Tenecteplase in Stroke Patients Between 4.5 and 24 Hours

Study Overview
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Brief Summary
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This study will evaluate the efficacy and safety of tenecteplase compared with placebo in participants with acute ischemic stroke (AIS). All participants will receive standard-of-care therapy according to AmericanHeart Association/American Stroke Association clinical guidelines (2018). To determine eligibility for randomization, all participants will undergo multimodal CT or MRI at baseline. Only participants with a vessel occlusion (ICA or MCA M1/M2) and penumbral tissue will be randomized. The primary analysis is to compare the efficacy of tenecteplase versus placebo in all participants at Day 90.

Official Title
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A Phase III, Prospective, Double-blind, Randomized, Placebo-controlled Trial of Thrombolysis in Imaging-eligible, Late-window Patients to Assess the Efficacy and Safety of Tenecteplase (TIMELESS)

Conditions
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THROMBOLYSIS

Intervention / Treatment
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* Biological: Tenecteplase
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient/legally authorized representative has signed the Informed Consent Form Age >= 18 years AIS symptom onset within 4.5 to 24 hours Signs and symptoms consistent with the diagnosis of an acute anterior circulation ischemic stroke involving occlusion of the ICA, M1, or M2 vessels Functionally independent (mRS 0-2) prior to stroke onset Baseline NIHSS >=5 and that remains >=5 immediately prior to randomization Neuroimaging: ICA or M1, M2 occlusion (carotid occlusions can be cervical or intracranial, with or without tandem MCA lesions) by magnetic resonance angiography (MRA) or computed tomography angiography (CTA) AND target mismatch profile on CT perfusion or MR perfusion (ischemic core volume <70 mL, mismatch ratio is >=1.8 and mismatch volume is >= 15 mL) The mismatch volume is determined by FDA-approved imaging software in real time based on the difference between the ischemic core lesion volume and the Tmax>6s lesion volume. If both a CT perfusion and a multimodal MRI scan are performed prior to enrollment, the later of the 2 scans is assessed to determine eligibility. Only an intracranial MRA is required for patients screened with MRA; cervical MRA is not required. Cervical and intracranial CTA are typically obtained simultaneously in patients screened with CTA, but only the intracranial CTA is required for enrollment. Alternative neuroimaging: If CTA (or MRA) is technically inadequate: Tmax>6s perfusion deficit consistent with an ICA or M1, M2 occlusion AND target mismatch profile (ischemic core volume <70 mL, mismatch ratio >= 1.8 and mismatch volume >= 15 mL as determined by RAPID software) If magnetic resonance perfusion (MRP) is technically inadequate: ICA or M1, M2 occlusion (carotid occlusions can be cervical or intracranial; with or without tandem MCA lesions) by MRA (or CTA, if MRA is technically inadequate and a CTA was performed within 60 minutes prior to the MRI) AND diffusion-weighted imaging (DWI) lesion volume <=25 mL for an M1 or ICA occlusion and =<15 mL for an M2 occlusion If CTP is technically inadequate: patient can be screened with MRI and randomized if neuroimaging criteria are met. Ability to comply with the study protocol, in the investigator's judgment Exclusion Criteria: General Current participation in another investigational drug or device study Active internal bleeding Known hypersensitivity or allergy to any ingredients of tenecteplase Known bleeding diathesis Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; recent oral anticoagulant therapy with INR >1.7 Use of one of the new oral anticoagulants within the last 48 hours (dabigatran, rivaroxaban, apixaban, edoxaban) Pregnant Intracranial neoplasm (except small meningioma), arteriovenous malformation, or aneurysm Seizures at stroke onset if it precludes obtaining an accurate baseline NIHSS Severe, uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure > 110 mmHg) For participants with suspected coagulopathy, platelet count must be checked prior to randomization and participant is excluded if baseline platelet count <100,000/microL Baseline blood glucose >400 mg/dL (22.20 mmol/L) Baseline blood glucose <50 mg/dL needs to be normalized prior to randomization Clot retrieval attempted using a neurothrombectomy device prior to randomization Intracranial or intraspinal surgery or trauma within 2 months Treatment with a thrombolytic