Ketamine to Treat Patients With Post-comatose Disorders of Consciousness

Sponsor

University of Liege (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05343507

Collaborator

Centre Hospitalier Universitaire de Liege (Other), William Lennox Neurological Center UCLouvain (Other)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Disorder of Consciousness	Drug: Ketalar 50 MG/ML Injectable Solution Drug: Placebo	Phase 2/Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Double-blind, placebo-controlled, cross-over RCTDouble-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

Official Title:

Complexity-enhancing Drugs to Treat Disorders of Consciousness (DoC): a Ketamine Study

Anticipated Study Start Date :

May 1, 2022

Anticipated Primary Completion Date :

May 1, 2025

Anticipated Study Completion Date :

May 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: Ketalar 50 MG/ML Injectable Solution Intravenous solution (other info already provided) Other Names: Ketamine
Placebo Comparator: Placebo arm Patients will receive placebo (saline solution)	Drug: Placebo Saline Solution

Arm

Intervention/Treatment

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.

Drug: Ketalar 50 MG/ML Injectable Solution

Intravenous solution (other info already provided)

Other Names:

Ketamine

Placebo Comparator: Placebo arm

Patients will receive placebo (saline solution)

Drug: Placebo

Saline Solution

Outcome Measures

Primary Outcome Measures

New conscious behaviours [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 [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.

Secondary Outcome Measures

PET biomarker [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 [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 [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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