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