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

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ClinicalTrials.gov Identifier: NCT02398656
Recruitment Status : Recruiting
First Posted : March 25, 2015
Last Update Posted : April 17, 2019
Sponsor:
Information provided by (Responsible Party):
Dr. Michael Hill, University of Calgary

Tracking Information
First Submitted Date  ICMJE March 20, 2015
First Posted Date  ICMJE March 25, 2015
Last Update Posted Date April 17, 2019
Study Start Date  ICMJE April 2015
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 24, 2015)
Modified Rankin Scale (mRS) [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 24, 2015)
Major Bleeding [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: March 24, 2015)
  • Complete or partial recanalization [ Time Frame: 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) [ Time Frame: 90 Days ]
    This scale will be used at the Day 90 follow-up visit.
  • Quality of life measured on EuroQol38 [ Time Frame: 90 Days ]
    This scale will be used at the Day 90 follow-up visit.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE A Randomized Controlled Trial of TNK-tPA Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Stroke, Acute
Intervention  ICMJE
  • Drug: Tenecteplase
    TNK will be administered as a single intravenous bolus over 1-2 minutes within 90 minutes of the CT scan.
    Other Name: TNK-tPA
  • 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 Name: ASA, Clopidogrel
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Tenecteplase
  • 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.
    Intervention: Drug: Antiplatelet treatment
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 24, 2015)
1274
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2023
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Shelagh B Coutts, MD 403-944-1581 scoutts@ucalgary.ca
Contact: Carol C Kenney, RN, CCRP 403-944-4286 tempo2@ucalgary.ca
Listed Location Countries  ICMJE Australia,   Austria,   Canada,   Ireland,   Singapore,   Spain,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02398656
Other Study ID Numbers  ICMJE Version 3.3 , Mar 24,2017
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Overall data will be shared once the trial has been closed and data analysed. No individual participant data will be available.
Responsible Party Dr. Michael Hill, University of Calgary
Study Sponsor  ICMJE University of Calgary
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Michael D Hill, MD University of Calgary
PRS Account University of Calgary
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP