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

Phase 3

Completed

Conditions: Stroke, Acute

Interventions: Drug: Tenecteplase
Drug: Antiplatelet treatment

Registration Number: NCT02398656

Lead Sponsor: University of Calgary

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1274

Inclusion Criteria

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.

Exclusion Criteria

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.
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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tenecteplase (tNK)	Tenecteplase	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.
Control (Antiplatelet Agents)	Antiplatelet treatment	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Return to Baseline Neurological Functioning Measured by the Modified Rankin Scale (mRS)	90 Days	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Modified Rankin Score (mRS) 0-1 at 90 Days	90 days	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. This is a scale from 0-6. Higher scores mean a worse outcome. mRS 0-1 represents excellent functional outcome.

Trial Locations

Locations (61): Kingston General Hospital
🇨🇦
Kingston, Ontario, Canada
Queen Elizabeth University Hospital
🇬🇧
Glasgow, Scotland, United Kingdom
Vancouver General Hospital
🇨🇦
Vancouver, British Columbia, Canada
University College London Hospital
🇬🇧
London, England, United Kingdom
Calvary Public Hospital Bruce
🇦🇺
Canberra, Australian Capital Territory, Australia
Beaumont Hospital
🇮🇪
Dublin, Leinster, Ireland
St George's University Hospitals NHS Foundation trust
🇬🇧
London, England, United Kingdom
St. John's of God Hospital Vienna
🇦🇹
Vienna, Austria
Stoke University of North Midlands
🇬🇧
London, England, United Kingdom
Singapore General Hospital
🇸🇬
Singapore, Singapore
Mater Misericordiae University Hospital Dublin
🇮🇪
Dublin, Leinster, Ireland
Victoria General Hospital
🇨🇦
Victoria, British Columbia, Canada
Countess of Chester
🇬🇧
London, England, United Kingdom
Medical University of Vienna (Coordinating Centre)
🇦🇹
Vienna, Austria
Americas Medical City
🇧🇷
Rio De Janeiro, Brazil
Hospital Geral de Fortaleza
🇧🇷
Fortaleza, Brazil
Clinica Neurologica e Neurocirurgica de Joinville Ltda
🇧🇷
Joinville, Brazil
Porto Alegre Hospital
🇧🇷
Porto Alegre, Brazil
Gold Coast University Hospital
🇦🇺
Gold Coast, Queensland, Australia
John Hunter Hospital
🇦🇺
Newcastle, New South Wales, Australia
Royal Adelaide Hospital
🇦🇺
Adelaide, South Australia, Australia
Box Hill Hospital
🇦🇺
Box Hill, Victoria, Australia
Fiona Stanley Hospital
🇦🇺
Murdoch, Western Australia, Australia
Royal Melbourne Hospital
🇦🇺
Melbourne, Victoria, Australia
Hospital de Clínicas de Botucatu
🇧🇷
Botucatu, Brazil
Instituto Hospital de Base do Distrito Federal
🇧🇷
Brasília, Brazil
Hospital Celso Ramos Florianopolos
🇧🇷
Celso Ramos, Brazil
Hospital Universitário Maria Aparecida Pedrossian
🇧🇷
Campo Grande, Brazil
Santa Casa de Porto Alegre
🇧🇷
Porto Alegre, Brazil
Hospital de Clínicas de Ribeirão Preto
🇧🇷
Ribeirão Preto, Brazil
Hospital São Paulo UNIFESP
🇧🇷
São Paulo, Brazil
University of Calgary/Foothills Medical Centre
🇨🇦
Calgary, Alberta, Canada
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
🇧🇷
São Paulo, Brazil
Irmandade Da Santa Casa de Misericordia de Sao Paulo
🇧🇷
São Paulo, Brazil
Hospital Estadual Central
🇧🇷
Vitória, Brazil
University of Alberta
🇨🇦
Edmonton, Alberta, Canada
Royal Columbian Hospital
🇨🇦
New Westminster, B.C., Canada
Hamilton Health Sciences Centre
🇨🇦
Hamilton, Ontario, Canada
London Health Sciences Centre
🇨🇦
London, Ontario, Canada
Sunnybrook Health Sciences Centre
🇨🇦
Toronto, Ontario, Canada
St. Michael's Hospital
🇨🇦
Toronto, Ontario, Canada
Ottawa General Hospital
🇨🇦
Ottawa, Ontario, Canada
Toronto Western
🇨🇦
Toronto, Ontario, Canada
McGill University
🇨🇦
Montreal, Quebec, Canada
CHU de Québec-Université Laval
🇨🇦
Quebec City, Quebec, Canada
University Central Hospital HUCH
🇫🇮
Helsinki, Finland
University of Saskatchewan/ Royal University Hospital
🇨🇦
Saskatoon, Saskatchewan, Canada
Christchurch Hospital
🇳🇿
Christchurch, New Zealand
Kings College Hospital
🇬🇧
London, United Kingdom
National Neuroscience Institute Tan Tock Seng Hospital
🇸🇬
Singapore, Singapore
Vall d'Hebron Institut de Recerca (VHIR)
🇪🇸
Barcelona, Spain
Complejo Jospitalario Universitario A Coruna
🇪🇸
A Coruña, Spain
Vall d'Hebron Institut de Recerca
🇪🇸
Barcelona, Spain
Hospital Universitari Doctor Josep Trueta
🇪🇸
Girona, Spain
Clinc University Hospital Valladolid
🇪🇸
Valladolid, Spain
Queen Elizabeth Hospital
🇬🇧
Birmingham, United Kingdom
Addenbrooke Hospital
🇬🇧
Cambridge, United Kingdom
Charring Cross Hospital
🇬🇧
London, United Kingdom
John Radcliffe Hospital
🇬🇧
Oxford, United Kingdom
Nottingham University Hospital
🇬🇧
Nottingham, United Kingdom
Royal Victoria Hospital
🇬🇧
Belfast, Northern Ireland, United Kingdom