Clinical trial NCT03978988: Thrombectomy In TANdem Occlusion
Official title: Intracranial Thrombectomy and Extracranial Carotid Stenting Versus Intracranial Thrombectomy Alone In Acute Anterior Circulation Strokes With TANdem Occlusion : the Randomized Controlled TITAN Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Carotid Artery Diseases
Thrombectomy
Tandem Occlusion
Stroke
Keywords: stroke
tandem occlusion
carotid stenting
thrombectomy
Lead sponsor: Central Hospital, Nancy, France
Sponsor class: OTHER
First posted: 2019-06-07
Enrollment: 432
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: Tandem occlusion is defined by an acute ischemic stroke (AIS) with concomitant steno-occlusive disease of the extra cranial carotid artery and concerned about 10% of AIS patients. Whereas endovascular treatment has shown its efficiency in AIS by large vessel occlusion (LVO), to date, there is no consensus on the endovascular management of the extra cranial carotid artery in tandem occlusion. Only few of them were included in previous randomized trials who evaluated mechanical thrombectomy and were often listed in the non-inclusion criteria. Therapeutic management of this population was not specifically addressed in recent trials. Endovascular management can be complex with the need of acute stenting of the extra cranial carotid lesion along with the potential need of antithrombotic therapy initiation, the benefit and the safety of stenting of the cervical lesion in acute phase of AIS have shown encouraging results but however remains to be assessed. The TITAN (Thrombectomy In TANdem lesion) trial aims to demonstrate the superiority of the combined use of intracranial thrombectomy and extracranial carotid stenting compared to intracranial thrombectomy alone on the complete reperfusion rate in patients with acute ischemic stroke due to tandem lesion.

Detailed description: The TITAN trial is a prospective, randomized, multi center, controlled, open-label, blinded clinical trial. This academic trial designed to answer the question: "What is the best endovascular management of the extra cranial carotid artery lesion in tandem occlusion with LVO" Patients will be recruited at 13 comprehensive stroke centers in France, all of which regular conduct mechanical thrombectomy and carotid stenting.

This study will enroll adults patients admitted with cerebral infarction of the anterior circulation, proven by computed tomography (CT) or magnetic resonance (MR) angiography, associated with tandem lesion, within 8 hours of symptoms onset, with a neurological deficit NIHSS \> 5, and eligible to thrombectomy according to the recommendations of the French societies of neurovascular disease and neuroradiology (SFNR and SFNV).

Tandem occlusion of the anterior circulation will be proven on digital subtraction angiography, defined as a proximal intracranial occlusion and an extracranial severe internal carotid artery (ICA) lesion (complete occlusion or stenosis ≥90% North American Symptomatic Carotid Endarterectomy Trial).

Informed Consent according to the French laws will be sought from the patient if their level of consciousness is sufficient or from a relative. This study will operate using an emergency inclusion protocol due to the nature of the condition.

After emergency inclusion procedure according to French regulations, eligible patients will be randomized in two balanced parallel groups to receive either combined treatment intracranial thrombectomy with carotid stenting or intracranial thrombectomy alone.

Treatment and Intervention Intravenous thrombolysis will be administered if possible. Standard MT will be performed with a balloon Guide Catheter (BGC). MT technique (contact aspiration, stent retriever, or solumbra) will be left at the discretion of the operators.

Concerning the cervical disease, emergent carotid stenting will be performed if the patient is randomized in the intervention arm. The order to treat (head first or neck first), and the choice of a previous angioplasty of the extracranial carotid artery lesion will be left to the interventionist discretion. An intravenous bolus of 250mg of Aspirin will be given at the end of the procedure in case of absence of complication. (Aspirin 250mg IV up to Imaging 24H).A second antiplatelet agent is used if a thrombus is formed : IV or nasogastric tube (choice by operator)

Primary objective :

To demonstrate the superiority of intracranial thrombectomy and extracranial carotid stenting compared to intracranial thrombectomy alone on the complete reperfusion (mTICI 3 at the end of the endovascular procedure) rate and on the rate of NIHSS ≥ 4 points improvement at 24 hours in AIS patients with a tandem occlusion of the anterior circulation.

