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Ketamine Infusion in Neurologic Deficit (KIND)

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ClinicalTrials.gov Identifier: NCT02636218
Recruitment Status : Recruiting
First Posted : December 21, 2015
Last Update Posted : October 22, 2020
Sponsor:
Collaborator:
Defence Research and Development Canada
Information provided by (Responsible Party):
Dr. Andrew Baker, Unity Health Toronto

Tracking Information
First Submitted Date  ICMJE December 8, 2015
First Posted Date  ICMJE December 21, 2015
Last Update Posted Date October 22, 2020
Study Start Date  ICMJE January 2016
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 12, 2016)
Changes in physiologic parameters as specified below [ Time Frame: During infusion and 1 hour post-infusion ]
Temperature, heart rate (HR), mean arterial pressure (MAP), intracranial pressure (ICP), central venous pressure (CVP) if available, peak airway pressure (PAP) if available, end-tidal carbon dioxide (ETCO2) will be evaluated during infusion. Collected measurement data will be analyzed based on the occurrence of adverse events such as increase in ICP by more than 3 mmHg, increase in HR by more than 30 bpm, increase in partial pressure of CO2 (pCO2) by more than 20 mmHg, increase in lactate by more than 0.5, drop in pH by more than 0.2, increase in systolic blood pressure (SBP0 to over 200 mmHg, or any other unforeseen event that is deemed to be related to the drug treatment with adverse effects on the patient.
Original Primary Outcome Measures  ICMJE
 (submitted: December 16, 2015)
  • Physiological parameters [ Time Frame: Within 4 hours of infusion ]
    Temperature, heart rate (HR), mean arterial pressure (MAP), intracranial pressure (ICP), central venous pressure (CVP) if available, peak airway pressure (PAP) if available, end-tidal carbon dioxide (ETCO2) will be evaluated during infusion. Collected measurement data will be analyzed based on the occurrence of adverse events such as increase in ICP by more than 3 mmHg, increase in HR by more than 30 bpm, increase in partial pressure of CO2 (pCO2) by more than 20 mmHg, increase in lactate by more than 0.5, drop in pH by more than 0.2, increase in systolic blood pressure (SBP0 to over 200 mmHg, or any other unforeseen event that is deemed to be related to the drug treatment with adverse effects on the patient.
  • Physiologic parameters [ Time Frame: 1 hour post-infusion ]
    Temperature, heart rate (HR), mean arterial pressure (MAP), intracranial pressure (ICP), central venous pressure (CVP) if available, peak airway pressure (PAP) if available, end-tidal carbon dioxide (ETCO2) will be evaluated during infusion. Collected measurement data will be analyzed based on the occurrence of adverse events such as increase in ICP by more than 3 mmHg, increase in HR by more than 30 bpm, increase in partial pressure of CO2 (pCO2) by more than 20 mmHg, increase in lactate by more than 0.5, drop in pH by more than 0.2, increase in systolic blood pressure (SBP) to over 200 mmHg, or any other unforeseen event that is deemed to be related to the drug treatment with adverse effects on the patient.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 12, 2016)
  • Biologic samples [ Time Frame: Day 1-2 post-infusion ]
    Blood and cerebrospinal fluid (CSF) samples will be collected and analyzed for biomarker levels which would indicate extent of neuronal injury.
  • Neurocognitive test Montreal Cognitive Assessment Scale (MoCA) [ Time Frame: Day 30 or Day 60 post-DCI ]
    Neurocognitive function will be assessed using the MoCA to determine preliminary effects of ketamine on neurocognitive outcome.
  • Neurocognitive test modified Rankin Scale (mRS) [ Time Frame: Day 30 or Day 60 post-DCI ]
    Neurocognitive function will be assessed using the mRS determine preliminary effects of ketamine on neurocognitive outcome.
  • Brain imaging using Magnetic Resonance Imaging (MRI) [ Time Frame: Day 30 or Day 60 post-DCI ]
    Structural and functional brain imaging will be conducted using Tesla MRI system to assess white matter integrity.
  • Hospital anxiety and depression score [ Time Frame: Day 30 or Day 60 post-DCI ]
    Assessments for neuro-cognitive outcomes and correlation with MRI findings
  • EQ-5D-5L [ Time Frame: Day 30 or Day 60 post-DCI ]
    Neurocognitive outcome assessment and correlation with MRI results
  • Trail making test [ Time Frame: Day 30 or Day 60 post-DCI ]
    Neurocognitive outcome assessment and correlation with MRI results
  • Verbal fluency tests [ Time Frame: Day 30 or Day 60 post-DCI ]
    Neurocognitive outcome assessment and correlation with MRI results
Original Secondary Outcome Measures  ICMJE
 (submitted: December 16, 2015)
  • Biologic samples [ Time Frame: Day 1-2 post-infusion ]
    Blood and cerebrospinal fluid (CSF) samples will be collected and analyzed for biomarker levels which would indicate extent of neuronal injury.
  • Neurocognitive test Montreal Cognitive Assessment Scale (MoCA) [ Time Frame: Day 30 post-DCI ]
    Neurocognitive function will be assessed using the MoCA to determine preliminary effects of ketamine on neurocognitive outcome.
  • Neurocognitive test modified Rankin Scale (mRS) [ Time Frame: Day 30 post-DCI ]
    Neurocognitive function will be assessed using the mRS determine preliminary effects of ketamine on neurocognitive outcome.
  • Brain imaging using Magnetic Resonance Imaging (MRI) [ Time Frame: Day 30 post-DCI ]
    Structural and functional brain imaging will be conducted using Tesla MRI system to assess white matter integrity.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ketamine Infusion in Neurologic Deficit
Official Title  ICMJE A Pilot Study of Sub-anesthetic Ketamine Infusion for Neuroprotection After Aneurysmal Subarachnoid Hemorrhage: Effects on White Matter Integrity, Inflammatory Biomarkers and Neurocognitive Outcome
Brief Summary

