublin	Leinster
Ireland	Mater Misericordiae University Hospital Dublin	Dublin	Leinster
New Zealand	Christchurch Hospital	Christchurch
Singapore	National Neuroscience Institute Tan Tock Seng Hospital	Singapore
Singapore	Singapore General Hospital	Singapore
Spain	Complejo Jospitalario Universitario A Coruna	A Coruña
Spain	Vall d'Hebron Institut de Recerca	Barcelona
Spain	Vall d'Hebron Institut de Recerca (VHIR)	Barcelona
Spain	Hospital Universitari Doctor Josep Trueta	Girona
Spain	Clinc University Hospital Valladolid	Valladolid
United Kingdom	Royal Victoria Hospital	Belfast	Northern Ireland
United Kingdom	Queen Elizabeth Hospital	Birmingham
United Kingdom	Addenbrooke Hospital	Cambridge
United Kingdom	Queen Elizabeth University Hospital	Glasgow	Scotland
United Kingdom	Charring Cross Hospital	London
United Kingdom	Countess of Chester	London	England
United Kingdom	Kings College Hospital	London
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	Nottingham University Hospital	Nottingham
United Kingdom	John Radcliffe Hospital	Oxford

Sponsors (1)

Lead Sponsor	Collaborator
University of Calgary

Countries where clinical trial is conducted

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

References & Publications (1)

Coutts SB, Dubuc V, Mandzia J, Kenney C, Demchuk AM, Smith EE, Subramaniam S, Goyal M, Patil S, Menon BK, Barber PA, Dowlatshahi D, Field T, Asdaghi N, Camden MC, Hill MD; TEMPO-1 Investigators. Tenecteplase-tissue-type plasminogen activator evaluation for minor ischemic stroke with proven occlusion. Stroke. 2015 Mar;46(3):769-74. doi: 10.1161/STROKEAHA.114.008504. Epub 2015 Feb 12. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Complete or partial recanalization	Recanalization will be assessed by the central core-imaging lab blinded to all clinical information- TICI2b-3.	4-8 hours post treatment
Other	Lawton Instrumental Activities of Daily Living Scale (IADL)	This scale will be used at the Day 90 follow-up visit.	90 Days
Other	Quality of life measured on EuroQol38	This scale will be used at the Day 90 follow-up visit.	90 Days
Primary	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 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.	90 Days
Secondary	Major Bleeding	1) Proportion of patients with major bleeding: This will include an analysis of symptomatic intracranial hemorrhage alone and then combined with major extracranial hemorrhage. This is the main safety outcome.	90 Days