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Ketamine to Treat Patients With Post-comatose Disorders of Consciousness

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ClinicalTrials.gov Identifier: NCT05343507
Recruitment Status : Not yet recruiting
First Posted : April 25, 2022
Last Update Posted : April 25, 2022
Sponsor:
Collaborators:
Centre Hospitalier Universitaire de Liege
William Lennox Neurological Center UCLouvain
Information provided by (Responsible Party):
Olivia Gosseries, University of Liege

Tracking Information
First Submitted Date  ICMJE March 29, 2022
First Posted Date  ICMJE April 25, 2022
Last Update Posted Date April 25, 2022
Estimated Study Start Date  ICMJE May 1, 2022
Estimated Primary Completion Date May 1, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 19, 2022)
  • New conscious behaviours [ Time Frame: Max 90 minutes from Ketamine Infusion ]
    New conscious behaviours (i.e., command following, visual pursuit) after the infusion of the ketamine as recorded via the "simplified evaluation of consciousness disorders" (SECONDs) behavioural scale, that are not seen before ketamine, during placebo infusion, or in baseline. The SECONDs has 8 items, with the most complex item linked to a higher conscious state. The score goes from 0 (coma) to 8 (emergent from the minimally conscious state).
  • Higher brain complexity [ Time Frame: Max 90 minutes from Ketamine Infusion ]
    Higher brain complexity [perturbational complexity index (PCI) or Lempel-Ziv complexity (LZC)] during the infusion of ketamine. The investigators expect complexity to increase when new conscious behaviors are observed. If the patient does not show new signs of consciousness but has high complexity, the investigators expect to record memories of the experience in the follow-up phase. PCI and LZC values range from 0 (no complexity) to 1 (high complexity). The investigators expect complexity values to be proportional to the concentration of the drug.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: April 19, 2022)
  • PET biomarker [ Time Frame: From baseline ]
    Different baseline PET signal between responders (patients who show new signs of consciousness or higher brain complexity after the drug), and non-responders (who do not show new signs of consciousness or higher brain complexity). In particular, higher metabolism [measured by standardized uptake value (SUV)] in responders compared to non-responders.
  • MRI biomarker [ Time Frame: From baseline ]
    Different baseline MRI between responders (patients who show new signs of consciousness or higher brain complexity after the drug), and non-responders (who do not show new signs of consciousness or higher brain complexity). In particular, higher resting-state BOLD activity in responders compared to non-responders and more preserved brain structures.
  • EEG power [ Time Frame: From baseline ]
    Different baseline EEG signal between responders (patients who show new signs of consciousness or higher brain complexity after the drug), and non-responders (who do not show new signs of consciousness or higher brain complexity). In particular, higher alpha-band activity in responders compared to non-responders.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ketamine to Treat Patients With Post-comatose Disorders of Consciousness
Official Title  ICMJE Complexity-enhancing Drugs to Treat Disorders of Consciousness (DoC): a Ketamine Study
Brief Summary The investigators will run a Randomized Clinical Trial with 30 patients with disorders of consciousness (DoC), with intravenous subanesthetic doses of ketamine. Patients will simultaneously undergo TMS-EEG. The piloting will be done on 3 patients, with EEG only.
Detailed Description The protocol will be organized in three phases: baseline, experimental, and follow-up. In the baseline, patients will receive a multimodal assessment [functional magnetic resonance imaging (fMRI), positron emission tomography (PET), electroencephalogram (EEG)]. The experimental phase is made of 2 sessions spaced 5 days apart: on day 1, patients will receive placebo (or ketamine), on day 5 patients will receive ketamine (or placebo). The order will be randomized and balanced. The investigators will use a targeted-controlled infusion (TCI) system to infuse a continuous subanesthetic dose of ketamine, which is known to have psychedelics effects, or a saline solution. The investigators will periodically assess for new signs of consciousness with the "simplified evaluation of consciousness disorders" (SECONDs) scale. The investigators will use transcranial magnetic stimulation coupled to EEG (TMS-EEG) to measure brain activity and calculate brain complexity. TMS-EEG will be performed from 20 minutes before the beginning of the infusion up to the max duration of the experiment (90 minutes). Another SECONDs will be performed on the following day of each session to control for carry-over effects. The primary outcomes are the emergence of new conscious behaviours and higher brain complexity following ketamine infusion. The secondary outcomes are baseline brain differences in neurophysiological and brain imaging measures between responders (new conscious behaviors or higher brain complexity) and non-responders (no new conscious behaviors or higher brain complexity). In the follow-up phase, patients' health will be evaluated at 1, 6, and 12 months.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
Double-blind, placebo-controlled, cross-over RCT
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:
One investigator not involved in the data acquisition and analysis, and the pharmacist who will prepare the syringe for the TCI will not be blind.
Primary Purpose: Treatment
Condition  ICMJE Disorder of Consciousness
Intervention  ICMJE
  • Drug: Ketalar 50 MG/ML Injectable Solution
    Intravenous solution (other info already provided)
    Other Name: Ketamine
  • Drug: Placebo
    Saline Solution
Study Arms  ICMJE
  • Experimental: Ketalar arm
    Patients will receive ketamine (sold in the form of Ketalar) intravenously, up to 0.75 µg/ml concentration, for a maximum of 90' minutes. Ketalar concentration will be increased slowly in a step-wise manner unless new signs of consciousness are evident.
    Intervention: Drug: Ketalar 50 MG/ML Injectable Solution
  • Placebo Comparator: Placebo arm
    Patients will receive placebo (saline solution)
    Intervention: Drug: Placebo
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 Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: April 19, 2022)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 1, 2026
Estimated Primary Completion Date May 1, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Clinically stable
  • Diagnosis of UWS or MCS based on repeated "coma recovery scale-revised) (CRS-R) or SECONDs
  • More than 28 days post-insult
  • Informed consent from the legal representative of the patient

Exclusion Criteria:

  • Neurological medications other than anti-spasticity drugs in the last 2 weeks or 4 half-lives
  • Previous neurological functional impairment other than related to their DoC
  • A history of psychotic disorders
  • Contraindication to MRI, EEG, PET or TMS
  • Use of nitrates or other vasodilators, central nervous system acting agents such as barbiturates, morphine and related drugs.
  • Use of drugs known to interact with ketamine (i.e., CYP3A4, diazepam, ...)
  • Coronary insufficiency
  • Other sympathomimetic drugs
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Paolo Cardone, MSc 0456309880 ext +32 p.cardone@uliege.be
Contact: Charlotte Martial, PhD cmartial@uliege.be
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05343507
Other Study ID Numbers  ICMJE 2021_211
2021-002321-23 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Data will be anonymized and shared among collaborators upon reasonable request and agreement. If possible, data will be shared in an open-access database to ensure the values of open science.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: Data will be shared with collaborators for the specified time allocated to each respective project. Whereas, data shared on the database will be anonymized and available indefinitely.
Access Criteria: A written agreement between the groups (university or research teams)
Current Responsible Party Olivia Gosseries, University of Liege
Original Responsible Party Same as current
Current Study Sponsor  ICMJE University of Liege
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Centre Hospitalier Universitaire de Liege
  • William Lennox Neurological Center UCLouvain
Investigators  ICMJE
Principal Investigator: Olivia Gosseries, PhD Coma Science Group (ULiege) & Centre du Cerveau2 (CHU Liege)
PRS Account University of Liege
Verification Date April 2022

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