within the last 3 months prior to randomization Other serious, advanced, or terminal illness (investigator judgment) with life expectancy less than 6 months Pre-existing medical, neurological, or psychiatric disease that would confound the neurological or functional evaluations History of cerebrovascular accident in the last 90 days Presumed septic embolus; suspicion of bacterial endocarditis Any other condition that, in the opinion of the investigator, precludes an endovascular procedure or poses a significant hazard to the patient if an endovascular procedure was to be performed Imaging Unable to undergo a contrast brain perfusion scan with either MRI or CT Extensive early ischemic change (hypodensity) on non-contrast CT estimated to be >1/3 MCA territory, or significant hypodensity outside the Tmax>6s perfusion lesion that invalidates mismatch criteria (if patient is enrolled based on CT perfusion criteria) Significant mass effect Acute symptomatic arterial occlusions in more than one vascular territory confirmed on CTA/MRA (e.g., bilateral MCA occlusions, or an MCA and a basilar artery occlusion) Evidence of intracranial tumor (except small meningioma) acute intracranial hemorrhage, neoplasm, or arteriovenous malformation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tenecteplase<br>Patients in this arm will receive Tenecteplase (0.25 mg/kg, maximum 25 mg) administered as a single bolus injection over 5 seconds. | Biological: Tenecteplase<br>* The investigational medicinal product (IMP) for this study is tenecteplase. The recommended total dose for this study is weight-based with 0.25 mg of tenecteplase per kg, not exceeding a maximum dose of 25 mg. A single bolus dose should be administered over 5 seconds based on patient weight.<br>|
| Placebo Comparator: Placebo<br>Patients in this arm will receive placebo administered as a single bolus injection over 5 seconds. | Other: Placebo<br>* Placebo is being used as the comparator since a thrombolytic is only FDA-approved in the United States for use out to 3 hours, and the standard of care guidelines support use out to 4.5 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ordinal modified Rankin scale (mRS) score | The Efficacy of Tenecteplase compared to placebo is evaluated in terms of Ordinal mRS score at day 90. | Day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with functional independence | The efficacy of Tenecteplase is evaluated in terms of proportion of patients with functional independence, defined as an mRS of 0-2, at Day 90 | Day 90 | 
| Proportion of patients with angiographic reperfusion | The efficacy of Tenecteplase is evaluated in terms of proportion of patients with angiographic reperfusion at completion of angiographic procedure (endovascular patients only). | Day 1 | 
| Median NIHSS score | The efficacy of Tenecteplase is evaluted in terms of Median NIHSS score at Day 90. | Day 90 | 
| Proportion of patients with a Barthel Index (BI) score >=95 | The efficacy of Tenecteplase is evaluated in terms of Proportion of patients with a BI score >=95 at Day 90. | Day 90 | 
| Proportion of patients with good recovery based on the Glasgow Outcome Scale (GOS) at Day 90 | The efficacy of Tenecteplase is evaluated in terms of the proportion of patients with good recovery based on the GOS at Day 90. | Day 90 | 
| Proportion of patients with reperfusion at 24 hours post-randomization | The efficacy of Tenecteplase is evaluated in terms of proportion of patients with reperfusion at 24 hours post-randomization, defined as >90% reduction in Tmax>6s lesion volume | Day 2 | 
| Proportion of patients with recanalization at 24 hours post-randomization | The efficacy of Tenecteplase is evaluated in terms of proportion of patients with recanalization at 24 hours post-randomization, defined as complete or partial recanalization on CT angiography (CTA)/magnetic resonance angiography (MRA). | Day 2 | 
| Number of patients with symptomatic intracranial hemorrhage (sICH a) | The safety profile of Tenecteplase is evaluated in terms of number of patients with sICH within 36 hours | Day 2 | 
| Incidence and severity of adverse events | The safety profile of Tenecteplase is evaluated in terms of incidence and severity of adverse events. | From baseline up to day 90 | 
| Mortality rate up to Day 30 and Day 90 | The safety profile of Tenecteplase is evaluated in terms of mortality rate up to Day 30 and Day 90 | Day 30 and Day 90 | 
| Proportion of patients with parenchymal hematoma type 2 (PH2) at the 72-96 hour visit | The safety profile of Tenecteplase is evaluated in terms of proportion of patients with PH2 at the 72-96 hour visit | Day 3 |