♦  Study objective
 

Primary Objective: To assess the effect of direct intra-arterial thrombectomy compared IV alteplase followed by intra-arterial thrombectomy in patients with acute ischemic stroke due to an anterior circulation large vessel occlusion.
Secondary Objective: To assess treatment effect modification by the presence of intracranial atherosclerosis.

♦  Study design
 

This is a parallel group, RCT of direct intra-arterial thrombectomy versus bridging therapy, using a non-inferiority design(a sample size of n=636). The trial has observer blinded assessment of the primary outcome and of neuro-imaging at baseline and follow up (PROBE design). The trial is executed in collaboration with the MR CLEAN - NO IV investigators.

♦  Study population
 

Patients with acute ischemic stroke due to an anterior circulation intracranial large vessel occlusion confirmed by CTA. Initiation of IVT must be feasible within 4.5 hours from symptom onset. Age must be 18 or over and NIHSS 2 or more.

♦  Inclusion criteria
 

1. a clinical diagnosis of acute ischemic stroke;
2. caused by a large vessel occlusion of the anterior circulation (distal intracranial carotid artery or middle
    M1/proximal M2) cerebral artery confirmed by CTA;
3. CT or MRI ruling out intracranial hemorrhage;
4. eligible for IVT (within 4.5 hours after symptom onset) and IAT;
5. NIHSS ≥ 2;
6. age ≥ 18;
7. written informed consent.

♦  Exclusion criteria

1. Pre-stroke disability which interferes with the assessment of functional outcome at 90 days, i.e. mRS >2;
2. Any contraindications for IVT, according to guidelines of the American Heart Association, i.e.:
       o    blood pressure > 185/110 mmHg,
       o    blood glucose < 2.7 or> 22.2 mmol/L,
       o    cerebral infarction in the previous 6 weeks with residual neurological deficit or signs of recent
             infarction on neuro-imaging,
       o    serious head trauma in the previous 3 months,
       o    major surgery or serious trauma in the previous 2 weeks,
       o    gastrointestinal or urinary tract hemorrhage in the previous 3 weeks,
       o    previous intracerebral hemorrhage,
       o    use of anticoagulant with INR exceeding 1.7,
       o    known thrombocyte count less than 100 × 109/L
       o    treatment with direct thrombin or factor X inhibitors,
       o    treatment with heparin (APTT exceeds the upper limit of normal value) in the previous 48 hours.

♦  Study procedures
 

After enrollment, the patient is followed up 3 times:

       o    24-72 hours after the intervention, CT and CTA examinations are acquired.
       o    5-7 days after the intervention or before discharge, the patient undergoes a physical examination and a
              CT examination..
       o    90 days after the operation, the patients receives a telephone call to assess functional outcome.
              The retrieved thrombus (as it is “waste” material) may be retained for follow-up analysis.

♦  Literature

(1). Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic
       stroke. The New England journal of medicine. 2015;372(1):11-20. – MR CLEAN
(2). Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion-imaging
       selection. The New England journal of medicine. 2015;372(11):1009-1018. – EXTEND IA
(3). Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of
       ischemic
       stroke. The New England journal of medicine. 2015;372(11):1019-1030. – ESCAPE
(4). Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in
      stroke. The New England journal of medicine. 2015;372(24):2285-2295. – SWIFT PRIME
(5). Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke.
       The New England journal of medicine. 2015;372(24):2296-2306. – REVASCAT

♦  Statistical analysis plan

This Statistical Analysis Plan (SAP) is developed based on the most recent study protocol (Version 3.0, 20-Aug-2019) and Case Report Form (CRF, Version 1.4, 13-Nov-2018), and details the statistical analysis strategies and methods for the study.

DIRECT-MT Statistical Analysis Plan version 2.0