Ketamine for Thrombolysis in Acute Ischemic Stroke (KETA)

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

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.

Study Overview

• Status: Unknown
• Conditions: Stroke
• Intervention / Treatment: Drug: Placebo; Drug: Ketamine

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.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Caen, France
    • Recruiting
    • CHU Caen
    • Contact: Emmanuel Touzé, MD PhD; Phone Number: +33231064624; Email: touze-e@chu-caen.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: tPA-placebo; 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
Experimental: tPA-ketamine; 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; Co-administration of subanesthetic dose of ketamine with tPA for thrombolysis in acute ischemic stroke.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University Hospital, Caen
• Collaborators: Société Française d'Anesthésie Réanimation; Fondation NRJ

Publications and helpful links

General Publications

• Nicole O, Docagne F, Ali C, Margaill I, Carmeliet P, MacKenzie ET, Vivien D, Buisson A. The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling. Nat Med. 2001 Jan;7(1):59-64. doi: 10.1038/83358.
• Gakuba C, Gauberti M, Mazighi M, Defer G, Hanouz JL, Vivien D. Preclinical evidence toward the use of ketamine for recombinant tissue-type plasminogen activator-mediated thrombolysis under anesthesia or sedation. Stroke. 2011 Oct;42(10):2947-9. doi: 10.1161/STROKEAHA.111.620468. Epub 2011 Aug 4.

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Anticipated): December 1, 2017
• Study Completion (Anticipated): February 1, 2018

Study Registration Dates

• First Submitted: October 3, 2014
• First Submitted That Met QC Criteria: October 6, 2014
• First Posted (Estimate): October 7, 2014

Study Record Updates

• Last Update Posted (Estimate): February 24, 2016
• Last Update Submitted That Met QC Criteria: February 23, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: Magnetic resonance imaging; Neuroprotection; Thrombolysis; Cerebral Infarct; Tissue-type plasminogen activator; Anesthetic agent
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: KETA