Ketamine to Treat Patients With Post-comatose Disorders of Consciousness

• ClinicalTrials.gov Identifier: NCT05343507
• Recruitment Status: Not yet recruiting
• First Posted: April 25, 2022
• Last Update Posted: April 25, 2022
• Sponsor: University of Liege
• 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: March 29, 2022
• First Posted Date: April 25, 2022
• Last Update Posted Date: April 25, 2022
• Estimated Study Start Date: May 1, 2022
• Estimated Primary Completion Date: May 1, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (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: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Ketamine to Treat Patients With Post-comatose Disorders of Consciousness
• Official Title: 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: Interventional
• Study Phase: Phase 2; Phase 3

Study Design

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: Disorder of Consciousness

Intervention

• Drug: Ketalar 50 MG/ML Injectable Solution
  Intravenous solution (other info already provided)
  Other Name: Ketamine
• Drug: Placebo
  Saline Solution

Study Arms

• 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 *

• Casali AG, Gosseries O, Rosanova M, Boly M, Sarasso S, Casali KR, Casarotto S, Bruno MA, Laureys S, Tononi G, Massimini M. A theoretically based index of consciousness independent of sensory processing and behavior. Sci Transl Med. 2013 Aug 14;5(198):198ra105. doi: 10.1126/scitranslmed.3006294.
• Scott G, Carhart-Harris RL. Psychedelics as a treatment for disorders of consciousness. Neurosci Conscious. 2019 Apr 21;2019(1):niz003. doi: 10.1093/nc/niz003. eCollection 2019.

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: April 19, 2022): 30
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 1, 2026
• Estimated Primary Completion Date: May 1, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Paolo Cardone, MSc; 0456309880 ext +32; p.cardone@uliege.be

Contact: Charlotte Martial, PhD; cmartial@uliege.be

• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT05343507
• Other Study ID Numbers: 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

• 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: University of Liege
• Original Study Sponsor: Same as current

Collaborators

• Centre Hospitalier Universitaire de Liege
• William Lennox Neurological Center UCLouvain

Investigators

• Principal Investigator: Olivia Gosseries, PhD; Coma Science Group (ULiege) & Centre du Cerveau2 (CHU Liege)

• PRS Account: University of Liege
• Verification Date: April 2022