TEMPO-2: A Randomized Controlled Trial of TNK-tPA Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion

Sponsor

University of Calgary (Other)

Overall Status

Recruiting

CT.gov ID

NCT02398656

Collaborator

(none)

1,274

Enrollment

Locations

Arms

116

Anticipated Duration (Months)

20.9

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Stroke, Acute	Drug: Tenecteplase Drug: Antiplatelet treatment	Phase 3

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.

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1274 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Apr 1, 2015

Anticipated Primary Completion Date :

Dec 1, 2024

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Tenecteplase TNK will be administered as a single intravenous bolus over 1-2 minutes within 90 minutes of the CT scan. Other Names: TNK-tPA
Active Comparator: 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.	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. Other Names: ASA, Clopidogrel

Arm

Intervention/Treatment

Experimental: 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.

Drug: Tenecteplase

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

Other Names:

TNK-tPA

Active Comparator: 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.

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.

Other Names:

ASA, Clopidogrel

Outcome Measures

Primary Outcome Measures

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 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.

Secondary Outcome Measures

Major Bleeding [90 Days]
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.

Other Outcome Measures

Complete or partial recanalization [4-8 hours post treatment]
Recanalization will be assessed by the central core-imaging lab blinded to all clinical information- TICI2b-3.
Lawton Instrumental Activities of Daily Living Scale (IADL) [90 Days]
This scale will be used at the Day 90 follow-up visit.
Quality of life measured on EuroQol38 [90 Days]
This scale will be used at the Day 90 follow-up visit.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Calvary Public Hospital Bruce	Canberra	Australian Capital Territory	Australia
2	John Hunter Hospital	Newcastle	New South Wales	Australia
3	Gold Coast University Hospital	Gold Coast	Queensland	Australia
4	Royal Adelaide Hospital	Adelaide	South Australia	Australia
5	Box Hill Hospital	Box Hill	Victoria	Australia
6	Royal Melbourne Hospital	Melbourne	Victoria	Australia
7	Fiona Stanley Hospital	Murdoch	Western Australia	Australia
8	Medical University of Vienna (Coordinating Centre)	Vienna		Austria
9	St. John's of God Hospital Vienna	Vienna		Austria
10	Hospital de Clínicas de Botucatu	Botucatu		Brazil
11	Instituto Hospital de Base do Distrito Federal	Brasília		Brazil
12	Hospital Universitário Maria Aparecida Pedrossian	Campo Grande		Brazil
13	Hospital Celso Ramos Florianopolos	Celso Ramos		Brazil
14	Hospital Geral de Fortaleza	Fortaleza		Brazil
15	Clinica Neurologica e Neurocirurgica de Joinville Ltda	Joinville		Brazil
16	Porto Alegre Hospital	Porto Alegre		Brazil
17	Santa Casa de Porto Alegre	Porto Alegre		Brazil
18	Hospital de Clínicas de Ribeirão Preto	Ribeirão Preto		Brazil
19	Americas Medical City	Rio De Janeiro		Brazil
20	Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo	São Paulo		Brazil
21	Hospital São Paulo UNIFESP	São Paulo		Brazil
22	Irmandade Da Santa Casa de Misericordia de Sao Paulo	São Paulo		Brazil
23	Hospital Estadual Central	Vitória		Brazil
24	University of Calgary/Foothills Medical Centre	Calgary	Alberta	Canada	T2N 2T9
25	University of Alberta	Edmonton	Alberta	Canada
26	Royal Columbian Hospital	New Westminster	B.C.	Canada	V3L 3W7
27	Vancouver General Hospital	Vancouver	British Columbia	Canada
28	Victoria General Hospital	Victoria	British Columbia	Canada
29	Hamilton Health Sciences Centre	Hamilton	Ontario	Canada
30	Kingston General Hospital	Kingston	Ontario	Canada
31	London Health Sciences Centre	London	Ontario	Canada
32	Ottawa General Hospital	Ottawa	Ontario	Canada
33	St. Michael's Hospital	Toronto	Ontario	Canada
34	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada
35	Toronto Western	Toronto	Ontario	Canada
36	McGill University	Montreal	Quebec	Canada
37	CHU de Québec-Université Laval	Quebec City	Quebec	Canada
38	University of Saskatchewan/ Royal University Hospital	Saskatoon	Saskatchewan	Canada
39	University Central Hospital HUCH	Helsinki		Finland
40	Beaumont Hospital	Dublin	Leinster	Ireland
41	Mater Misericordiae University Hospital Dublin	Dublin	Leinster	Ireland
42	Christchurch Hospital	Christchurch		New Zealand
43	National Neuroscience Institute Tan Tock Seng Hospital	Singapore		Singapore
44	Singapore General Hospital	Singapore		Singapore
45	Complejo Jospitalario Universitario A Coruna	A Coruña		Spain
46	Vall d'Hebron Institut de Recerca (VHIR)	Barcelona		Spain
47	Vall d'Hebron Institut de Recerca	Barcelona		Spain
48	Hospital Universitari Doctor Josep Trueta	Girona		Spain
49	Clinc University Hospital Valladolid	Valladolid		Spain
50	Countess of Chester	London	England	United Kingdom
51	St George's University Hospitals NHS Foundation trust	London	England	United Kingdom
52	Stoke University of North Midlands	London	England	United Kingdom
53	University College London Hospital	London	England	United Kingdom
54	Royal Victoria Hospital	Belfast	Northern Ireland	United Kingdom
55	Queen Elizabeth University Hospital	Glasgow	Scotland	United Kingdom
56	Queen Elizabeth Hospital	Birmingham		United Kingdom
57	Addenbrooke Hospital	Cambridge		United Kingdom
58	Charring Cross Hospital	London		United Kingdom
59	Kings College Hospital	London		United Kingdom
60	Nottingham University Hospital	Nottingham		United Kingdom
61	John Radcliffe Hospital	Oxford		United Kingdom