Study Synopsis

Protocol Title

Endovascular Acute Stroke Intervention – Tandem OCclusion trial (EASI-TOC): a trial of acute cervical internal carotid artery stenting during endovascular thrombectomy for anterior circulation stroke (NCT04261478)

Clinical Trial Phase

Phase III study

Planned Study Duration

6 years

Clinical Sites

12-14 high-volume comprehensive stroke centres in Canada  

Coordinating Site

Centre Hospitalier de l’Université de Montréal (CHUM)

Center for the Integration and Analysis of Medical Data (CITADEL) 

Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM)

Objectives

The primary objective:

To determine if, in patients undergoing intracranial thrombectomy for anterior circulation stroke with concurrent ipsilateral symptomatic high-grade (>70%) atherosclerotic stenosis or occlusion of the cervical ICA (tandem lesion), acute cervical ICA stenting in addition to intracranial thrombectomy is superior to intracranial thrombectomy alone without acute cervical ICA stenting with regards to functional outcome at 90 days.

Experimental Design

A multi-centre, prospective, randomized, open-label, blinded endpoint (PROBE) controlled trial (1:1 allocation).

Population

458 male and female adult (aged ≥ 18 years) patients.

Inclusion criteria:

• Acute ischemic anterior circulation stroke eligible for endovascular therapy according to local guidelines, with or without prior intravenous thrombolysis:

  • Occlusion of the carotid terminus, M1 or M2 segments of the middle cerebral artery (MCA)

  • A neurological deficit judged to be disabling by the patient and/or treating physician

  • Any acute imaging judged by the treating physician to demonstrate salvageable brain tissue possibly amenable to EVT

  • Groin puncture within 24-hours of onset or last known normal

• Tandem ipsilateral high-grade (≥70%) cervical internal carotid artery (ICA) stenosis or occlusion of presumed atherosclerotic etiology on initial non-invasive vascular imaging

• Informed consent from patient or surrogate or deferral of consent, according to local ethics policies

Exclusion criteria:

• Pre-existing neurological impairment (modified Rankin score ≥3)

• Any underlying disease or condition making protocol adherence and/or 3-month follow-up unlikely

• Any known contra-indication to EVT, angioplasty/stenting, or antiplatelet therapy

• Tandem ipsilateral high-grade (≥70%) cervical internal carotid artery (ICA) stenosis or occlusion NOT confirmed on conventional angiography

• Ipsilateral ICA stenosis or occlusion attributable to clinically or radiologically confirmed arterial dissection

•  Isolated cervical carotid occlusion without intracranial occlusion

• Pregnancy

Treatment

Patients will be randomized (1:1) to undergo acute ICA stenting during the thrombectomy procedure (either before or after intracranial thrombectomy, at the discretion of the treating physician) or to intracranial thrombectomy alone without ICA stenting. Deferred ICA intervention is allowed, if indicated.

Duration of Treatment

Patients will be treated acutely and followed up to one year.

Evaluation Criteria

Primary outcome:

The proportion of patients achieving a favorable modified Rankin scale score (mRS 0-2) at 90 days (dichotomized)

 Secondary outcomes:

• Proportion of patients achieving a favorable modified Rankin scale score (mRS 0-2) at 90   days (dichotomized) according to sex

• Modified Rankin scale score at 90 days, treated as an ordinal scale (mRS = 0 to 6) merging mRS 5 (severe disability) and 6 (death) into a single category

• Median NIHSS score at 24 hours after stroke

• Median mRS at 90 days after stroke

• Rate of clinically confirmed recurrent ipsilateral stroke or retinal ischemia within 90 days  (imaging as clinically indicated)

• Proportion of patients with complete or near-complete recanalization (TICI 2b/3) at the  end of the endovascular procedure

• Proportion of patients with ICA thrombosis (with or without stent) within 90 days after  stroke

• Median Montreal Cognitive Assessment (MoCA) score at 90 days after stroke

• Quality of life (EQ-5D-5L) at 90 days after stroke

• Rate of any recurrent stroke or retinal ischemia at 12 months after stroke

• Proportion of patients achieving a favorable modified Rankin scale score (mRS 0-2) at 12  months after stroke

Safety outcomes:

• Proportion of patients with any intracranial hemorrhage on follow-up imaging at 24 hours

• Proportion of patients with symptomatic intracranial hemorrhage (sICH) within 72 hours of EVT (ECASS-2 definition)

• All-cause mortality at 90 days

• Procedural complications, including: vessel perforation, iatrogenic vessel dissection, embolization into a previously unaffected artery, access site complications

Tertiary (descriptive) outcomes:

• Timing of ICA stenting relative to intracranial thrombectomy (before/anterograde or after/retrograde)

• Antiplatelet and/or anticoagulant regimens used peri-interventionally

• Use of distal or proximal embolic protection among patients undergoing stenting

• Proportion of patients with presumed tandem occlusion on non-invasive imaging (CTA or MRA) having no tandem occlusion on conventional angiography (pseudo-occlusions)

• The proportion of patients in the no stent group undergoing deferred ICA revascularization and the type of revascularization (endarterectomy or stenting) used, within 12 months after stroke

• Minimum and maximum blood pressure (systolic and diastolic) and heart rate during EVT procedure

• (Optional) Cerebral blood flow characteristics as measured by transcranial doppler (TCD) at 24 hours after stroke

Sample Size

Our primary hypothesis assumes a greater proportion of patients with 90-day mRS 0-2 in the stenting group versus the no stenting group (55% versus 40%). In order to detect this 15% absolute risk difference in the primary outcome with power of 0.8, 173 patients per group will be required. A 15% minimal clinically important difference thus translates into an expected difference of 13.5 % (15%*0.9) with crossover. A sample of 217 patients per group (n total = 434) would detect the alternative hypothesis with 80% power at a 5% significance level. This includes adjustments for one interim analysis when 67% of the data has been collected, using the O’Brien-Fleming α-spending function stopping boundaries for efficacy.  Further adjusting for a loss to follow-up of 5%, the study would require a total sample size of 458 patients (n= 229 per group).  

Primary analysis will be by Intention-to-treat. Pre-specified per-protocol and sex-specific analyses will also be performed.

Randomization

Randomization will be 1:1 to acute cervical ICA stenting or to no stenting. Randomization will be centralized and web-based. Stratification will be performed for use or not of IV alteplase.

Consent

Informed consent will be obtained from patients or their surrogate. Deferral of consent will be allowed if permitted by local ethics committees.