Ketamine for Thrombolysis in Acute Ischemic Stroke

Stroke Clinical Trial

— KETA  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02258204
• Other study ID #: KETA
• Status: Recruiting
• Phase: Phase 1/Phase 2
• First received: October 3, 2014
• Last updated: February 23, 2016
• Start date: March 2015
• Est. completion date: February 2018

Study information

• Verified date: February 2016
• Source: University Hospital, Caen
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Agence Nationale de Sécurité du Médicament et des produits de santé
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: February 2018
• Est. primary completion date: December 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 85 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Stroke

Intervention

Drug:
• Ketamine
Co-administration of subanesthetic dose of ketamine with tPA for thrombolysis in acute ischemic stroke.
• Placebo

Locations

Country	Name	City	State
France	CHU Caen	Caen

Sponsors (3)

Lead Sponsor	Collaborator
University Hospital, Caen	Fondation NRJ, Société Française d'Anesthésie Réanimation

Country where clinical trial is conducted

France, 

References & Publications (2)

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	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 0, 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	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	No