Ketamine to Treat Patients With Post-comatose Disorders of Consciousness

Disorder of Consciousness Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05343507
• Other study ID #: 2021_211
• Secondary ID: 2021-002321-23
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: May 1, 2022
• Est. completion date: May 1, 2026

Study information

• Verified date: November 2022
• Source: University of Liege
• Contact: Paolo Cardone, MSc
• Phone: 0456309880
• Email: p.cardone[@]uliege.be
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: May 1, 2026
• Est. primary completion date: May 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Consciousness Disorders
• Disorder of Consciousness

Intervention

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

Locations

Country	Name	City	State
Belgium	Centre Hospitalier Neurologique William Lennox	Ottignies-Louvain-la-Neuve	Wallonia

Sponsors (3)

Lead Sponsor	Collaborator
University of Liege	Centre Hospitalier Universitaire de Liege, William Lennox Neurological Center UCLouvain

Country where clinical trial is conducted

Belgium, 

References & Publications (2)

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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	New conscious behaviours	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).	Max 90 minutes from Ketamine Infusion
Primary	Higher brain complexity	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.	Max 90 minutes from Ketamine Infusion
Secondary	PET biomarker	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.	From baseline
Secondary	MRI biomarker	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.	From baseline
Secondary	EEG power	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.	From baseline