Ketamine to Treat Patients With Post-comatose Disorders of Consciousness

University of Liege

Status and phase: Enrolling; Phase 3; Phase 2

Conditions: Disorder of Consciousness

Treatments: Drug: Placebo; Drug: Ketalar 50 MG/ML Injectable Solution

Study type: Interventional

Funder types: Other

Identifiers

NCT05343507

2021_211

2021-002321-23 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 30 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Triple Blind

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30 participants in 2 patient groups, including a placebo group

Ketalar arm

Experimental group

Description:

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.

Treatment:

Drug: Ketalar 50 MG/ML Injectable Solution

Placebo arm

Placebo Comparator group

Description:

Patients will receive placebo (saline solution)

Treatment:

Drug: Placebo