Subarachnoid hemorrhage (SAH) or bleeding in the brain as a result of ruptured aneurysm is a devastating type of stroke. Many patients who undergo emergent neurosurgery to repair the aneurysm and remove the bleeding suffer from complications in their subsequent hospital stay, the most frequent and morbid of which is delayed cerebral ischemia (DCI) or small strokes resulting from impaired blood flow to certain vital brain centers. This occurs because of changes to the brain's blood vessels that occur after the bleed. The arteries can become narrow (spasm) or small clots can form within the vasculature that disrupts normal blood flow. Patients are left with profound neurologic deficits from these secondary complications.

Anesthesiologists, neurosurgeons, and intensivists are in need of a way to protect the brain during this vulnerable period following aneurysm repair. One drug that may provide such protection is ketamine, a compound frequently used in operating rooms and intensive care units to provide anesthesia and analgesia. Ketamine works by blocking glutamate receptor ion channels that play a pivotal role in promoting brain cell death during strokes by flooding the brain with too much calcium and dangerous chemicals. This project is designed to test the efficacy of ketamine in protecting the brain following aneurysm repair by using a controlled infusion of the drug in the intensive care unit (ICU) when patients return from their operation.

Detailed Description Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating type of stroke, with significant long-term morbidity for patients who survive the initial bleed. The most frequent and morbid complication is delayed cerebral ischemia (DCI) resulting from angiographic vasospasm of the arteries of the circle of Willis. At present, there is no protective therapy aimed at neuronal preservation during this period of ischemia. The standard medical care is primarily to maintain intravascular volume status to improve cerebral perfusion during arterial narrowing, or calcium channel blockers for smooth muscle relaxation on the arterial wall. Experimental and clinical data suggest a primary mechanism of neuronal injury during ischemia is excitotoxicity, glutamate-induced cell death resulting from overstimulation of ionotropic N-methyl-D-aspartate (NMDA) receptors and resultant excessive calcium influx. Ketamine is a dissociative anesthetic with a mechanism of action of non-competitive antagonism of the NMDA receptor, routinely used in operating rooms and intensive care units as an analgesic and anesthetic. In addition to its anesthetic properties, ketamine is also an anti-inflammatory agent and a sympathomimetic, maintaining sedation without the adverse effects of hemodynamic instability. Identification of a neuroprotective entity for DCI following SAH would vastly improve the quality of life and shorten hospital stay for patients with a ruptured intracerebral aneurysm. It is critical to identify such agents so that patients survive their injury, spend shorter time in the ICU, and can return to work and maintain relationships.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Subarachnoid Hemorrhage
Intervention  ICMJE
  • Drug: Ketamine
    500 ml of ketamine (0.2 mg/ml) infused at 5 ug/kg/min for 4 hours.
    Other Name: Ketamine HCl
  • Drug: 0.9% NaCl
    500 ml of 0.9% NaCl infused at 5 ug/kg/min for 4 hours.
    Other Name: NS
Study Arms  ICMJE
  • Active Comparator: 0.9% NaCl control
    Normal saline
    Intervention: Drug: 0.9% NaCl
  • Experimental: Ketamine
    Anesthetic
    Intervention: Drug: Ketamine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 16, 2015)
50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2021
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male or female 18 to 80 years old.
  2. World Federation of Neurological Surgeons (WFNS) grade 2 to 4, obtained after resuscitation and prior to dosing.
  3. SAH on admission cranial computed tomography (CT) scan (diffuse clot present in both hemispheres, thin or thick [>4 mm], or local thick SAH (>4 mm).
  4. Ruptured saccular aneurysm, confirmed by catheter angiography (CA) or CT angiography (CTA) and treated by neurosurgical clipping or endovascular coiling.
  5. External ventricular drain placed as part of routine care.
  6. Able to be dosed within 4 hours of new neurologic deficit.
  7. Historical modified Rankin score of 0 or 1.
  8. Hemodynamically stable after resuscitation (systolic blood pressure > 100 mm Hg)
  9. Haemoglobin >85 g/L, platelets >125,000 cells/mm3
  10. Informed consent.
  11. New neurologic deficits that were not present previously, identified by 1) a decrease of 2 points on the modified Glasgow coma scale (mGCS) or 2) an increase in 2 points on the National Institute of Health Stroke Scale (NIHSS). i.e., a CODE VASOSPASM initiated in the ICU.

