DIRECT-SAFE: A Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval Versus Standard Bridging Thrombolysis With Endovascular Clot Retrieval

Study Overview
=================
Brief Summary
-----------------
The study will be a multicentre, prospective, randomized, open label, blinded endpoint (PROBE) phase 3 trial (2 arm with 1:1 randomization) in ischemic stroke patients within 4.5 hours of stroke onset. Randomised patients will be stratified for site of baseline arterial occlusion into one of three groups: 1. internal carotid artery (ICA) 2. middle cerebral artery (MCA) 3. basilar artery (BA). Patients will be randomised to either bridging intravenous thrombolysis with endovascular clot retrieval (ECR), or direct endovascular clot retrieval.

Detailed Description
-----------------
The DIRECT-SAFE trial will include patients with acute ischemic stroke, who are ≥18 years of age and are eligible for standard intravenous tPA therapy within 4.5 hours of stroke onset. Patients will be assessed for large vessel occlusion to determine their eligibility for randomization into the trial. Eligible vessel occlusions include the internal carotid artery, basilar artery or middle cerebral artery (M1 or M2). Patients will be consented after large vessel occlusion is confirmed based on standard care multimodal imaging. Patients will be recruited in Australia, New Zealand, China, Taiwan, Vietnam, Singapore and Europe. Randomisation either direct to ECR or standard thrombolytic therapy and ECR shall be in a 1:1 ratio. All patients will have a multimodal MR (or CT/CTP at investigator's discretion if MRI not possible) at 18 to 30 hours post treatment to assess reperfusion, recanalization, ischemic core growth and hemorrhagic transformation. Final follow up will occur at Day 90.

Official Title
-----------------
DIRECT-SAFE: A Randomized Controlled Trial of DIRECT Endovascular Clot Retrieval Versus Standard Bridging Thrombolysis With Endovascular Clot Retrieval Within 4.5 Hours of Stroke Onset

Conditions
-----------------
Ischemic Stroke

Intervention / Treatment
-----------------
* Other: Direct endovascular clot retrieval
* Other: Bridging thrombolysis followed by ECR


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients presenting with acute ischemic stroke eligible using standard criteria to receive IV thrombolysis within 4.5 hours of stroke onset Patient's age is ≥18 years Intra-arterial clot retrieval treatment can commence (groin puncture) within 6 hours of stroke onset. Arterial occlusion on CTA or MRA of the ICA, M1, M2 or basilar artery Exclusion Criteria: Intracranial hemorrhage (ICH) identified by CT or MRI Rapidly improving symptoms at the discretion of the investigator Pre-stroke mRS score of ≥ 4 (indicating previous disability) Hypodensity in >1/3 MCA territory on non-contrast CT Contra indication to imaging with contrast agents Any terminal illness such that patient would not be expected to survive more than 1 year Any condition that, in the judgment of the investigator could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study. Pregnant women

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomised to either direct endovascular clot retrieval or to bridging intravenous thrombolysis with endovascular clot retrieval.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Direct endovascular clot retrieval<br>Endovascular clot retrieval (ECR) within 4.5 hours stroke | Other: Direct endovascular clot retrieval<br>* Direct endovascular clot retrieval within 4.5 hours of stroke onset<br>|
| Other: Bridging thrombolysis followed by ECR<br>Intravenous tPA (at the standard licensed dose of 0.9 mg/kg up to a maximum of 90mg, 10% as bolus and the remainder over 1 hour) followed by ECR | Other: Bridging thrombolysis followed by ECR<br>* Bridging thrombolysis followed by ECR within 4.5 hours of stroke onset<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Rankin Scale (mRS)- ordinal analysis | Modified Rankin Scale (mRS) 0-2 or no change from baseline | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| modified Rankin Scale (mRS)- ordinal analysis | mRS 0-1 or no change from baseline | 3 months | 
| Death | Death due to any cause | 3 months | 
| Angiographic reperfusion | Proportion of patients with good angiographic reperfusion (mTICI 2b-3) | Baseline | 
| Symptomatic intracranial haemorrhage (sICH) | Proportion of patients with sICH | 24 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Stroke, Ischemia, Cerebral Infarction, Cerebrovascular Disorders, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Vascular Diseases, Cardiovascular Diseases, Pathologic Processes, Brain Infarction, Brain Ischemia, Tissue Plasminogen Activator, Plasminogen, Fibrinolytic Agents, Fibrin Modulating Agents, Molecular Mechanisms of Pharmacological Action