Secondary objectives :

1. To assess the feasibility and the efficacy of the combined approach associating intracranial thrombectomy and extracranial carotid stenting compared to intracranial thrombectomy alone using a composite criterion (mTICI3 at the end of the endovascular procedure or NIHSS improvement ≥ 4 points at 24h).
2. To compare the safety of intracranial thrombectomy and extracranial carotid stenting compared to intracranial thrombectomy alone.
3. To evaluate the cost-effectiveness and cost-utility of the combined approach compared to intracranial thrombectomy alone.

The Data and Safety Monitored Board (DSMB) will provide subject safety oversight and make recommendations to the Sponsor regarding continuing enrollment, modifying, or stopping the study early based upon a review of safety data and more specifically the comparative rates of symptomatic intracranial hemorrhage and, neurological worsening (NIHSS4 points increase), at D1, and mortality rates. They will take into account in their decision making and recommendations the rates of procedure-related and device-related events in the treatment group.

DSMB meetings will be organized by call conference by the sponsor before the start of the study and every year until the end of the study. The members will also receive the results of interim analyses. Additional extraordinary meetings will be set if necessary.

It will be constituted with two independent clinicians and one expert in methodology.

Sample Size Estimates Prior data indicate that a reperfusion rate of 30% mTICI 3 was observed with mechanical thrombectomy in patients with tandem lesions. Assuming acute carotid stenting will bring a 15% gain, a sample size of 162 patients per group will allow to evidence such gain with a 80% power at a 5% type I error (PS v3.0). Allowing 5% loss to follow up leads to include 216 patients per group, i.e. 432 patients in total

Eligibility criteria: Inclusion Criteria:

1. Subject aged ≥ 18 years
2. Tandem occlusion confirmed by MR angiography or CT-angiography or digital subtraction angiography of supra-aortic vessels, in connection with atheromatous plaque or dissection, defined with:

   * Proximal intracranial occlusion (ICA, M1 and/or M2) eligible for thrombectomy
   * Extracranial lesion of the internal carotid artery (stenosis ≥90% NASCET or complete occlusion).
3. NIHSS Score ≥ 6
4. Arterial puncture performed :

   -\> Within 8 hours (after the first symptoms or last seen well) with ASPECTS Score ≥5 by CT or MRI (DWI)

   OR

   -\> Between 8 and 24 hours :
   * If perfusion imaging performed: according to the DEFUSE3 trial criteria (ischemia ≤70 mL, ischemia-hypoperfusion ratio≥1.8, and hypoperfusion volume ≥15 mL)
   * If perfusion imaging not performed: according to the DAWN trial criteria :

     * Age ≥80 years with NIHSS ≥10 and ischemia ≤21 mL
     * Age \<80 years with NIHSS ≥10 and ischemia ≤31 mL
     * Age \<80 years with NIHSS ≥20 and ischemia ≤51 mL
5. The patient or his or her representative has received information about the study organization and has signed and dated the informed consent form/ inclusion in emergency situation in accordance with Article L1122-1-3 of the Public Health Code.
6. Person affiliated to or beneficiary of a social security plan
7. Person undergone the medical examination adapted to research Subjects treated with prior intravenous thrombolysis are eligible for participation

Exclusion Criteria:

1. Extracranial internal carotid artery stenosis \< 90% (NASCET)
2. Rankin score (mRS) \> 2
3. Contraindication to antiplatelet (Aspirin, Plavix), or thrombolytic therapy (Actilyse), or contrast agents, or endovascular products.
4. Patient unable to present or be available for follow-up
5. Patient's refusal to participate
6. Woman of childbearing age without effective contraception
7. Pregnant, parturient or breastfeeding woman
8. Minor person (non emancipated)
9. Adult person under legal protection (any form of public guardianship)
10. Person deprived of liberty for judicial or administrative decision
11. Person under psychiatric care according to articles L. 3212-1 and L. 3213-1 of the Public Health Code.