Exclusion Criteria:

  1. Subarachnoid hemorrhage due to causes other than a saccular aneurysm (e.g., trauma or rupture of fusiform or infective aneurysm).
  2. WFNS Grade 1 or 5 assessed after the completion of aneurysm repair.
  3. Increased intracranial pressure (ICP) >30 mm Hg in sedated patients lasting >4 hours anytime since admission.
  4. Intraventricular or intracerebral hemorrhage in absence of SAH or with only local, thin SAH.
  5. Angiographic vasospasm prior to aneurysm repair procedure, as documented by catheter angiogram or CT angiogram.
  6. Major complication during aneurysm repair such as, but not limited to, massive intraoperative hemorrhage, brain swelling, arterial occlusion, or inability to secure the ruptured aneurysm.
  7. Aneurysm repair requiring flow diverting stent or stent-assisted coiling and dual antiplatelet therapy.
  8. Hemodynamically unstable prior to administration of study drug (i.e., SBP <90 mm Hg, requiring >6 L colloid or crystalloid fluid resuscitation).
  9. Cardiopulmonary resuscitation was required following SAH.
  10. Female patients with positive pregnancy test (blood or urine) at screening.
  11. History within the past 6 months and/or physical finding on admission of decompensated heart failure (New York Heart Association [NYHA] Class III and IV or heart failure requiring hospitalization).
  12. Acute myocardial infarction within 3 months prior to the administration of the study drug.
  13. Symptoms or electrocardiogram (ECG)-based signs of acute myocardial infarction or unstable angina pectoris on admission.
  14. Electrocardiogram evidence and/or physical findings compatible with second or third degree heart block or of cardiac arrhythmia associated with hemodynamic instability.
  15. Echocardiogram, if performed as part of standard-of-care before treatment, revealing a left ventricular ejection fraction (LVEF) <40%.
  16. Severe or unstable concomitant condition or disease (e.g., known significant neurologic deficit, cancer, hematologic, or coronary disease), or chronic condition (e.g., psychiatric disorder) that, in the opinion of the Investigator, may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results.
  17. Patients who have received an investigational product or participated in another interventional clinical study within 30 days prior to randomization.
  18. Kidney disease as defined by plasma creatinine ≥2.5 mg/dl (221 umol/l); liver disease as defined by total bilirubin >3 mg/dl (51.3 mmol/l); and/or known diagnosis or clinical suspicion of liver cirrhosis.
  19. Known hypersensitivity or contraindication to ketamine per product monograph.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Marlene S. Santos, MD 416-864-6060 ext 2322 Marlene.Santos@unityhealth.to
Contact: Joshua Bell, MD, PhD 647-200-4568 josh.bell@mail.utoronto.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02636218
Other Study ID Numbers  ICMJE KTM-3007
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Dr. Andrew Baker, Unity Health Toronto
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Dr. Andrew Baker
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Defence Research and Development Canada
Investigators  ICMJE
Principal Investigator: Andrew Baker, MD, FRCPC Unity Health Toronto
PRS Account Unity Health Toronto
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP