Title
Ketamine for Thrombolysis in Acute Ischemic Stroke
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
Phase
Phase 1/Phase 2Lead Sponsor
University of Caen-NormandieStudy Type
InterventionalStatus
Unknown statusIndication/Condition
StrokeIntervention/Treatment
ketamine ...Study Participants
50KETA 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.
Co-administration of subanesthetic dose of ketamine with tPA for thrombolysis in acute ischemic stroke.
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).
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.
