Ketamine for Thrombolysis in Acute Ischemic Stroke
Ketamine for Thrombolysis in Acute Ischemic Stroke
KETA trial is a nonprofit, double-blind, randomized, controlled pilot trial with aiming to
 determine if co-administration of ketamine with recombinant of tissue type plasminogen
 activator (tPA) for thrombolysis in acute ischemic stroke compared with tPA co-administered
 with placebo, decreases cerebral infarction growth in diffusion weighted imaging between
 admission and day 1. Eligibility applies to patients with symptomatic ischemic stroke seen
 within 4.5 h of onset with middle cerebral artery or distal internal carotid artery
 occlusion, no contraindication to intravenous tPA-mediated thrombolysis and eligible to
 endovascular treatment of stroke (i.e. thrombectomy). The study has been designed to have 80%
 power to detect a 80% decrease of infarct volume growth in the tPA-ketamine group at a
 two-sided type I error rate of 5%. For this purpose, at least 25 patients per arm should be
 enrolled.
Rationale - Tissue-type plasminogen activator (tPA) is a double-sided molecule, with
 beneficial effect in acute ischemic stroke due to its intravascular fibrinolytic activity but
 with potential deleterious effect due to its ability to potentiate neuronal
 N-methyl-D-aspartate (NMDA) receptor signalling (Nicole et al., 2001). Co-administration of
 sub-anesthetic dose of ketamine - a non-competitive inhibitor of NMDA receptor - was shown to
 improve efficacy of tPA-mediated thrombolysis following stroke in rodents (Gakuba et al,
 2011).

 Aims - To assess efficacy and safety of co-administration of ketamine with tPA compared with
 tPA-placebo infusion in patients with acute ischemic stroke.

 Sample size estimates -With 25 patients per group, the trial has a 80% probability of
 detecting a 80% decrease of infarct volume growth in the tPA-ketamine group compared with the
 tPA-placebo group on day 1 after admission at a two-sided type I error rate of 5%.

 Study outcomes - The primary efficacy outcome is cerebral infarction growth on diffusion
 weighted imaging between admission and day 1. The primary safety measure is mortality and/or
 symptomatic intracerebral hemorrhage rate at 3 months.
Inclusion Criteria:

 -  Sudden focal neurological deficit attributable to acute ischemic stroke.

 -  Age between 18 and 85.

 -  Time from symptom onset less than 4.5 hours.

 -  NIHSS score between 7 and 20.

 -  Informed consent for participation.

 -  Ketamine can be administered within 15 minutes after onset of tPA infusion.

 -  MRI-based AIS diagnosis.

 -  Middle cerebral (M1 or M2 segment) and/or distal internal carotid artery occlusion.

 -  No intracranial hemorrhage on MRI.

 -  Patient eligible for thrombectomy.

 Exclusion Criteria:

 -  Contraindication to IV tPA treatment.

 -  Contraindication to ketamine.

 -  Contraindication to MRI.

 -  Contraindication to intravascular iodinated contrast media.

 -  Consciousness level >1 on question 1a of NIHSS.

 -  Pre-stroke mRS ≥3.

 -  Concomitant medical illness that would interfere with outcome assessments and
 follow-up (e.g. advanced cancer or respiratory disease).

 -  Previous participation in this trial or current participation in another
 investigational drug trial.

 -  Infarct volume on diffusion weighted MRI more than 100 mL.