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Subarachnoid HemorrhagePhase 2/3KINDNCT02636218

Ketamine Infusion in Neurologic Deficit

A Phase 2/3 study testing Ketamine and 0.9% NaCl in people with Subarachnoid Hemorrhage, run by Unity Health Toronto at 1 site in Canada.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 80 years
Conditions the study is for
Subarachnoid Hemorrhage
What is being tested?
Ketamine and 0.9% NaCl
Could I receive a placebo?
No, everyone receives an active treatment
How many people
9 participants
Where
1 siteCanada
Study dates
26 Jan 2016to 15 Nov 2023
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Male or female 18 to 80 years old.
  • World Federation of Neurological Surgeons (WFNS) grade 2 to 4, obtained after resuscitation and prior to dosing.
  • 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).
  • Ruptured saccular aneurysm, confirmed by catheter angiography (CA) or CT angiography (CTA) and treated by neurosurgical clipping or endovascular coiling.
  • External ventricular drain placed as part of routine care.
  • Able to be dosed within 4 hours of new neurologic deficit.
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  • Historical modified Rankin score of 0 or 1.
  • Hemodynamically stable after resuscitation (systolic blood pressure > 100 mm Hg)
  • Haemoglobin >85 g/L, platelets >125,000 cells/mm3
  • Informed consent.
  • 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.

Who cannot join

  • Subarachnoid hemorrhage due to causes other than a saccular aneurysm (e.g., trauma or rupture of fusiform or infective aneurysm).
  • WFNS Grade 1 or 5 assessed after the completion of aneurysm repair.
  • Increased intracranial pressure (ICP) >30 mm Hg in sedated patients lasting >4 hours anytime since admission.
  • Intraventricular or intracerebral hemorrhage in absence of SAH or with only local, thin SAH.
  • Angiographic vasospasm prior to aneurysm repair procedure, as documented by catheter angiogram or CT angiogram.
  • 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.
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  • Aneurysm repair requiring flow diverting stent or stent-assisted coiling and dual antiplatelet therapy.
  • Hemodynamically unstable prior to administration of study drug (i.e., SBP <90 mm Hg, requiring >6 L colloid or crystalloid fluid resuscitation).
  • Cardiopulmonary resuscitation was required following SAH.
  • Female patients with positive pregnancy test (blood or urine) at screening.
  • 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).
  • Acute myocardial infarction within 3 months prior to the administration of the study drug.
  • Symptoms or electrocardiogram (ECG)-based signs of acute myocardial infarction or unstable angina pectoris on admission.
  • Electrocardiogram evidence and/or physical findings compatible with second or third degree heart block or of cardiac arrhythmia associated with hemodynamic instability.
  • Echocardiogram, if performed as part of standard-of-care before treatment, revealing a left ventricular ejection fraction (LVEF) <40%.
  • 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.
  • Patients who have received an investigational product or participated in another interventional clinical study within 30 days prior to randomization.
  • 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.
  • Known hypersensitivity or contraindication to ketamine per product monograph.

Trial locations and contacts

1 site in 1 country.

Canada1 site

  • St Michael's Hospital

    Toronto, Ontario, M5B 1W8

Other trials in Canada

About this study

Official title: A Pilot Study of Sub-anesthetic Ketamine Infusion for Neuroprotection After Aneurysmal Subarachnoid Hemorrhage: Effects on White Matter Integrity, Inflammatory Biomarkers and Neurocognitive Outcome

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.

Read the 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.

Being tested
Ketamine, 0.9% NaCl
Keywords
Ketamine
Medical subject headings
Subarachnoid Hemorrhage

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • KetamineDrug

    Also called Ketamine HCl

    500 ml of ketamine (0.2 mg/ml) infused at 5 ug/kg/min for 4 hours.

  • 0.9% NaClDrug

    Also called NS

    500 ml of 0.9% NaCl infused at 5 ug/kg/min for 4 hours.

Study groups in NCT02636218
Study groupRoleWhat they receive
0.9% NaCl controlActive comparatorNormal saline
Receives: Drug: 0.9% NaCl
KetamineExperimentalAnesthetic
Receives: Drug: Ketamine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Changes in physiologic parameters as specified below

    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.

    Measured: During infusion and 1 hour post-infusion

Secondary outcomes (8)

  1. Biologic samples

    Blood and cerebrospinal fluid (CSF) samples will be collected and analyzed for biomarker levels which would indicate extent of neuronal injury.

    Measured: Day 1-2 post-infusion

  2. Neurocognitive test Montreal Cognitive Assessment Scale (MoCA)

    Neurocognitive function will be assessed using the MoCA to determine preliminary effects of ketamine on neurocognitive outcome.

    Measured: Day 30 or Day 60 post-DCI

  3. Neurocognitive test modified Rankin Scale (mRS)

    Neurocognitive function will be assessed using the mRS determine preliminary effects of ketamine on neurocognitive outcome.

    Measured: Day 30 or Day 60 post-DCI

  4. Brain imaging using Magnetic Resonance Imaging (MRI)

    Structural and functional brain imaging will be conducted using Tesla MRI system to assess white matter integrity.

    Measured: Day 30 or Day 60 post-DCI

  5. Hospital anxiety and depression score

    Assessments for neuro-cognitive outcomes and correlation with MRI findings

    Measured: Day 30 or Day 60 post-DCI

  6. EQ-5D-5L

    Neurocognitive outcome assessment and correlation with MRI results

    Measured: Day 30 or Day 60 post-DCI

  7. Trail making test

    Neurocognitive outcome assessment and correlation with MRI results

    Measured: Day 30 or Day 60 post-DCI

  8. Verbal fluency tests

    Neurocognitive outcome assessment and correlation with MRI results

    Measured: Day 30 or Day 60 post-DCI

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Dec 2015 (estimated)
  2. Study start26 Jan 2016
  3. Primary completion31 Mar 2021
  4. Study completion15 Nov 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
9 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02636218
Sponsor's protocol ID
KTM-3007
Acronym
KIND
Status last verified
Aug 2024
First submitted
8 Dec 2015
Last updated
16 Aug 2024
Results posted
No
Data monitoring committee
Yes
Individual data sharing
No

Publications

  • Etminan N, Vergouwen MD, Ilodigwe D, Macdonald RL. Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2011 Jun;31(6):1443-51. doi: 10.1038/jcbfm.2011.7. Epub 2011 Feb 2.

    PubMed 21285966

  • Nilsson OG, Saveland H, Boris-Moller F, Brandt L, Wieloch T. Increased levels of glutamate in patients with subarachnoid haemorrhage as measured by intracerebral microdialysis. Acta Neurochir Suppl. 1996;67:45-7. doi: 10.1007/978-3-7091-6894-3_10.

    PubMed 8870801

  • Beal MF. Mechanisms of excitotoxicity in neurologic diseases. FASEB J. 1992 Dec;6(15):3338-44.

    PubMed 1464368

  • Forder JP, Tymianski M. Postsynaptic mechanisms of excitotoxicity: Involvement of postsynaptic density proteins, radicals, and oxidant molecules. Neuroscience. 2009 Jan 12;158(1):293-300. doi: 10.1016/j.neuroscience.2008.10.021. Epub 2008 Nov 1.

    PubMed 19041375

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Ketamine and 0.9% NaCl in people with Subarachnoid Hemorrhage, run by Unity Health Toronto at 1 site in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 16 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Changes in physiologic parameters as specified below (time frame: During infusion and 1 hour post-infusion). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02636218, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Aug 2024.

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