E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
To demonstrate the efficacy of using TNK-tPA (tenecteplase), a thrombolytic agent that is relatively novel to the treatment ischemic stroke but well-established in the treatment of myocardial infarction, to treat minor ischemic stroke patients with proven acute symptomatic occlusions or perfusion abnormalities.
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E.1.1.1 | Medical condition in easily understood language |
To demonstrate the efficacy of using TNK-tPA to treat minor ischemic stroke with proven arterial occlusion.
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective: to demonstrate the efficacy of using TNK-tPA to treat minor ischemic stroke with proven arterial occlusion.
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. Transient Ischemic Attack or minor stroke defined as a baseline National Institutes of Health Stroke Scale (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 (Thrombolysis in cerebral ischemia (TICI) 0 or 1) (Middle Cerebal Artery, Anterior Cerebral Artery, Posterior Cerebral Artery, Vertebrobasilar territories) defined by non-invasive acute imaging Computed Tomography Angiography (CTA) or Magnetic Resonance angiography (MRA) ) that is neurologically relevant to the presenting symptoms and signs. Multiphase Computed Tomographic Angiography (CTA) or Computed Tomography (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 (Time To Peak (TTP), Mean Transit Time (MTT) or Time to Peak of the impulse response (T Max) ), in a region of brain concordant with clinical symptoms and signs. 5. Pre-stroke independent functional status-structured Modified Rankin Scale 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.
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E.4 | Principal 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. 4. 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. 5. Pregnancy. 6. Planned thrombolysis with intravenous tPA or endovascular acute treatment. 7. In-hospital stroke unless these patients are at their baseline prior to the stroke. 8. Commonly accepted exclusions for medical thrombolytic treatment that potentially put the patient at an increased risk of bleeding. Country specific product monographs and stroke thrombolysis guidelines should be consulted. 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: a. Significant bleeding disorder either at present or within the past 6 months b. 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. c. 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] d. Prolonged cardiopulmonary resuscitation (> 2 minutes) within the past 2 weeks e. Acute pericarditis and/or subacute bacterial endocarditis f. Acute pancreatitis g. Severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis h. Neoplasm with increased bleeding risk i. Arterial aneurysm and known arterial/venous malformation j. Patients who have been acutely treated with GP2b3a inhibitors. k. Arterial puncture at a non-compressible site in the previous seven days l. Clinical stroke or serious head or spinal trauma in the preceding three months that would normally preclude use of a thrombolytic agent. m. History of intracranial hemorrhage, subarachnoid hemorrhage or other brain hemorrhage that would normally preclude use of a thrombolytic agent. n. Major surgery within the last 3 months that the treating physician considers a contraindication to thrombolytic therapy. o. Severe hypo- (< 50 mg/dL or 2.8mmol/l )or hyperglycemia (>400 or 22.2mmol/l) p. Hypertension refractory to anti-hypertensive medication such that target blood pressure <185/110 cannot be achieved before treatment. q. 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] r. Gastrointestinal or genitourinary bleeding within the past 3 months that would normally preclude use of a thrombolytic agent. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary outcome: Return to baseline neurological functioning as measured by the 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.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At day 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.
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E.5.2 | Secondary end point(s) |
Secondary outcomes: Safety, recanalization, ordinal shift analysis of mRS, NIHSS 0 at day 5 (or discharge), Euroqol, everyday activities sub-question on Euroqol, Lawton Instrumental Activities of Daily Living Scale (IADL), all cause mortality, recurrent stroke or progression, mRS 0-1 at 90days, mRS 0-2 at 90 days, mean mRS using linear regression, composite of recanalization or mRS 0-1 at 90days and mortality.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Assessments at Day 1, Day 5 or discharge and Day 90 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Prospective Randomised Open Label Blinded Endpoint Assessment |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Canada |
Ireland |
New Zealand |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |