Ketamine for Thrombolysis in Acute Ischemic Stroke (KETA)

• ClinicalTrials.gov Identifier: NCT02258204
• Recruitment Status: Unknown
• First Posted: October 7, 2014
• Last Update Posted: February 24, 2016
• Sponsor: University Hospital, Caen
• Collaborators: Société Française d'Anesthésie Réanimation; Fondation NRJ
• Information provided by (Responsible Party): Emmanuel TOUZE, University Hospital, Caen

Tracking Information

• First Submitted Date: October 3, 2014
• First Posted Date: October 7, 2014
• Last Update Posted Date: February 24, 2016
• Study Start Date: March 2015
• Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: October 6, 2014): Cerebral infarction growth on diffusion weighted magnetic resonance imaging between admission and day 1. [ Time Frame: Day 1 ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 23, 2016)

• National Institute of Health Stroke Scale [ Time Frame: day 0, day 1, day 7 and day 90 ]
• Modified Rankin Scale [ Time Frame: day 90 ]
• Infarction volume on diffusion weighted magnetic resonance imaging [ Time Frame: day 1 ]
• T2-weighted Fluid Attenuated Inversion Recovery Imaging infarct volume [ Time Frame: day 90 ]
• Symptomatic intracerebral hemorrhage and/or death [ Time Frame: day 90 ]
• Arterial patency [ Time Frame: 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).

Original Secondary Outcome Measures (submitted: October 6, 2014)

• National Institute of Health Stroke Scale [ Time Frame: day 1, day 7 and day 90 ]
• Modified Rankin Scale [ Time Frame: day 90 ]
• Infarction volume on diffusion weighted magnetic resonance imaging [ Time Frame: day 1 ]
• T2-weighted Fluid Attenuated Inversion Recovery Imaging infarct volume [ Time Frame: day 90 ]
• Symptomatic intracerebral hemorrhage and/or death [ Time Frame: day 90 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Stroke

Intervention

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

Study Arms

• 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).

  Intervention: 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).

  Intervention: Drug: Ketamine

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.
• 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.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: October 6, 2014): 50
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 2018
• Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT02258204
• Other Study ID Numbers: KETA
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Emmanuel TOUZE, University Hospital, Caen
• Original Responsible Party: Same as current
• Current Study Sponsor: University Hospital, Caen
• Original Study Sponsor: Same as current

Collaborators

• Société Française d'Anesthésie Réanimation
• Fondation NRJ

• Investigators: Not Provided
• PRS Account: University Hospital, Caen
• Verification Date: February 2016