Ketamine for Thrombolysis in Acute Ischemic Stroke "KETA"

Recruiting

Phase 1/2 Results N/A

Trial Description

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.

Detailed Description

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.

Conditions

Interventions

  • Placebo Drug
    ARM 1: Kind: Experimental
    Label: tPA-placebo
    Description: 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).
  • Ketamine Drug
    Intervention Desc: Co-administration of subanesthetic dose of ketamine with tPA for thrombolysis in acute ischemic stroke.
    ARM 1: Kind: Experimental
    Label: tPA-ketamine
    Description: 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).

Trial Design

  • Allocation: Randomized
  • Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
  • Purpose: Treatment
  • Endpoint: Safety/Efficacy Study
  • Intervention: Parallel Assignment

Outcomes

Type Measure Time Frame Safety Issue
Primary Cerebral infarction growth on diffusion weighted magnetic resonance imaging between admission and day 1. Day 1 No
Secondary National Institute of Health Stroke Scale day 1, day 7 and day 90 No
Secondary Modified Rankin Scale day 90 No
Secondary Infarction volume on diffusion weighted magnetic resonance imaging day 1 No
Secondary T2-weighted Fluid Attenuated Inversion Recovery Imaging infarct volume day 90 No
Secondary Symptomatic intracerebral hemorrhage and/or death day 90 Yes
Secondary Arterial patency day 0 (before and after thrombectomy) and day 1 No

Sponsors