Ketamine for Thrombolysis in Acute Ischemic Stroke

Ketamine

Brief Summary

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.

Intervention / Treatment

  • Ketamine (DRUG)
    Co-administration of subanesthetic dose of ketamine with tPA for thrombolysis in acute ischemic stroke.
  • Placebo (DRUG)
    N/A

Condition or Disease

  • Stroke

Phase

  • Phase 1
  • Phase 2

    • Study Design

    Study type: INTERVENTIONAL
    Status: Unknown status
    Study results: No Results Available
    Age: 18 Years to 85 Years
    Enrollment: 50 (ESTIMATED)
    Funded by: Other
    Allocation: Randomized
    Primary Purpose: Treatment

    Masking

    QUADRUPLE:
    • Participant
    • Care Provider
    • Investigator
    • Outcomes Assessor

    Clinical Trial Dates

    Start date: Mar 01, 2015
    Primary Completion: Dec 01, 2017 ESTIMATED
    Completion Date: Feb 01, 2018 ESTIMATED
    Study First Posted: Oct 07, 2014 ESTIMATED
    Results First Posted: Aug 31, 2020
    Last Updated: Feb 23, 2016

    Sponsors / Collaborators

    Lead Sponsor: University Hospital, Caen
    Responsible Party: N/A

    Location

    Caen, Normandy, France

    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.

    Participant Groups

    • tPA infusion : 0.9 mg/kg (90 mg maximum), 10% of the total dose is administered as an initial IV bolus dose over 1 minute and the remainder of the dose is infused over 60 minutes. Saline infusion : 0.15 mL/kg IV bolus (maximum 15 mL) followed by an IV infusion of 0.15 mL/kg over 60 minutes (maximum 15 mL).

    • tPA infusion : 0.9 mg/kg (90 mg maximum), 10% of the total dose is administered as an initial IV bolus dose over 1 minute and the remainder of the dose is infused over 60 minutes. Ketamine infusion : 0.15 mg/kg IV bolus (maximum 15 mg) followed by an IV infusion of 0.15 mg/kg over 60 minutes (maximum 15 mg).

    Eligibility Criteria

    Sex: All
    Minimum Age: 18
    Maximum Age: 85
    Age Groups: Adult / Older Adult
    Healthy Volunteers: Yes

    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.

    Primary Outcomes
    • Cerebral infarction growth on diffusion weighted magnetic resonance imaging between admission and day 1. Day 1
    Secondary Outcomes
    • National Institute of Health Stroke Scale day 0, day 1, day 7 and day 90
    • Modified Rankin Scale day 90
    • Infarction volume on diffusion weighted magnetic resonance imaging day 1
    • T2-weighted Fluid Attenuated Inversion Recovery Imaging infarct volume day 90
    • Symptomatic intracerebral hemorrhage and/or death day 90

    • Arterial patency will be assessed with the Thrombolysis in Cerebral Infarction (TICI) Score on day 0 before and after thrombectomy (digital subtraction angiography) and day 1 (magnetic resonance angiography).

    More Details

    NCT Number: NCT02258204
    Acronym: KETA
    Other IDs: KETA
    Study URL: https://clinicaltrials.gov/study/NCT02258204
    Last updated: Sep 29, 2023