Endovascular Thrombectomy With and Without Intravenous Thrombolysis in Extended Time Window

Phase 3

Recruiting

• Conditions: Stroke, Acute Ischemic
• Interventions: Drug: Intravenous thrombolysis agents; Procedure: endovascular thrombectomy

• Registration Number: NCT05634382
• Lead Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University

Brief Summary

The primary hypothesis being tested in this trial is that ischemic stroke patients in large vessel occlusion of anterior circulation at 4.5 - 9 hours post onset of stroke will have improved clinical outcomes when given endovascular thrombectomy with intravenous thrombolysis compared with that of given direct endovascular thrombectomy alone.

Detailed Description

A number of multicenter randomized controlled trials have provided evidence supporting the application of endovascular therapy for acute ischemic stroke with anterior circulation large vessel occlusion. However, whether intravenous thrombolysis is necessary before endovascular therapy is still controversial. The combined trial data (including DEVT, DIRECT-MT, MR-CLEAN NO-IV and SKIP) assessing direct mechanical thrombectomy versus bridging therapy showed no difference in improving good functional outcome. However, a recent observational cohort study of 15832 patients treated with EVT, intravenous alteplase treatment was associated with better in-hospital survival and functional outcomes after adjusting for other covariates.

The 2019 AHA/ASA guidelines for the early management of patients with ischemic stroke states that mechanical thrombectomy is recommended for patients with anterior circulation large vessel occlusion within 6-24 hours of last known normal who meet the DWAN or DEFUSE-3 criteria (level I recommendation, level A evidence). The DEFUSE 3 perfusion-infarction core mismatch criteria is: core infarct volume \<70mL, ischemic penumbra volume \>15mL, and hypoperfusion volume/core infarct volume \>1.8. Intravenous thrombolytic therapy is recommended for patients with ischemic stroke within 4.5 hours of onset. A meta-analysis of three randomized controlled trials recently published in the Lancet found that ischemic stroke at 4.5 to 9 hours of onset or wake stroke was consistent with a core infarct volume \<70mL, a penumbra volume \>10mL, and a hypoperfusion volume/core infarct volume \>1.2. Benefit from intravenous thrombolytic therapy (3 month mRS 0-1 ratio, thrombolytic vs non-thrombolytic: 36% vs 29%). It was also strongly recommended by 2021 ESO guidelines on intravenous thrombolysis for acute ischemic stroke.

For these reasons the investigators hypothesize that endovacular thrombectomy bridging with intravenous thrombolysis is superior to direct thrombectomy in patients of stroke at 4.5 to 9 hours, guided with perfusion imaging.

Study Timeline

• Study First Submitted: 2022-11-21
• Study First Submitted QC: 2022-11-21
• Study First Posted: 2022-12-02
• Study Start: 2022-12-03
• Status Verified: 2023-02
• Last Update Submitted: 2023-02-10
• Last Update Posted: 2023-02-14
• Primary Completion: 2024-11-28
• Study Completion: 2025-02-28

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 222

Inclusion Criteria

1. Patient/Legally Authorized Representative has signed the Informed Consent form
2. Age ≥ 18
3. Clinical signs consistent with an acute ischemic stroke
4. Neurological deficit with a NIHSS of ≥ 6 (deficits judged to be clearly disabling at presentation)
5. Patient is eligible for intravenous thrombolysis
6. Patient is eligible for endovascular treatment
7. Randomization no later than 8 hours 45 minutes after stroke symptom onset and initiation of IV t-PA must be started within 9 hours of stroke symptoms onset (for stroke with unknown time of onset, the midpoint of the time last known to be well and symptom recognition time)
8. ICA or MCA-M1 occlusion (carotid occlusions can be cervical or intracranial; with or without tandem MCA lesions) by MRA or CTA (including the reconstructed CTA derived from CTP). And target Mismatch Profile on CT perfusion or MRI (ischemic core volume is < 70 ml, mismatch ratio is >/= 1.8 and mismatch volume is >/= 15 ml)
9. Core-infarct volume of Alberta Stroke Program Early CT Score (ASPECTS) ≥ 6 based on baseline CT or MR imaging (MRI) (a region has to have diffusion abnormality in 20% or more of its volume to be considered MR-ASPECTS positive)

