<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02258204</url>
  </required_header>
  <id_info>
    <org_study_id>KETA</org_study_id>
    <nct_id>NCT02258204</nct_id>
  </id_info>
  <brief_title>Ketamine for Thrombolysis in Acute Ischemic Stroke</brief_title>
  <acronym>KETA</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Caen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Société Française d'Anesthésie Réanimation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Fondation NRJ</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital, Caen</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      KETA trial is a nonprofit, double-blind, randomized, controlled pilot trial with aiming to&#xD;
      determine if co-administration of ketamine with recombinant of tissue type plasminogen&#xD;
      activator (tPA) for thrombolysis in acute ischemic stroke compared with tPA co-administered&#xD;
      with placebo, decreases cerebral infarction growth in diffusion weighted imaging between&#xD;
      admission and day 1. Eligibility applies to patients with symptomatic ischemic stroke seen&#xD;
      within 4.5 h of onset with middle cerebral artery or distal internal carotid artery&#xD;
      occlusion, no contraindication to intravenous tPA-mediated thrombolysis and eligible to&#xD;
      endovascular treatment of stroke (i.e. thrombectomy). The study has been designed to have 80%&#xD;
      power to detect a 80% decrease of infarct volume growth in the tPA-ketamine group at a&#xD;
      two-sided type I error rate of 5%. For this purpose, at least 25 patients per arm should be&#xD;
      enrolled.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rationale - Tissue-type plasminogen activator (tPA) is a double-sided molecule, with&#xD;
      beneficial effect in acute ischemic stroke due to its intravascular fibrinolytic activity but&#xD;
      with potential deleterious effect due to its ability to potentiate neuronal&#xD;
      N-methyl-D-aspartate (NMDA) receptor signalling (Nicole et al., 2001). Co-administration of&#xD;
      sub-anesthetic dose of ketamine - a non-competitive inhibitor of NMDA receptor - was shown to&#xD;
      improve efficacy of tPA-mediated thrombolysis following stroke in rodents (Gakuba et al,&#xD;
      2011).&#xD;
&#xD;
      Aims - To assess efficacy and safety of co-administration of ketamine with tPA compared with&#xD;
      tPA-placebo infusion in patients with acute ischemic stroke.&#xD;
&#xD;
      Sample size estimates -With 25 patients per group, the trial has a 80% probability of&#xD;
      detecting a 80% decrease of infarct volume growth in the tPA-ketamine group compared with the&#xD;
      tPA-placebo group on day 1 after admission at a two-sided type I error rate of 5%.&#xD;
&#xD;
      Study outcomes - The primary efficacy outcome is cerebral infarction growth on diffusion&#xD;
      weighted imaging between admission and day 1. The primary safety measure is mortality and/or&#xD;
      symptomatic intracerebral hemorrhage rate at 3 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>March 2015</start_date>
  <completion_date type="Anticipated">February 2018</completion_date>
  <primary_completion_date type="Anticipated">December 2017</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Cerebral infarction growth on diffusion weighted magnetic resonance imaging between admission and day 1.</measure>
    <time_frame>Day 1</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>National Institute of Health Stroke Scale</measure>
    <time_frame>day 0, day 1, day 7 and day 90</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Modified Rankin Scale</measure>
    <time_frame>day 90</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infarction volume on diffusion weighted magnetic resonance imaging</measure>
    <time_frame>day 1</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T2-weighted Fluid Attenuated Inversion Recovery Imaging infarct volume</measure>
    <time_frame>day 90</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Symptomatic intracerebral hemorrhage and/or death</measure>
    <time_frame>day 90</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Arterial patency</measure>
    <time_frame>day 0 (before and after thrombectomy) and day 1</time_frame>
    <description>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).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Stroke</condition>
  <arm_group>
    <arm_group_label>tPA-placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>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.&#xD;
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).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>tPA-ketamine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.&#xD;
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).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ketamine</intervention_name>
