Randomization to Endovascular Treatment Alone or Preceded by Systemic Thrombolysis With Tenecteplase in Ischemic Stroke

Study Overview
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Brief Summary
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A phase III randomized, multi-center, double-blinded, placebo-controlled clinical trial that will examine two strategies for the treatment of acute ischemic stroke associated with a large vessel anterior occlusion within 4.5 hours from symptoms onset: direct endovascular treatment vs. endovascular treatment preceded by intravenous tenecteplase.

Detailed Description
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Randomized, prospective, multicenter, double-blinded, placebo-controlled clinical trial. Randomization will be 1:1 according to reperfusion treatment modalities: (A) (with placebo TNK) direct mechanical thrombectomy vs. (B) Intravenous thrombolysis with TNK (0.25 mg/kg) plus mechanical thrombectomy. Randomization will be done by a minimization process using age, National Institute of Health Stroke Scale (NIHSS) score, and site of the occluded artery. For the primary outcome, the subjects will be followed up within 90 days after randomization. The primary outcome will be the ordinal distribution from the modified Rankin scale score (mRS).

Official Title
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Randomization to EndoVascular Treatment Alone or Preceded by Systemic Thrombolysis With Tenecteplase in Acute Ischemic Stroke Due to Large Intracranial VEssel OcclusioN Trial - DIRECT Thrombectomy vs. Intravenous TNK Plus Thrombectomy

Conditions
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Stroke, Ischemic, Stroke, Acute

Intervention / Treatment
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* Drug: Tenecteplase
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute ischemic stroke where a patient is eligible for IV thrombolytic treatment within 4.5 hours of stroke onset. No significant pre-stroke functional disability (mRS ≤ 1) Baseline NIHSS scores obtained before randomization must be equal to or higher than 6 points Age equal ≥ 18 and =< 85 years Occlusion (TICI 0-1) of the proximal MCA segments (M1 or M2) suitable for endovascular treatment, as evidenced by CTA, MRA, or angiogram, with or without concomitant cervical carotid stenosis. Patient randomized within 4.5 hours of symptom onset. Symptoms onset is defined as the point in time the patient was last seen well (at baseline). Treatment start is defined as groin puncture, max 90 minutes after randomization. Informed consent obtained from the patient or acceptable patient surrogate. Exclusion Criteria: Known hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR > 1.7 or direct oral anticoagulants such as thrombin antagonists (ex: dabigatran) or X factor (ex: rivaroxaban, apixaban, edoxaban) at the least 48 hours. Baseline platelet count < 100.000/μL Baseline blood glucose of < 50mg/dL or > 400mg/dl Severe, sustained hypertension (SBP > 185 mm Hg or DBP > 110 mm Hg) NOTE: If the blood pressure can be successfully reduced and maintained at the acceptable level using AHA guidelines recommended medication (including iv antihypertensive drips), the patient can be enrolled. Patients in coma (NIHSS item of consciousness >1) (Intubated patients for transfer could be randomized only in case an NIHSS is obtained by a neurologist prior transportation). Seizures at stroke onset which would preclude obtaining a baseline NIHSS Serious, advanced, or terminal illness with anticipated life expectancy of less than one year. History of life-threatening allergy (more than rash) to contrast medium. Subjects who has received IV t-PA treatment before the randomization. Renal failure with serum creatinine ≥ 3 mg/dl Woman of childbearing potential who is known to be pregnant or who has a positive pregnancy test on admission. Subject participating in a study involving an investigational drug or device that would impact this study. Cerebral vasculitis, endocarditis or subarachnoid hemorrhage. Patients with a pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations. Unlikely to be available for 90-day follow-up (e.g. no fixed home address, visitor from overseas). Hypodensity on CT more than one third of MCA territory or hypersignal in more than one third of MCA territory on MR-DWI. ASPECTS score < 6 (no contrast at least 5 mm cut imaging on CT) or on MR-DWI sequence. CT or MR evidence of hemorrhage (the presence of < 5 GRE, SWI, SWAN microbleeds is allowed). Significant mass effect with midline shift. Evidence of ipsilateral carotid occlusion, high grade stenosis or arterial dissection in the extracranial or petrous segment of the internal carotid artery that cannot be treated or will prevent access to the intracranial clot or excessive tortuosity of cervical vessels precluding device delivery/deployment. Subjects with occlusions in multiple vascular territories (e.g., bilateral anterior circulation, or anterior/posterior circulation). Evidence of intracranial tumor (except small meningioma).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Mechanical Thrombectomy preceded by TNK<br>Subjects assigned to this arm will receive an intravenous bolus of tenecteplase (0.25mg/kg) before the mechanical thrombectomy. | Drug: Tenecteplase<br>* Intravenous thrombolysis with tenecteplase 0.25mg/kg<br>* Other names: TNK;|
| Placebo Comparator: Mechanical Thrombectomy preceded by Placebo<br>Subjects assigned to this arm will receive an intravenous bolus of matching placebo (with the same volume of infusion as of 0.25mg/kg of tenecteplase) before the mechanical thrombectomy. | Drug: Placebo<br>* Intravenous administration of placebo, matching the volume of tenecteplase 0.25mg/kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distribution of the modified Rankin Scale scores at 90 days | Distribution of the modified Rankin Scale scores (shift analysis). | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional independence defined as modified Rankin Score ≤ 2 | Functional independence defined as modified Rankin Score ≤ 2 | 90 days | 
| Infarct volume evaluated on CT at 24 hours (-2/+12 hours). | Infarct volume evaluated on CT at 24 hours (-2/+12 hours). | 24 hours | 
| Dramatic early favorable response as determined by a National Institute of Health Stroke Scale (NIHSS) of 0-2 or NIHSS improvement ≥ 10 points at 24 (-2/+12 hours) hours. | Dramatic early favorable response as determined by a National Institute of Health Stroke Scale of 0-2 or NIHSS improvement ≥ 10 points at 24 (-2/+12 hours) hours. | 24 hours | 
| Cost-effectiveness analysis of endovascular therapy alone vs. endovascular therapy associated with tenecteplase | Cost-effectiveness analysis of endovascular therapy alone vs. endovascular therapy associated with tenecteplase | 12 months | 
| Quality of life analysis as measured by EuroQol/EQ5D at 3 month, 6 months and one year among the groups | Quality of life analysis as measured by EuroQol/EQ5D at 3 month, 6 months and one year among the groups | 3 months, 6 months and 12 months | 
| Score distribution of mRS at 90 days (shift analysis) in patients presenting M2-CMA occlusion | Score distribution of mRS at 90 days (shift analysis) in patients presenting M2-CMA occlusion | 90 days | 
| Vessel recanalization evaluated by CT angiography or MRA at 24 hours in both treatment groups | Vessel recanalization evaluated by CT angiography or MRA at 24 hours in both treatment groups | 24 hours | 
| Vessel recanalization post procedure in the endovascular arm assessed by TIMI grades and adjudicated by a central core-lab. Successful recanalization is defined as TICI (Thrombolysis in Cerebral Infarction) 2b or 3 on the post-procedure angiogram. | Vessel recanalization post procedure in the endovascular arm assessed by TIMI grades and adjudicated by a central core-lab. Successful recanalization is defined as TICI (Thrombolysis in Cerebral Infarction) 2b or 3 on the post-procedure angiogram. | Immediately Post-procedure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tenecteplase, TNK, MT, Mechanical Thrombectomy