Exclusion Criteria

1. Acute intracranial hemorrhage
2. Any contraindication for IV t-PA
3. Pre-treatment with IV t-PA
4. Pregnancy or lactating women. A negative pregnancy test before randomization is required for all women with child-bearing potential.
5. Known (serious) sensitivity to radiographic contrast agents, nickel, titanium metals, or their alloys
6. Known current participation in a clinical trial (investigational drug or medical device)
7. Renal insufficiency as defined by a serum creatinine > 2.0 mg/dl (or 176.8 µmol/l) or glomerular filtration rate (GFR) < 30 mL/min or requirement for hemodialysis or peritoneal dialysis
8. Severe comorbid condition with life expectancy less than 90 days at baseline
9. Known advanced dementia or significant pre-stroke disability (mRS score of ≥2)
10. Foreseeable difficulties in follow-up due to geographic reasons (e.g. patients living abroad)
11. Comorbid disease or condition that would confound the neurological and functional evaluations or compromise survival or ability to complete follow-up assessments
12. Subject currently uses or has a recent history of illicit drug(s) or abuses alcohol (defined as regular or daily consumption of more than four alcoholic drinks per day).
13. Known history of arterial tortuosity, pre-existing stent, other arterial disease and/or known disease at the femoral access site that would prevent the device from reaching the target vessel and/or preclude safe recovery after MT
14. Radiological confirmed evidence of mass effect or intracranial tumor (except small meningioma)
15. Radiological confirmed evidence of cerebral vasculitis
16. CTA or MRA evidence of carotid artery dissection
17. Evidence of additional distal intracranial vessel occlusion in another territory (i.e. A2 segment of anterior cerebral artery or M3, M4 segment of MCA) on initial NCCT/MRI or CTA/MRA

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Intravenous thrombolysis bridging with endovascular thrombectomy	Intravenous thrombolysis agents	-
Intravenous thrombolysis bridging with endovascular thrombectomy	endovascular thrombectomy	-
Direct endovascular thrombectomy without intravenous thrombolysis	endovascular thrombectomy	-

Primary Outcome Measures

Name	Time	Method
Good clinical outcome	90 days after randomization	Score in modified Rankin Scale (mRS) ≤ 2 (mRS is short for modified ranking score, with minimum value of 0 and maximum value of 6. Higher score means a worse outcome.)

Secondary Outcome Measures

Name	Time	Method
Overall costs incurred during hospitalisation	90 days after randomization	include charges and expenses of every description
Serious adverse events	day 0 until 90 days after randomization	Leading to death or prolonged hospitalisation
Intracranial hemorrhage	day 1 after randomization	Hemorrhagic finding on CT or MRI
Mortality	90 days after randomization	Mortality due to any cause
Thrombolysis in Cerebral Infarction (TICI) scale	day 0 and day 1 after randomization	TICI is for "Thrombolysis in cerebral Infarction", with minimum value of 0 and maximum value of 3. Higher score means a better reperfusion state.
Quality of life assessed by questionnaire	90 days after randomization	Include but not limited to the Barthelindex of ADL, which is the abbreviation of " activities of daily living", with minimum value of 0 and maximum value of 100. Higher score means a worse outcome.
Modified Rankin Scale (mRS) shift analysis	day 0 and 90 days after randomization	(mRS is short for National Institute of health stroke scale, with minimum value of 0 and maximum value of 6. Higher score means a worse outcome.)
National Institute of Health Score Scale (NIHSS)	day 0 and day 1 after randomization	(NIHSS is short for modified ranking score, with minimum value of 0 and maximum value of 42. Higher score means a worse outcome.)

Trial Locations

Locations (1)

The Second Affiliated Hospital of Zhejiang University; 🇨🇳 Hangzhou, Zhejiang, China