Post-thrombectomy Intra-arterial Tenecteplase for Acute manaGement of Non-retrievable Thrombus and No-reflow in Emergent Stroke

Study Overview
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Brief Summary
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Multicentre, prospective, Multi-arm Multi-stage (MAMS) seamless phase 2b/3 interventional randomized placebo-controlled double-blinded parallel-assignment (2 arms with 1:1 randomization) efficacy and safety trial to test intra-arterial tenecteplase at the completion of thrombectomy versus best practice in participants with anterior circulation LVO receiving mechanical thrombectomy within 24 hours of symptoms onset.

Official Title
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Post-thrombectomy Intra-arterial Tenecteplase for Acute manaGement of Non-retrievable Thrombus and No-reflow in Emergent Stroke (EXTEND-AGNES TNK)

Conditions
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Ischemic Stroke, Acute, Cerebrovascular Disorders, Brain Disorder, Central Nervous System Diseases

Intervention / Treatment
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* Drug: Intra-arterial tenecteplase injection at the completion of thrombectomy
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult participants (age≥18 years) presenting with ischemic stroke with arterial LVO on CT/MR Angiogram of the intracranial internal carotid or middle cerebral artery (MCA) first segment (M1) or proximal second segment (M2) committed to thrombectomy using standard criteria within 24 hours of onset: For 0-6 hours of symptom onset: Presence of arterial occlusion as defined above and ASPECTS≥3 on NCCT For 6-24 hours of symptom onset: Additional imaging criteria on CTP or MRI perfusion of core volume <100ml. Qualifying CT/MR within 4hrs of randomisation (repeat CT for transferred participants required if >4hr) Pre-stroke Modified Rankin Scale (mRS) score of ≤2 (mild pre-existing disability permitted) Local legal requirements for consent have been satisfied. Exclusion Criteria: Intracranial hemorrhage identified by CT or MRI ASPECTS 0-2 on NCCT CTP or MRI perfusion ischemic core volume >100ml if presenting within 6-24 hours from symptoms onset Anticipated endovascular stenting required for intracranial or extracranial atherosclerotic stenosis/occlusion. More than six retrieval attempts in the same vessel Alteplase being infused within 30 minutes ( 5x half-life) of anticipated trial drug administration Contraindication to imaging with contrast agents Any condition (eg.mid-arterial phase early venous filling) that in the judgment of investigators could impose hazards if study therapy is initiated Pregnant women. Current participation in another intervention research study that includes experimental interventions beyond standard-of-care. Anticoagulation. INR ≤1.7 if on warfarin, and dabigatran reversal by idarucizumab are permitted. Other standard contraindications to thrombolysis apart from time window. Known terminal illness such that the participants would not be expected to survive a year. Planned withdrawal of care or comfort care measures.

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 |
| --- | --- |
| Placebo Comparator: Placebo<br>Intra-arterial bolus of placebo (0.9% Sodium Chloride solution) representing standard of care (no intra-arterial thrombolytic treatment). | Drug: Placebo<br>* intra-arterial bolus of 0.9% Sodium Chloride solution<br>|
| Experimental: Intra-arterial tenecteplase injection at the completion of thrombectomy<br>intra-arterial tenecteplase (0.062mg/kg, maximum 6.25mg) administered as a bolus at the completion of thrombectomy through a microcatheter at the site of the initial-but-now-retrieved intracranial occlusion or in direct contact with the residual thrombus | Drug: Intra-arterial tenecteplase injection at the completion of thrombectomy<br>* Intra-arterial tenecteplase (0.062mg/kg, maximum 6.25mg) administered as a bolus at the completion of thrombectomy through a microcatheter at the site of the initial-but-now-retrieved intracranial occlusion, or in direct contact with the residual thrombus<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early Neurological Improvement (Phase 2b) | Proportion of participants with Early Neurological Improvement (ENI) defined as NIHSS reduction>4 | 24-36 hours from time of randomisation | 
| Functional independence (Phase 3) | Proportion of participants with Modified Rankin Scale (mRS) 0-2 (functional independence) | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional improvement | Reduction of ≥ 1 mRS category (ordinal analysis merging mRS categories 5-6) | 3 months | 
| Infarct growth | Infarct growth volume on follow-up MRI or CT | 24 hours | 
| No-reflow | Proportion of participants with radiological no-reflow on MR perfusion or CTP | 24 hours | 
| Symptomatic Intracerebral Hemorrhage | Proportion of participants with sICH defined as parenchymal haematoma type 2 (PH2) or SAH/IVH within 36 hours combined with neurological deterioration leading to an increase of NIHSS ≥4 from baseline or leading to death | 36 hours | 
| All cause mortality | Proportion of participants with death due to any cause | 3 months | 
| Quality of life assessment on EQ-5D | EQ-5D score | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tenecteplase, Fibrinolytic agents, Thrombectomy, No-reflow