Clinical trial NCT05343507: Ketamine to Treat Patients With Post-comatose Disorders of Consciousness
Official title: Complexity-enhancing Drugs to Treat Disorders of Consciousness (DoC): a Ketamine Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Disorder of Consciousness
Keywords: Psychedelics
Complexity
Ketamine
Clinical Diagnosis
Consciousness level
Lead sponsor: University of Liege
Sponsor class: OTHER
Collaborators: name: Centre Hospitalier Universitaire de Liege
name: William Lennox Neurological Center UCLouvain
First posted: 2022-04-25
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Double-blind, placebo-controlled, cross-over RCT
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: New conscious behaviours
timeFrame: Max 90 minutes from Ketamine Infusion
measure: Higher brain complexity
timeFrame: Max 90 minutes from Ketamine Infusion
Secondary outcomes:
measure: PET biomarker
timeFrame: From baseline
measure: MRI biomarker
timeFrame: From baseline
measure: EEG power
timeFrame: From baseline
Other outcomes:
Locations:
city: Ottignies-Louvain-la-Neuve
country: Belgium
facility: Centre Hospitalier Neurologique William Lennox
state: Wallonia
Study officials:
affiliation: Coma Science Group (ULiege) & Centre du Cerveau2 (CHU Liege)
name: Olivia Gosseries, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.