    <description>Co-administration of subanesthetic dose of ketamine with tPA for thrombolysis in acute ischemic stroke.</description>
    <arm_group_label>tPA-ketamine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>tPA-placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Sudden focal neurological deficit attributable to acute ischemic stroke.&#xD;
&#xD;
          -  Age between 18 and 85.&#xD;
&#xD;
          -  Time from symptom onset less than 4.5 hours.&#xD;
&#xD;
          -  NIHSS score between 7 and 20.&#xD;
&#xD;
          -  Informed consent for participation.&#xD;
&#xD;
          -  Ketamine can be administered within 15 minutes after onset of tPA infusion.&#xD;
&#xD;
          -  MRI-based AIS diagnosis.&#xD;
&#xD;
          -  Middle cerebral (M1 or M2 segment) and/or distal internal carotid artery occlusion.&#xD;
&#xD;
          -  No intracranial hemorrhage on MRI.&#xD;
&#xD;
          -  Patient eligible for thrombectomy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Contraindication to IV tPA treatment.&#xD;
&#xD;
          -  Contraindication to ketamine.&#xD;
&#xD;
          -  Contraindication to MRI.&#xD;
&#xD;
          -  Contraindication to intravascular iodinated contrast media.&#xD;
&#xD;
          -  Consciousness level &gt;1 on question 1a of NIHSS.&#xD;
&#xD;
          -  Pre-stroke mRS ≥3.&#xD;
&#xD;
          -  Concomitant medical illness that would interfere with outcome assessments and&#xD;
             follow-up (e.g. advanced cancer or respiratory disease).&#xD;
&#xD;
          -  Previous participation in this trial or current participation in another&#xD;
             investigational drug trial.&#xD;
&#xD;
          -  Infarct volume on diffusion weighted MRI more than 100 mL.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>CHU Caen</name>
      <address>
        <city>Caen</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Emmanuel Touzé, MD PhD</last_name>
      <phone>+33231064624</phone>
      <email>touze-e@chu-caen.fr</email>
    </contact>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <reference>
    <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>
    <PMID>11135617</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>21817137</PMID>
  </reference>
  <verification_date>February 2016</verification_date>
  <study_first_submitted>October 3, 2014</study_first_submitted>
  <study_first_submitted_qc>October 6, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 7, 2014</study_first_posted>
  <last_update_submitted>February 23, 2016</last_update_submitted>
  <last_update_submitted_qc>February 23, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 24, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital, Caen</investigator_affiliation>
    <investigator_full_name>Emmanuel TOUZE</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Cerebral Infarct</keyword>
  <keyword>Thrombolysis</keyword>
  <keyword>Tissue-type plasminogen activator</keyword>
  <keyword>Neuroprotection</keyword>
  <keyword>Anesthetic agent</keyword>
  <keyword>Magnetic resonance imaging</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Stroke</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ketamine</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02258204
org study id: KETA
nct id: NCT02258204
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Cerebral infarction growth on diffusion weighted magnetic resonance imaging between admission and day 1.
time frame: Day 1
measure: National Institute of Health Stroke Scale
time frame: day 0, day 1, day 7 and day 90
measure: Modified Rankin Scale
time frame: day 90
measure: Infarction volume on diffusion weighted magnetic resonance imaging
time frame: day 1
measure: T2-weighted Fluid Attenuated Inversion Recovery Imaging infarct volume
time frame: day 90
measure: Symptomatic intracerebral hemorrhage and/or death
time frame: day 90
measure: Arterial patency
time frame: day 0 (before and after thrombectomy) and day 1
description: 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).
arm group label: tPA-placebo
arm group type: Placebo Comparator
description: 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).
arm group label: tPA-ketamine
arm group type: Experimental
description: 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 type: Drug
intervention name: Ketamine
description: Co-administration of subanesthetic dose of ketamine with tPA for thrombolysis in acute ischemic stroke.
arm group label: tPA-ketamine
intervention type: Drug
intervention name: Placebo
arm group label: tPA-placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
facility: 
status: Recruiting
contact: 
country: France
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.
PMID: 11135617
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.
PMID: 21817137
responsible party type: Principal Investigator
investigator affiliation: University Hospital, Caen
investigator full name: Emmanuel TOUZE
investigator title: Professor
mesh term: Stroke
mesh term: Ketamine