E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Disorders of consciousness as Unresponsive Wakefulness Syndrome (UWS) and Minimally Conscious State (MCS) after a coma due to acquired brain injury. Patients who emerged from the minimally conscious state (EMCS) |
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E.1.1.1 | Medical condition in easily understood language |
Disorders of consciousness |
Troubles de l'état de conscience |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
This clinical trial aims to evaluate the efficacy of intravenous ketamine for the treatment of patients with disorders of consciousness (DoC) after a coma and assess the prevalence of responders. |
Cet essai clinique vise à évaluer l'efficacité de la kétamine par voie intraveineuse comme traitement pour les patients présentant des troubles de la conscience post-coma et mesurer la prévalence des répondeurs. |
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E.2.2 | Secondary objectives of the trial |
This study aims to also better characterize the phenotype of potential good candidates to ketamine treatment and identify a set of biomarkers that correlate with responsiveness (or non-responsiveness) to the therapy, as well to help underpinning the neural networks underlying the modulating action of ketamine on consciousness and brain complexity. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- More than 18 years old - Clinically stable, not dependent on medical ventilators for respiration - Diagnosed as an unresponsive wakefulness syndrome, a minimally conscious state, or emergent from the minimally conscious state according to the international criteria and based on at least 2 standardized behavioral assessments with the Simplified Evaluation of CONsciousness Disorders (SECONDs) - More than 28 days post-insult - Informed consent from a legal representative of the patient |
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E.4 | Principal exclusion criteria |
- Known allergy or hypersensitivity to ketamine - Active epilepsy (contrary advice by a neurologist upon standard EEG) - A history of previous neurological functional impairment other than related to their acquired brain injury - A history of psychotic disorders (schizophrenia or bipolar disorder) - Use of drugs known to interact with ketamine. Among them: thyroid hormones, diazepam and barbitudes, drugs that interact with CYP3A4, other anesthetic like tramadol or anestethic halogen - Patient with coronary insufficiency - Other sympathomimetic drugs - Conditional exclusion criteria: contraindication to MRI, PET, or TMS (e.g., electronic implanted devices, external ventricular drain). In case of those, the participant would be included only for the techniques without contradiction. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Our main focus is on the link between consciousness and brain complexity. Thus, our primary endpoints are: 1. New signs of consciousness (e.g., response to command) measured by the SECONDs. 2. Brain complexity measured by LZC and/or PCI in the ketamine session at the highest dose, compared to placebo and the baseline.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Two sessions separated by 5 days |
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E.5.2 | Secondary end point(s) |
We will investigate the additional index of SECONDs, baseline biomarkers of (behavior and brain) responders, and effects on spasticity. As such, our secondary endpoints are: 1. The “additional index” (from 0 to 100) of the SECONDs; 2. Baseline fMRI activity in the fronto-parietal network and the thalamo-cortical loop; 3. Baseline metabolic PET level in the fronto-parietal network and the thalamo-cortical loop; 4. EEG alpha connectivity measured via alpha centrality; 5. Spasticity measured via the Modified Ashworth Score; 6. Spasticity measured via EMG recording (H/M ratio); 7. Range of Motion. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Recording with EEG done from 20 minutes before giving ketamine to a maximum of 90 minutes after the reached concentration of blood ketamine. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Theoretical proof-of-concept for link between complexity and consciousness |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last follow-up phone call of the last subject |
Dernier appel téléphonique de suivi du dernier sujet |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |