Stroke
Conditions
Keywords
Cerebral Infarct, Thrombolysis, Tissue-type plasminogen activator, Neuroprotection, Anesthetic agent, Magnetic resonance imaging
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.
Interventions
DRUGKetamine
Co-administration of subanesthetic dose of ketamine with tPA for thrombolysis in acute ischemic stroke.
DRUGPlacebo
Sponsors
Société Française d'Anesthésie Réanimation
Fondation NRJ
University Hospital, Caen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Cerebral infarction growth on diffusion weighted magnetic resonance imaging between admission and day 1. | Day 1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Modified Rankin Scale | day 90 | — |
| Infarction volume on diffusion weighted magnetic resonance imaging | day 1 | — |
| National Institute of Health Stroke Scale | day 0, day 1, day 7 and day 90 | — |
| Symptomatic intracerebral hemorrhage and/or death | day 90 | — |
| Arterial patency | day 0 (before and after thrombectomy) and day 1 | 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). |
| T2-weighted Fluid Attenuated Inversion Recovery Imaging infarct volume | day 90 | — |
Countries
France
Outcome results
None listed