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    Summary
    EudraCT Number:2021-002321-23
    Sponsor's Protocol Code Number:V1ComplexitDOC
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-02-11
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2021-002321-23
    A.3Full title of the trial
    Complexity-enhancing drugs to treat disorders of consciousness (DoC): a ketamine study
    Agents pharmacologiques augmentant la complexité cérébrale pour traiter les troubles de la conscience après un coma (TDC) : étude sur la kétamine
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Ketamine to treat patients with post-comatose disorders of consciousness
    A.3.2Name or abbreviated title of the trial where available
    ComplEXIT-DOC_KET
    A.4.1Sponsor's protocol code numberV1ComplexitDOC
    A.5.4Other Identifiers
    Name:Ethical Committee - University Hospital of LiègeNumber:2021-211
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity of Liège
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportUniversity of Liege
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportFonds Léon Fredericq
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportFonds de la Recherche Scientifique – FNRS
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Liège
    B.5.2Functional name of contact pointComa Science Group
    B.5.3 Address:
    B.5.3.1Street AddressCHU de Liège, GIGA-Consciousness B34, Avenue de l'Hopital, 1
    B.5.3.2Town/ cityLiège
    B.5.3.3Post code4000
    B.5.3.4CountryBelgium
    B.5.6E-mailcoma@uliege.be
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Ketalar
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameKetamine
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboInfusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical 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)
    E.1.1.1Medical condition in easily understood language
    Disorders of consciousness
    Troubles de l'état de conscience
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary 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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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
    E.4Principal 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.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Two sessions separated by 5 days
    E.5.2Secondary 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.
    E.5.2.1Timepoint(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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Theoretical proof-of-concept for link between complexity and consciousness
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    Last follow-up phone call of the last subject
    Dernier appel téléphonique de suivi du dernier sujet
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 40
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients with disorders of consciousness, more specifically with an
    unresponsive wakefulness syndrome or in a minimally conscious state. Consent will be given by the legal representative. If the patient recovers s/he will be asked directly.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    If patients might be included for other treatments currently available or studied (i.e., apomorphine or zolpidem) after a wash-out period of 4 weeks.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-03-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-12-06
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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