Primary outcomes:
measure: Change in Modified treatment in cerebral ischemia (mTICI) score AND National Institutes of Health Stroke Scale (NIHSS) score
timeFrame: at the end of angiography(mTICI score) , at 24 hours (NIHSS score)
Secondary outcomes:
measure: Efficacy outcomes : Rate of reperfusion with change in Modified treatment in cerebral ischemia (mTICI) score
timeFrame: at the end of the endovascular procedure
measure: Efficacy outcomes : Change in National Institutes of Health Stroke Scale (NIHSS) score
timeFrame: at 24 hours (±6) hours
measure: Efficacy outcomes : number of participants with delays of symptoms
timeFrame: at the end of the endovascular procedure
measure: Efficacy outcomes : Number of passes
timeFrame: at the end of the endovascular procedure
measure: Efficacy outcomes : Infarct growth (volume)
timeFrame: At 24hours (±6) hours
measure: Efficacy outcomes : Type and dose of antiplatelet agents administered
timeFrame: at 24 (±6) hours, at discharge (5-7 days)
measure: Efficacy outcomes : Rate of recurrent clinical ischemic event
timeFrame: at 90 days for rate of recurrent clinical ischemic event
measure: Efficacy outcomes : Rate of functional independence
timeFrame: at 90 days and 12 months for mRS
measure: Safety outcomes : Rate of procedural complications
timeFrame: At the end of endovascular procedure
measure: Safety outcomes : Rates of carotid stenosis and stent thrombosis
timeFrame: At the end of endovascular procedure
measure: Safety outcomes : Rate of symptomatic and asymptomatic intracerebral hemorrhage
timeFrame: at 24 hours (±6 hours)
measure: Safety outcomes : Rate of carotid stenosis and stent thrombosis
timeFrame: at 24 (±6) hours
measure: Safety outcomes :Rate of secondary decompressive craniotomy
timeFrame: at discharge (or 5-7 days)
measure: Safety outcomes : Rate of endarterectomy
timeFrame: at 90 days and 12 (±1) months
measure: Safety outcomes : Rate of mortality
timeFrame: at 24 (±6) hours, 90 (±15) days, and 12 (±1) months
measure: Cost effectiveness outcomes : value the additional cost of gaining additional clinical (NIHSS)
timeFrame: At 24 hours
measure: Cost effectiveness outcomes : value the additional cost of gaining additional clinical (mRS)
timeFrame: at 3 months
measure: Cost effectiveness outcomes : cost of safety issues
timeFrame: At 3 months
measure: Cost effectiveness outcomes : a cost-utility analysis
timeFrame: At 12 months
measure: Cost effectiveness outcomes : a budget impact analysis
timeFrame: At 12 months
Other outcomes:
Locations:
city: Vandoeuvre les Nancy
country: France
facility: CHRU de Nancy
Study officials:
affiliation: CHRU de Nancy
name: Benjamin GORY, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zhu F, Hossu G, Soudant M, Richard S, Achit H, Beguinet M, Costalat V, Arquizan C, Consoli A, Lapergue B, Rouchaud A, Macian-Montoro F, Biondi A, Moulin T, Marnat G, Sibon I, Paya C, Vannier S, Cognard C, Viguier A, Mazighi M, Obadia M, Hassen WB, Turc G, Clarencon F, Samson Y, Dumas-Duport B, Preterre C, Barbier C, Boulanger M, Janot K, Annan M, Bricout N, Henon H, Soize S, Moulin S, Labeyrie MA, Reiner P, Pop R, Wolff V, Ognard J, Timsit S, Reyre A, Perot C, Papagiannaki C, Triquenot-Bagan A, Bracard S, Anxionnat R, Derelle AL, Tonnelet R, Liao L, Schmitt E, Planel S, Guillemin F, Gory B. Effect of emergent carotid stenting during endovascular therapy for acute anterior circulation stroke patients with tandem occlusion: A multicenter, randomized, clinical trial (TITAN) protocol. Int J Stroke. 2021 Apr;16(3):342-348. doi: 10.1177/1747493020929948. Epub 2020 Jun 9.