Ketamine for Thrombolysis in Acute Ischemic Stroke

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effets de la kétamine en Association Avec le Rt-PA au Cours de l'Infarctus cérébral Aigu: étude Pilote contrôlée randomisée en Double Aveugle Avec critère de Jugement Radiologique

Conditions
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Stroke

Intervention / Treatment
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* Drug: Ketamine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: tPA-placebo<br>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). | Drug: Placebo<br> <br> |
| Experimental: tPA-ketamine<br>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). | Drug: Ketamine<br>* Co-administration of subanesthetic dose of ketamine with tPA for thrombolysis in acute ischemic stroke.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cerebral infarction growth on diffusion weighted magnetic resonance imaging between admission and day 1. |  | Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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). | day 0 (before and after thrombectomy) and day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cerebral Infarct, Thrombolysis, Tissue-type plasminogen activator, Neuroprotection, Anesthetic agent, Magnetic resonance imaging