Ketamine to Treat Patients With Post-comatose Disorders of Consciousness

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

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.

Study Overview

• Status: Recruiting
• Conditions: Disorder of Consciousness
• Intervention / Treatment: Drug: Placebo; Drug: Ketalar 50 MG/ML Injectable Solution

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
• Enrollment (Anticipated): 30
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Paolo Cardone, MSc; Phone Number: +32 0456309880; Email: p.cardone@uliege.be
• Study Contact Backup: Name: Charlotte Martial, PhD; Email: cmartial@uliege.be

Study Locations

• Belgium
  • Wallonia
    • Ottignies-Louvain-la-Neuve, Wallonia, Belgium, 1340
      • Recruiting
      • Centre Hospitalier Neurologique William Lennox
      • Contact: Paolo Cardone, M.Sc.; Phone Number: +32 0456309880; Email: p.cardone@uliege.be
      • Contact: Nicolas Lejeune, MD, PhD; Email: Nicolas.Lejeune@uliege.be
      • Principal Investigator: Nicolas Lejeune, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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

Collaborators and Investigators

• Sponsor: University of Liege
• 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)

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2022
• Primary Completion (Anticipated): May 1, 2025
• Study Completion (Anticipated): May 1, 2026

Study Registration Dates

• First Submitted: March 29, 2022
• First Submitted That Met QC Criteria: April 19, 2022
• First Posted (Actual): April 25, 2022

Study Record Updates

• Last Update Posted (Actual): November 7, 2022
• Last Update Submitted That Met QC Criteria: November 2, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Ketamine; Psychedelics; Complexity; Clinical Diagnosis; Consciousness level
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Consciousness Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: 2021_211; 2021-002321-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing 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.
• IPD Sharing Access Criteria: A written agreement between the groups (university or research teams)
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No