TEMPO-1 TNK- T PA EVALUATION FOR MINOR ISCHEMIC STROKE WITH PROVEN OCCLUSION
Selecting Patients • The principles of patient selection are based upon the broad criteria of: – TIA or minor stroke presentation with a diagnosis of an ischemic stroke syndrome – Minor initial symptoms that would not normally warrant use of thrombolytic medication in the judgment of the treating neurologist. – Imaging proof of an intracranial occlusion relevant to the presenting symptoms No region of well-defined hypodensity on the NCCT consistent with • the presenting symptoms or consistent with the suspected pathophysiology of the presenting symptoms (ie. fractured embolus to the MCA) that suggests well-evolved infarction, judged to be potentially prone to bleeding.
Selection and Enrolment of Subjects 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. • Minor stroke defined as a baseline NIHSS < 6 at the time of • randomization. Patients must have a demonstrable neurological deficit on physical neurological examination. Any acute intracranial occlusion (MCA, ACA, PCA, VB territories) • defined by non-invasive acute imaging (CT angiography) that is neurologically relevant to the presenting symptoms and signs. An acute occlusion is defined as TICI 0 or TICI 1 flow. 26 Pre-stroke independent functional status in activities of daily living • with pre-stroke estimated modified Barthel Index of 90 or greater AND premorbid mRS 0 or 1. Informed consent from the patient or surrogate. • Patients can be treated within 60 minutes of the CT/CTA being • completed.
Exclusion criteria Hyperdensity on NCCT consistent with any intracranial hemorrhage. • Any clinical suspicion of any intracranial hemorrhage even in the absence of visible blood on baseline brain imaging. Large acute stroke >1/3 MCA territory or ASPECTS<5 visible on • baseline CT scan. Core of established infarction. No area of white matter hypodensity • at a similar or lesser density to grey matter or in the judgment of the enrolling neurologist is consistent with a subacute ischemic stroke > 12 hours of age. Clinical history, past imaging and clinical judgment suggest that the • intracranial occlusion is chronic. Patient is a candidate for and should receive standard of care IV tPA. •
Exclusion criteria Stroke occurring as an in-patient. An in-patient is a person who has • been officially admitted to the hospital to a ward bed. A patient in the ED who has not been formally admitted is still considered to be an outpatient. 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. Patient cannot complete follow-up due to co-morbid non-fatal • illness (such as psychiatric illness) or is visiting the host sites city and cannot return for follow-up. Pregnancy. • Patient is actively taking dual antiplatelet medication (aspirin & • clopidogrel) in the last 48 hours. International normalized ratio ³ 1.4 •
Exclusion criteria Standard thrombolysis exclusions (Taken from Canadian guidelines) Historical • – History of intracranial hemorrhage – Stroke or serious head or spinal trauma in the preceding three months – Recent major surgery in the preceding three months. – Arterial puncture at a non-compressible site in the previous seven days – Any other condition that could increase the risk of hemorrhage after TNK-tPA administration
Exclusion criteria • Clinical – Symptoms suggestive of subarachnoid hemorrhage. – Stroke symptoms due to another non-ischemic acute neurological condition such as seizure with Post-ictal Todd's paralysis or focal neurological signs due to severe hypo- or hyperglycemia. – Hypertension refractory to antihypertensive medication such that target blood pressure <185/110 cannot be achieved before treatment .
Exclusion criteria • Laboratory – Elevated activated partial-thromboplastin time. – Platelet count below 100,000 per cubic millimeter. – Active use of any standard or novel anticoagulant therapy with full anticoagulant dosing. [DVT prophylaxis dosing shall not prohibit enrolment]. Active use means that the patient has taken at least one dose of drug within 5 half-lives of the drug.
Enrolment/Informed Consent • Subjects voluntarily confirm their willingness to participate in the study • Sign informed consent form, after subjects are informed of all aspects of the study relevant to their decision to participate • Consent process is documented by a written, signed and dated informed consent form • Give the subject adequate information • Allow subject to consider all available options • Respond to subject questions • Ensure subject comprehends information
Informed Consent Process (cont.) • Obtain subject’s voluntary consent to participate • If subject is unable to sign, but can indicate verbal/non- verbal approval, consent in the presence of a witness will be obtained • Study allows use of signed informed consent, verbal/nonverbal consent, or consent provided by a Legally Authorized Representative • Signed copy of consent should be provided to the subject, with the original remaining on file at the site • Consent process should be adequately documented in the site’s records • On-going process during the time of subjects’ study participation
Participating Sites: • Calgary • Ottawa • Vancouver • Montreal • Other possible sites to follow
Study Drug Administration An estimated weight will be used to calculate a weight adjusted • dose. There will be 2 dose tiers at 0.1mg/kg and 0.25mg/kg. (25pts/tier) • Advancement to the second dose tier will be dependent upon safe • completion of the 1rst dose tier and approval of the DSMB. Temperature Requirements for Tenecteplase: Store unreconstituted • product at 2-30° C. If not used immediately, reconstituted product in the vial at 2-8 °C and use within 8 hours. TNK-tPA will be stored in the 3T MRI medication cupboard. •
Nurse Coordinators will reconstitute and mix the TNK-tPA. Patients • will be enrolled between 0700-2300. 2 signatures will be required by the RN and Investigator to ensure • proper dosing and minimize any errors. TNK-tPA will be administered as a single intravenous bolus over 1-2 • minutes. Study drug must be given within 60 minutes of the CTA. TNK-tPA will be given in ER by the treating Investigator. •
Prohibited Meds and Procedures: No antiplatelet agent, other antithrombotic medicines should be • given within the first 24 hours (+/- 6h) of the treatment. • Patients should not undergo endovascular thrombectomy or repeat thrombolysis. • If the patient deteriorates, and the treating physician decides to pursue endovascular thrombectomy, this is a Protocol Violation…….expect MANY FORMS!
Schedule of Assessments Day 5 or Baseline 4-8 hour Day 1 Day 2 Day 30 Day 90 D/C Informed consent X History and examination X NIHSS X X X X X X X mRS X X X X Barthel Index X X X X CT head X X CTA COW X X Full Emergency Stroke Labs X Creatinine and CBC X ECG X X Adverse Event X X X X X X Study Drug X
Site Monitoring It is paramount that the trial is performed in accordance with all • regulatory requirements; it is vital that No Protocol Violations occur; No Protocol Waivers will be granted. An external independent monitor will ensure the completeness and • accuracy of information collected. There is a potential for Health Canada to perform an audit. This trial must be treated as a clinical trial, like all other industry • trials. All study material will be stored and archived for 25 years.
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