Ketamine for Thrombolysis in Acute Ischemic Stroke (KETA)

Caen University Hospital

Status and phase: Unknown; Phase 2; Phase 1

Conditions: Stroke

Treatments: Drug: Ketamine; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT02258204

KETA

Details and patient eligibility

About

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.

Full 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.

Enrollment: 50 estimated patients

Sex: All

Ages: 18 to 85 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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50 participants in 2 patient groups, including a placebo group

tPA-placebo

Placebo Comparator group

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).

Treatment:

Drug: Placebo

tPA-ketamine

Experimental group

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).

Treatment:

Drug: Ketamine