Clinical trial NCT02258204: Ketamine for Thrombolysis in Acute Ischemic Stroke
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Stroke
Keywords: Cerebral Infarct
Thrombolysis
Tissue-type plasminogen activator
Neuroprotection
Anesthetic agent
Magnetic resonance imaging
Lead sponsor: University Hospital, Caen
Sponsor class: OTHER
Collaborators: name: Société Française d'Anesthésie Réanimation
name: Fondation NRJ
First posted: 2014-10-07
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Cerebral infarction growth on diffusion weighted magnetic resonance imaging between admission and day 1.
timeFrame: Day 1
Secondary outcomes:
measure: National Institute of Health Stroke Scale
timeFrame: day 0, day 1, day 7 and day 90
measure: Modified Rankin Scale
timeFrame: day 90
measure: Infarction volume on diffusion weighted magnetic resonance imaging
timeFrame: day 1
measure: T2-weighted Fluid Attenuated Inversion Recovery Imaging infarct volume
timeFrame: day 90
measure: Symptomatic intracerebral hemorrhage and/or death
timeFrame: day 90
measure: Arterial patency
timeFrame: day 0 (before and after thrombectomy) and day 1
Other outcomes:
Locations:
city: Caen
country: France
facility: CHU Caen
Study officials:
References:
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. doi: 10.1038/83358.
citation: 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.